CADTH Reimbursement Review

Niraparib and Abiraterone Acetate (Akeega)

Sponsor: Janssen Inc.

Therapeutic area: Metastatic castration-resistant prostate cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information on Application Submitted for Review

mCRPC = metastatic castration-resistant prostate cancer; NOC = Notice of Compliance; NOC/c = Notice of Compliance with conditions.

Introduction

Prostate cancer is the most common cancer among Canadian males, affecting 1 in 8 males during their lifetime.¹ A patient may progress to metastatic castration-resistant prostate cancer (mCRPC) from metastatic castration-sensitive prostate cancer (mCSPC) based on biochemical recurrence (characterized by rising prostate-specific antigen [PSA] levels despite medical or surgical castration) or from nonmetastatic castration-resistant prostate cancer (nmCRPC) based on presentation of metastases (assessed radiographically).^2,3 This condition is characterized by increased symptomatic burden and reduced health-related quality of life (HRQoL),^4-6 and goals of treatment include delaying progression and improving HRQoL.⁵ Approximately 10% of all patients with mCRPC harbour BRCA gene alterations.⁷ When the disease progresses to the mCRPC stage, the 5-year survival rate reduces to approximately 26% to 28%.^8,9 Patients with BRCA gene–mutated mCRPC are more likely to present with advanced disease, nodal involvement, and distant metastases at diagnosis.¹⁰

Clinical experts consulted by CADTH indicated that there are several systemic therapies that are approved for the treatment of patients with mCRPC, and the sequencing of these treatments depends on patient and disease factors, and prior treatments used in the mCSPC setting. The clinical experts noted that docetaxel, cabazitaxel, abiraterone acetate, enzalutamide, olaparib (for BRCA1 and BRCA2, the ATM gene), radium-223 (for patients with bone-predominant disease and no visceral metastasis), and lutetium vipivotide tetraxetan are all Health Canada–approved and, with the exception of lutetium vipivotide tetraxetan, are widely available in all provinces across Canada. The clinical experts highlighted that chemotherapy is the most commonly used first-line treatment since most patients have already received an androgen receptor pathway inhibitor (ARPi) in the mCSPC setting.

The objective of CADTH’s Clinical Review Report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of niraparib (200 mg) and abiraterone acetate (1,000 mg) with prednisone (10 mg) for the treatment of adult patients with deleterious or suspected deleterious BRCA gene–mutated (germline [inherited] and/or somatic [acquired in tumour cells during tumourigenesis]) mCRPC who are asymptomatic or mildly symptomatic, and in whom chemotherapy is not clinically indicated.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups that responded to CADTH’s call for input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups, the Canadian Cancer Society (CCS) and the Canadian Cancer Survivor Network (CCSN), provided input for this review. In total, 24 responses were gathered by CCS (from 21 patients and 3 caregivers), and 8 responses (from 8 patients) were gathered by CCSN. Overall, 97% of respondents in a CCS survey and 6 of the patients in a CCSN survey lived in Canada. Patients reported that the following symptoms affected their quality of life and day-to-day living: changes in libido, sexual function or fertility, hot flushes, fatigue, low energy, difficulties with urination, loss of appetite, bone or skeletal pain, indigestion, bowel problems, peripheral neuropathy, dizziness, and muscle loss. From the patients’ perspective, the prospect of cure, the avoidance of metabolic syndrome, the avoidance of metastases progressing to other body locations, and the prevention or mitigation of the spread of cancer in the bones are the most important aspects of their disease to control. One patient from the CCSN survey who had taken niraparib reported constipation and decreased appetite as adverse effects. When asked about their experience with niraparib in comparison to other therapies, the respondent noted that there was little or no difference in symptom management, side effects, and ease of use. The patients also noted that the experience regarding disease progression was much better compared to that of other therapies.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Two clinical specialists with expertise in the diagnosis and management of mCRPC reported that since mCRPC is a terminal phase of prostate cancer, the unmet needs of patients would be prolonged overall survival (OS), improved HRQoL, and reduced toxicity. Both clinical experts highlighted that the balance between treatment efficacy and HRQoL would be important. They highlighted a need for new treatments since these patients have primary or acquired resistance to offered treatments in the mCRPC setting. Clinical experts agreed that it remains unclear whether niraparib and abiraterone acetate would lead to a shift in the current treatment paradigm due to the increased use of ARPi in the mCSPC setting. They believe many medical oncologists would favour a change to chemotherapy in patients progressing on an ARPi, although the CADTH review team noted this could vary across clinicians and treatment centres in Canada. In their opinion, niraparib and abiraterone acetate will be positioned as a second-line treatment for mCRPC due to the decreasing number of patients who are ARPi-naive. The clinical experts agreed that niraparib and abiraterone acetate would be for the BRCA gene–mutated mCRPC population. It was noted that most patients with mCRPC — especially those who are otherwise well — would be considered for treatment with cytotoxic chemotherapy. However, the clinical experts reported that it is rare for patients to have an absolute contraindication to chemotherapy. According to the clinical experts, clinicians may consider alternatives to chemotherapy in patients whose disease is asymptomatic or minimally symptomatic and palliative to minimize the toxic effects of treatments. Furthermore, the clinical experts noted that some patients may not want to receive chemotherapy due to adverse effects. In terms of assessing the response treatment, they noted that a combination of radiographic, biochemical, and clinical parameters are used to determine whether a patient with mCRPC is responding to treatment. The clinical experts indicated that treatment should be discontinued if it is intolerable, if the disease progresses, or if it’s the patient’s preference to stop the treatment. Clinical experts noted that poly-(ADP [adenosine diphosphate]-ribose) polymerase (PARP) inhibitors have the potential to be toxic. Therefore, they noted that patients receiving niraparib and abiraterone acetate must be under the care of a medical oncologist to manage toxicity.

Clinician Group Input

Clinician group input was received from the Ontario Health (Cancer Care Ontario) (OH-CCO) Genitourinary Cancer Drug Advisory Committee. A total of 8 clinicians provided input on behalf of OH-CCO. OH-CCO highlighted the need to have therapies in the first-line mCRPC setting that can prolong life, considering there is currently no cure and no targeted treatments are currently available at this setting. They also mentioned the need for treatments that can maximize quality of life. The group noted that niraparib and abiraterone acetate with prednisone would become a standard of care (SOC) in treatment-naive patients with mCRPC with homologous recombination repair (HRR) mutation, although the CADTH review team noted that the Health Canada–approved indication is for patients with BRCA mutations only. The group indicated that while PSA would be used to determine the burden of disease and to monitor response to therapy, serial radiographic imaging would also be used to monitor response and to determine progression as per SOC. They also noted that they would discontinue treatment in cases of significant side effects or disease progression.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following items were identified as key factors that could potentially impact the implementation of a CADTH recommendation for niraparib and abiraterone acetate:

• relevant comparators

• consideration for the initiation of therapy

• consideration for the continuation of therapy

• generalizability

• care provision issues

• funding algorithm.

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs (Table 4).

Clinical Evidence

Systematic Review

Description of Studies

One phase III, double-blind, placebo-controlled, randomized controlled trial (RCT) (MAGNITUDE study, N = 423) met the inclusion criteria for the systematic review conducted by the sponsor. A subgroup of the population accounted for patients with BRCA1 and BRCA2 gene alterations (N = 225) as per the Health Canada–approved indication and requested reimbursement population. In the BRCA subgroup, 113 patients were randomized to receive niraparib 200 mg and abiraterone acetate 1,000 mg with prednisone 10 mg once daily and 112 patients were randomized to receive placebo and abiraterone acetate 1,000 mg with prednisone 10 mg once daily. The objective of the MAGNITUDE trial was to evaluate the efficacy and safety of niraparib and abiraterone acetate with prednisone versus placebo and abiraterone acetate with prednisone in adult patients with mCRPC. The study is ongoing, and patients will be followed up every 3 months to 60 months (5 years) or until death, loss to follow-up, withdrawal of consent, or study termination. The primary outcome was radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1), and secondary outcomes were OS and time to symptomatic progression (TSP). Time to pain progression (TPP) and HRQoL measured by the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire were included as exploratory outcomes in the trial. These outcomes from the trial — OS, rPFS, TSP, TPP, and HRQoL measured with FACT-P — were the focus of this reimbursement review (refer to the section GRADE Summary of Findings and Certainty of Evidence).

Some baseline patient characteristics in the BRCA subgroup, such as body location of metastases, metastasis stage, Gleason scores, and Eastern Cooperative Oncology Group Performance Status (ECOG PS) score were not balanced between the treatment groups. The population was predominately white (72%), with an approximate mean age of 68 years. Most patients had a tumour stage of T3 (41.8%), a Gleason score of 8 or more (69.2%), and an ECOG PS score of 0 (66.2%). A similar proportion of patients in both groups had prior prostate cancer therapy.

Efficacy Results

All results are from the second interim analysis of the MAGNITUDE trial, with a data cut-off date of June 17, 2022.

Overall Survival

The median follow-up time was 24.80 months for all patients in the BRCA subgroup. The median duration of follow-up with patients was 20.18 months in the niraparib and abiraterone acetate with prednisone group and 19.98 months in the placebo and abiraterone acetate with prednisone group. More patients had died in the placebo and abiraterone acetate group (44%) than in the niraparib and abiraterone acetate group (38%) by the data cut-off date. The median OS was 29.27 months in the niraparib and abiraterone acetate with prednisone group and 28.55 months in the placebo and abiraterone acetate with prednisone group, with an adjusted hazard ratio (HR) of 0.68 (95% confidence interval [CI], 0.445 to 1.046) and a stratified HR of 0.881 (95% CI, 0.58 to 1.33). The probability of OS at 12 months was 84.1% (95% CI, 75.9% to 89.7%) and 83.9% (95% CI, 75.7% to 89.5%), and the probability of OS at 24 months was 65.6% (95% CI, 55.4% to 74.1%) and 56.6% (95% CI, 45.5% to 66.3%) in the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone acetate with prednisone group, respectively. The results from the nonstratified sensitivity analysis of OS for the BRCA subgroup were consistent with the stratified analysis.

Radiographic Progression-Free Survival

The between–treatment group difference in rPFS met the prespecified criteria for declaring the primary analysis successful at the first interim analysis, and therefore no formal statistical testing was performed at the second interim analysis. At the second interim analysis, approximately 50% of patients receiving niraparib and abiraterone acetate with prednisone had progression events compared with nearly 70% of those in the placebo and abiraterone acetate with prednisone group by the June 17, 2022, data cut-off date in the BRCA subgroup. The median rPFS was 19.52 months in the niraparib and abiraterone acetate with prednisone group and 10.87 months in the placebo and abiraterone acetate with prednisone group, with a stratified HR of 0.55 (95% CI, 0.39 to 0.78) favouring the niraparib and abiraterone acetate with prednisone group. The probability of being event-free at 12 months was ||||| (95%CI, ||||| to |||||) and ||||| (||||| to |||||), and the probability of being event-free at 24 months was ||||| (95% CI, ||||| to |||||) and ||||| (95% CI, ||||| to |||||) in the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone acetate with prednisone group, respectively.

Time to Symptomatic Progression

More patients who received placebo and abiraterone acetate with prednisone (46%) than who received niraparib and abiraterone acetate with prednisone (27%) reported symptom progression in the BRCA subgroup. The median TSP in the niraparib and abiraterone acetate with prednisone group was not estimable and was 23.56 months in the placebo and abiraterone acetate with prednisone group. The stratified HR of 0.54 (95% CI, 0.34 to 0.85) favoured niraparib and abiraterone acetate with prednisone. The probability of TSP at 12 months was 83.4% (75% to 89.2%) and 75.1% (65.7% to 82.2%), and the probability of TSP at 24 months was 68% (95% CI, 57.3% to 76.6%) and 47.8% (95% CI, 36.1% to 58.5%) in the niraparib and abiraterone acetate with prednisone group and in the placebo and abiraterone acetate with prednisone group, respectively.

Time to Pain Progression

The median TPP in the niraparib and abiraterone acetate with prednisone group was not estimable and was 22.11 months in the placebo and abiraterone acetate with prednisone group, with a stratified HR of 0.70 (95% CI, 0.43 to 1.12). The probability of TPP at 12 months was 72.90% (62.9% to 80.6%) and 69.4% (59.3% to 77.5%), and the probability of TPP at 24 months was 66.9% (95% CI, 55.9% to 75.8%) and 49.9% (95% CI, 36.2% to 61.3%) in the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone acetate with prednisone group, respectively.

Change From Baseline in FACT-P Total Score

The difference in the least squares mean for the change from baseline in FACT-P total score at cycle 25 between the 2 treatment groups was |||| points (95% CI, ||||| to ||||). Data were available for only 26 of 133 patients in the niraparib and abiraterone acetate with prednisone group and for 13 of 112 patients in the placebo and abiraterone acetate with prednisone group at the latest (cycle 25) analysis time point.

Harms Results

At least 1 treatment-emergent adverse event (TEAE) was reported in almost all patients in both treatment groups (99.1% of patients in the niraparib and abiraterone acetate with prednisone group, and 97.3% of patients in the placebo and abiraterone acetate with prednisone group). The most common TEAEs in the niraparib and abiraterone acetate with prednisone group versus the placebo and abiraterone acetate with prednisone group, respectively, were anemia (|||||versus |||||), constipation (33.6% versus 19.6%), hypertension (32.7% versus 24.1%), and nausea (32.7% versus 20.5%). A larger proportion of patients in the niraparib and abiraterone acetate with prednisone group experienced at least 1 TEAE of a grade 3 or grade 4 compared to the placebo and abiraterone acetate with prednisone group (68.1% versus 50.9%). At least 1 serious adverse event (SAE) was reported in 40.7% of patients in the niraparib and abiraterone acetate with prednisone group, and 25% of patients in the placebo and abiraterone acetate with prednisone group. The most common SAE in both groups was COVID-19 (4.4% and 2.7% in the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone acetate with prednisone group, respectively). Overall, 15% of patients in the niraparib and abiraterone acetate with prednisone group versus 5.4% of patients in the placebo and abiraterone acetate with prednisone group withdrew from study treatment due to TEAEs. During the follow-up time where death occurred more than 30 days after the last dose of the study drug, deaths were reported in ||||| of patients in the niraparib and abiraterone acetate with prednisone group, and ||||| of patients in the placebo and abiraterone acetate with prednisone group. Most deaths were attributed to disease progression in both treatment groups (||||| with niraparib and abiraterone acetate with prednisone; ||||| with placebo and abiraterone acetate with prednisone).

Notable harms identified in the CADTH review included anemia, which occurred in ||||| of patients treated with niraparib and abiraterone acetate with prednisone and ||||| of patients treated with placebo and abiraterone acetate with prednisone, followed by hypertension (32.7% versus 24.1%, respectively), fatigue (||||| versus |||||, respectively), thrombocytopenia (||||| versus ||||, respectively), asthenia (||||| versus |||||, respectively), fluid retention (||||| versus |||||, respectively), neutropenia (||||| versus ||||, respectively), and peripheral edema (||||| versus ||||, respectively).

Critical Appraisal

Although the MAGNITUDE study was a randomized trial, several key baseline factors were imbalanced between the 2 treatment groups, such as body location of metastases, metastasis stage at diagnosis, and ECOG PS score, which confounds the results and makes it difficult to determine the true effects of the treatments. The relatively small sample sizes in the trial and in the prespecified BRCA subgroup may partially account for the between-group differences. Multivariate Cox regression analysis (only for OS) and other analysis methods were used to try to balance differences between the groups. The clinical experts consulted by CADTH indicated that the differences in baseline characteristics signalled that the niraparib and abiraterone acetate with prednisone group had more serious disease than the control group. Therefore, if the identified differences in characteristics were not fully accounted for in the analyses, then the likely direction of the bias would be to the null (i.e., against niraparib and abiraterone acetate with prednisone). There were major protocol deviations identified in the trial; however, the magnitude and direction of potential bias was unclear due to the lack of reported patient numbers affected by these deviations within the BRCA subgroup. Furthermore, the niraparib and abiraterone acetate with prednisone group received more treatment cycles than the placebo and abiraterone acetate with prednisone group (33.0% versus 23. 7%, respectively), which could lead to artificially inflating the perceived effectiveness of the niraparib and abiraterone acetate with prednisone group. However, this difference in cycles of treatment received also reflects the observed higher percentage of patients in the placebo and abiraterone acetate with prednisone group who had disease progression. The difference in treatment cycles may also increase the likelihood of reporting AEs with additional treatments in the niraparib and abiraterone acetate with prednisone group. CADTH reviewers could not determine whether the efficacy and safety results were influenced by this imbalance based on the available information, although it is anticipated to have a limited effect, if any.

According to clinical experts, patients in the MAGNITUDE trial were considered generally representative of patients with mCRPC. Patients in the cohort 1 BRCA subgroup of the MAGNITUDE trial all had BRCA mutations confirmed before being enrolled in the trial, which aligns with the indicated population and reimbursement request. However, there were potential gaps and implementation challenges related to the evidence from the MAGNITUDE trial versus the population of patients included in the approved indication. CADTH noted that the indication is line-agnostic, whereas no patients in the MAGNITUDE trial had received prior systemic therapy in an mCRPC setting (i.e., received niraparib and abiraterone acetate with prednisone or placebo and abiraterone acetate with prednisone as first-line treatment in this setting). Additionally, the clinical experts indicated that although asymptomatic patients could be easily identified, determining whether a patient is “mildly symptomatic” is a subjective judgment and may vary between clinicians. It is unclear if patients enrolled in the MAGNITUDE trial would be classified as asymptomatic or mildly symptomatic because the trial did not have eligibility criteria or report baseline characteristics directly related to this. Likewise, the clinical experts indicated that there is no objective definition for patients “in whom chemotherapy is not clinically indicated.” Health Canada reported that the definition of this component of the indication is based on the clinical judgment of the treating physician and was included to reflect the MAGNITUDE study exclusion criteria, where no prior chemotherapy in an mCRPC setting was allowed. However, the clinical experts consulted by CADTH for this review noted that any patient with mCRPC who was well enough for cytotoxic chemotherapy could be interpreted as having a clinical indication for it, although they and/or their clinicians might not wish to treat these patients with chemotherapy due to the associated adverse effects.

In addition, the clinical experts noted that the exclusion criteria of the MAGNITUDE trial reduce the generalizability of the results as many patients with mCRPC in Canada now would have received a second-generation androgen receptor (AR) targeted therapy in an earlier stage of the disease. The clinical experts indicated this might impact the choice of niraparib and abiraterone acetate in the mCRPC setting because there would be a small population that would not be considered for taxane chemotherapy as first-line mCRPC treatment. Therefore, the CADTH review team noted that the trial population could reflect a relatively small population in clinical settings based on treatment history and eligibility. Outcomes measured in the MAGNITUDE trial are those recommended by Prostate Cancer Clinical Trials Working Group 3 (PCWG3)¹¹ (i.e., OS, rPFS, and patient-reported outcomes such as symptoms and HRQoL) and some are clinically relevant and important to patients. According to clinical experts consulted by CADTH, although rPFS is a relevant end point for assessing efficacy in trials, it is not an ideal primary efficacy outcome. It should be noted that despite the improvement in rPFS, there did not appear to be a substantial OS advantage. This is because the emphasis on radiographic results to determine disease progression and treatment benefit in an mCRPC setting does not adequately reflect clinical practice, which involves a broader and more holistic assessment of determining treatment benefit. Although the experts noted that abiraterone acetate with prednisone was an appropriate comparator when the MAGNITUDE trial was designed, there are gaps in the direct comparative evidence since there are additional clinically relevant comparators used to treat patients with mCRPC in Canada that are now more commonly used (e.g., chemotherapy). Therefore, the absence of head-to-head evidence between niraparib and abiraterone acetate versus chemotherapy represents an evidence gap. Clinical experts also noted that enrolling patients with only an ECOG PS score of 0 and 1 in the MAGNITUDE study is not entirely representative of patients with mCRPC as they expect to find patients with higher ECOG PS scores in Canadian practice.

GRADE Summary of Findings and Certainty of Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^12,13

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The reference points for the certainty of evidence assessment for OS and rPFS were set according to the presence or absence of an important effect based on thresholds informed by the clinical experts consulted for this review; for the FACT-P total score, reference points were set according to the presence or absence of an important effect based on thresholds identified in the literature. The target of the certainty of evidence assessment was the presence or absence of any (non-null) effect for the TSP and TPP due to the lack of a formal minimal important difference (MID) estimate; for harms events, due to the unavailability of the absolute difference in effects, the certainty of evidence was summarized narratively.

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, on CADTH’s consultation with clinical experts, and on input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• survival outcomes (OS, rPFS, TSP, TPP)

• HRQoL outcome (FACT-P total score)

• harms (withdrawals due to adverse events [WDAEs], SAEs).

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for niraparib and abiraterone acetate with prednisone versus placebo and abiraterone acetate with prednisone.

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor.

Indirect Comparisons

Description of Studies

The sponsor provided 1 indirect treatment comparison (ITC)¹⁷ described as an unanchored matching-adjusted indirect comparison (MAIC). In the analysis, individual participant data (IPD) from patients with mCRPC treated with niraparib and abiraterone acetate with prednisone in the MAGNITUDE pivotal trial (N = 113) was compared with the IPD from patients with mCRPC treated with first-line enzalutamide in the CAPTURE study (N = 19). The CAPTURE study was an observational, multiple-cohort database study focusing on Spanish patients. Patients from the CAPTURE study were reweighted using propensity score weighting in an attempt to match the distribution of patient characteristics of the patient cohort from the MAGNITUDE study. Outcomes presented in the ITC included OS, rPFS, and time to treatment discontinuation.

Results

The median follow-up time for patients in the MAGNITUDE trial was 26.8 months, while in the CAPTURE trial, the median follow-up time was 25.2 months. Efficacy and safety results from the primary analyses (i.e., base-case adjustment with simple imputation) in the scenario 1 population (i.e., patients selected from the CAPTURE study with first-line treatment mCRPC and BRCA1 or BRCA2 mutations) are presented in Table 20. The HR for OS among patients receiving enzalutamide only was |||| ||||| || ||||). However, the Kaplan-Meier curves for OS crossed, indicating that the proportional hazards assumption did not hold (Figure 7). The HR for rPFS among patients receiving enzalutamide only was |||| ||||| || |||||. The HR for time to treatment discontinuation among patients receiving enzalutamide only was |||| ||||| || |||||. The results of all sensitivity analyses (data not shown) in the scenario 1 population favoured niraparib and abiraterone acetate with prednisone over comparators.

Table 2: Summary of Findings for Niraparib and Abiraterone Acetate With Prednisone vs. Placebo and Abiraterone Acetate With Prednisone for Patients With mCRPC Having BRCA Mutation

CI = confidence interval; FACT-P = Functional Assessment of Cancer Therapy–Prostate; HR = hazard ratio; HRQoL = health-related quality of life; NA = not applicable; LSM = least squares mean; mCRPC = metastatic castration-resistant prostate cancer; NR = not reported; OS = overall survival; RCT = randomized controlled trial; rPFS = radiographic progression-free survival; TPP = time to pain progression; TSP = time to symptomatic progression; SAE = serious adverse event; vs. = versus; WDAE = withdrawal due to adverse event.

Notes: Details included in Table 2 are from the sponsor’s Summary of Clinical Evidence.¹⁴

Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, the imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aThe sponsor provided the probability of an event at the time point (i.e., death).

^bRated down 2 levels for very serious imprecision. The 95% CI for the difference between groups included the possibility of both benefit and harm when compared with placebo and abiraterone acetate with prednisone. A between-group difference of greater than 5% was clinically significant according to the clinical experts. We did not rate down OS due to the risk of bias since there was a multivariate analysis for OS, adjusting for important imbalanced characteristics.

^cRated down 2 levels for very serious imprecision. The 95% CI for the difference between groups included the possibility of a trivial effect (little to no difference) and important harm when compared with placebo and abiraterone acetate with prednisone. A between-group difference of 5% (50 fewer or 50 more events per 1,000 patients) was clinically significant according to the clinical experts.

^dThe sponsor provided the probability of an event at the time point (i.e., radiographic progression).

^eWe did not rate down for the risk of bias due to important baseline imbalances since differences in baseline characteristics signalled that the niraparib and abiraterone acetate group had more serious disease than the control group and the point estimate was showing a benefit, we are then more confident that the result was true. Results were based on an interim analysis. However, we did not detect potential overestimation of the true effect.

^fRated down 1 level for serious imprecision and because clinical experts were uncertain of what the exact threshold for clinical importance would be. Therefore, the null was used as the threshold. The point estimate and entire CI excluded the null. However, it was based on a small number of events.

^gThe sponsor provided the probability of an event at the time point (i.e., symptomatic progression).

^hRated down 1 level for serious risk of bias due to important baseline imbalances; the direction of bias was potentially toward the placebo and abiraterone acetate with prednisone group. The point estimate was showing little to no difference.

ⁱRated down 1 level for serious imprecision. The 95% CI included the possibility of little to no difference. There was no known MID so the target of certainty appraisal was any effect.

^jThe sponsor provided the probability of an event at the time point (i.e., pain progression).

^kRated down 2 levels for very serious imprecision due to the 95% CI, which included the possibility of both important benefit and important harm. There was no known MID so the target of certainty appraisal was any effect.

^lThere was no imprecision in the estimate (the entire CI showed little to no difference). The point estimate and both the lower and upper boundaries of the 95% CI of the between-group comparison indicated trivial or no clinically meaningful difference. Based on literature, a 10-point change from baseline in FACT-P total score was clinically important.

^mRated down 1 level for serious imprecision. The number of events did not meet the optimal information size.

Sources: MAGNITUDE Second Interim Analysis Clinical Study Report¹⁵ and the sponsor’s response to requested additional information.¹⁶

Critical Appraisal

CADTH noted that the ITC analysis carried out by the sponsor was not a typical unanchored MAIC based on comparing IPD from 1 study with aggregate-level data from the other study. The analysis submitted to CADTH was more like a single exposure cohort (i.e., the niraparib and abiraterone acetate with prednisone group of the MAGNITUDE study) compared with an external comparator (e.g., enzalutamide-only group from the CAPTURE study), using population adjustment methods based on IPD from both groups.

One major concern that decreased CADTH’s certainty in the ITC estimates related to patient comparability. In the sponsor-submitted ITC analysis, more than 20 potential prognostic and effect modifying factors were identified from the literature (Table 17) that were considered relevant and comprehensive by the clinical experts consulted by CADTH. However, of these factors identified, only 9 factors (6 factors adjusted for the base-case analysis and an additional 3 factors for the sensitivity analysis) were involved in the propensity score weighting. It is understandable that many prognostic and effect modifying factors identified were not reported in the MAGNITUDE or CAPTURE study, which made it impossible to adjust. Yet, with many relevant factors unadjusted, it is likely that the differences unaccounted for would bias the results, although the degree of the bias remains unknown. Additionally, after adjustment in the base-case analysis, the absolute values of the standardized mean differences (SMDs) greater than 0.2 were identified for several prognostic factors such as age (SMD = 0.269), baseline PSA (SMD = 0.250), Gleason score at initial diagnosis (SMD = 0.460), and the presence of visceral metastases (SMD = 0.513), which suggested the existence of insufficient balance.

Another concern was that the Kaplan-Meier curves for OS, which was considered the most clinically relevant end point for patients with mCRPC, signalled that the proportional hazards assumption had been violated, and no further analyses addressing the nonproportional hazard issue were found. In addition, a lack of information in the sponsor-submitted ITC report made it challenging for CADTH to determine, for example, whether the discrepancy in the definitions of disease progression (and therefore rPFS) between the MAGNITUDE and CAPTURE studies would impact the ITC estimates and whether data from the CAPTURE study was temporally relevant to the data from the MAGNITUDE study.

Lastly, findings from the ITC focused on the comparison between niraparib and abiraterone acetate with prednisone versus enzalutamide in the first-line treatment setting only. Therefore, there remains a gap in the indirect comparative evidence related to the later lines of therapy.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies addressing gaps in the systematic review evidence were submitted by the sponsor.

Conclusions

mCRPC is an advanced stage of prostate cancer, and there is an unmet need for new treatments to prolong life, prevent disease progression, improve HRQoL, and reduce adverse events (AEs). The MAGNITUDE trial is an ongoing, double-blind, phase III RCT evaluating the efficacy and safety of first-line treatment with niraparib and abiraterone acetate with prednisone in patients with mCRPC. The trial did not demonstrate a benefit with niraparib and abiraterone acetate with prednisone compared to placebo and abiraterone acetate with prednisone on OS or HRQoL, which were identified as important outcomes by patients and clinical experts. Moderate certainty of evidence showed niraparib and abiraterone acetate with prednisone likely resulted in an increase in rPFS when compared with placebo and abiraterone acetate with prednisone; however, the clinical importance of this difference was uncertain. Results for TSP and TPP suggested that niraparib and abiraterone acetate with prednisone were favoured over placebo and abiraterone acetate with prednisone but the results for these efficacy outcomes were affected by concerns for imprecision and limitations in the trial, such as imbalanced baseline characteristics between treatment groups. Niraparib and abiraterone acetate with prednisone appeared to be associated with a higher frequency of TEAEs, grade 3 or grade 4 AEs, SAEs, withdrawals from treatment due to an AE (WDAEs), and notable harms compared with placebo and abiraterone acetate with prednisone. Findings from the sponsor-conducted indirect comparison with enzalutamide were considered of high uncertainty due to several major limitations, such as the fact that many relevant prognostic and effect modifying factors were not adjusted as well as the fact that the proportional hazards assumption was likely violated for OS.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of niraparib 200 mg and abiraterone acetate 1,000 mg (oral tablet) used with prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA mutated (germline and/or somatic) mCRPC who are asymptomatic or mildly symptomatic, and in whom chemotherapy is not clinically indicated.

Disease Background

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

Prostate cancer is the most common cancer among Canadian males, affecting 1 in 8 males during their lifetime¹ and accounting for 10% of cancer-related deaths.¹⁸ The 10-year prevalence of prostate cancer was 993.7 per 100,000 among those assigned male at birth in Canada (excluding Quebec) (492.7 per 100,000 people) in 2018.¹⁹ It was estimated that in 2022, 24,600 males in Canada would be diagnosed with prostate cancer.¹ The stages of prostate cancer are classified in terms of localized, locally advanced, or metastatic disease, with further subcategorization according to hormone therapy status, whether hormone-naive or hormone-sensitive, or mCRPC.¹¹ A patient may progress from mCSPC to mCRPC based on biochemical recurrence (characterized by rising PSA levels despite medical or surgical castration) or from nmCRPC based on the presentation of metastases (assessed radiographically).^2,3 Progressing to mCRPC is characterized by increased symptomatic burden and reduced HRQoL,^4-6 and goals of treatment include delaying progression and improving HRQoL.⁵ As per a recent systematic literature review of the epidemiology of advanced prostate cancer, the prevalence of mCRPC was estimated at 1.2% to 2.1% of prostate cancer cases.²⁰

Even though the expected 5-year survival for males diagnosed with prostate cancer in Canada is 91% for all stages combined,²¹ when the disease progresses to the mCRPC stage, the 5-year survival rate reduces to approximately 26% to 28%.^8,9 With current mCRPC treatments, median survival is low, ranging from approximately 9 months to 3 years in more recent studies.^22-26 Approximately 20% to 30% of patients with metastatic prostate cancer have pathogenic variants in DNA repair genes (e.g., BRCA1, BRCA2, ATM) that are associated with the HRR pathway.^27,28 When these mutations occur in the HRR pathway specifically, cancer cells rely on PARP to correct DNA damage and prevent cell death.²⁹

Approximately 10% of all patients with mCRPC harbour BRCA alterations.⁷ Half of pathogenic variants are of germline (inherited) origin and the other half are of somatic (acquired in tumour cells during tumourigenesis) origin.²⁸ Patients with BRCA gene–mutated mCRPC are more likely to present with advanced disease, nodal involvement, and distant metastases at diagnosis.¹⁰

Standards of Therapy

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

Clinical experts consulted by CADTH indicated that there are several systemic therapies that are approved for the treatment of patients with mCRPC, and the sequencing of these treatments depends on patient and disease factors, prior treatments used in the mCSPC setting, and access, which varies across Canada. Docetaxel, cabazitaxel, abiraterone acetate, enzalutamide, olaparib (for patients with BRCA1, BRCA2, and/or ATM mutations), radium-223 (for patients with bone-predominant disease and no visceral metastasis) and lutetium vipivotide tetraxetan are all Health Canada–approved and, with the exception of lutetium vipivotide tetraxetan, are widely available in all provinces across Canada. abiraterone acetate, enzalutamide, and docetaxel are treatment options in all lines of therapy for mCRPC. In addition, clinical experts noted that triplet therapy is an option in the first-line mCSPC setting. According to the clinical experts consulted by CADTH, chemotherapy is now the most commonly used first-line treatment for mCRPC since most patients have already received an ARPi in the mCSPC setting. Clinical experts indicated that in some rare situations, radium-223 is directly chosen in the first-line mCRPC setting. In a response to an additional information request, the sponsor indicated that niraparib and abiraterone acetate with prednisone could be used in all lines of mCRPC based on a physician’s clinical judgment.³⁰ The sponsor submitted an algorithm of current treatments for mCRPC in which the most common treatments used to treat castration-resistant prostate cancer (first-line to third-line treatments and beyond) are abiraterone, enzalutamide, docetaxel, and radium-223. Additionally, cabazitaxel, radium-223, lutetium vipivotide tetraxetan, and olaparib were reported as treatment options in second-line treatment, third-line treatment, and lines beyond of treatment, with olaparib for patients with BRCA gene–mutated or ATM-mutated mCRPC. This was aligned with a published CADTH provisional funding algorithm,³¹ a CADTH health technology review,³² recently published Canadian guidelines, recent Canadian publications detailing practice of care, and current international guidelines.^33-38

According to the literature, the goals of treatment in mCRPC include delaying disease progression, ameliorating symptoms, and improving HRQoL.⁵ Likewise, clinical experts consulted by CADTH noted that the goals of treatment in the mCRPC setting include prolonged life, improved quality of life, and reduced toxicity.

Drug Under Review

The drug under review is a fixed-dose dual combination of niraparib and abiraterone acetate. Niraparib is a highly selective PARP inhibitor, with potent activity against PARP-1 and PARP-2; abiraterone acetate is a CYP17 inhibitor.³⁹ This combination targets 2 oncogenic dependencies in patients with mCRPC and HRR gene alterations.³⁹ Niraparib and abiraterone acetate is an oral medication administered as a single daily dose and is used with 10 mg prednisone or prednisolone daily.³⁹ The recommended dose is 200 mg niraparib and 1,000 mg abiraterone acetate (two 100 mg/500 mg tablets). Niraparib and abiraterone acetate tablets are also available as a low-dose strength (50 mg niraparib and 500 mg abiraterone acetate) for dose adjustment.³⁹

The Health Canada–approved indication for niraparib and abiraterone acetate with prednisone or prednisolone is for the treatment of adult patients with deleterious or suspected deleterious BRCA gene–mutated (germline and/or somatic) mCRPC who are asymptomatic/mildly symptomatic, and in whom chemotherapy is not clinically indicated.³⁹ Patients must have confirmation of BRCA mutation before niraparib and abiraterone acetate treatment is initiated as per the product monograph. The sponsor’s reimbursement request aligns with the Health Canada–approved indication.

Key characteristics of niraparib, abiraterone acetate, and enzalutamide are summarized in the Table 3.

Table 3: Key Characteristics of Niraparib, Abiraterone Acetate, and Enzalutamide

mCRPC = metastatic castration-resistant prostate cancer; NA = not applicable; PARP = poly-(ADP [adenosine diphosphate]-ribose) polymerase; PARP-1 = poly-(ADP [adenosine diphosphate]-ribose) polymerase 1; PARP-2 = poly-(ADP [adenosine diphosphate]-ribose) polymerase 2.

^aGiven in combination with abiraterone acetate and prednisone or prednisolone.

^bGiven in combination with niraparib and prednisone or prednisolone.

^cHealth Canada–approved indication.

Sources: Akeega, Zytiga, and Xtandi product monographs.^39-41

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by patient groups. The full original patient input received by CADTH has been included in the Stakeholder section of this report.

Two patient groups, CCS and CCSN, provided input for the review of niraparib and abiraterone acetate for the treatment of adult patients with deleterious or suspected deleterious BRCA gene–mutated (germline and/or somatic) mCRPC who are asymptomatic or mildly symptomatic, and in whom chemotherapy is not clinically indicated. Patient input was gathered from surveys that were conducted from April until May 2023 by CCS and in June 2023 by CCSN. In total, 24 responses were gathered by CCS (from 21 patients and 3 caregivers), and 8 responses (from 8 patients) were gathered by CCSN. Overall, 97% of respondents in the CCS survey and 6 of the patients in the CCSN survey were living in Canada. One patient from the CCSN survey had experience with the drug under review.

With the use of currently available treatments, patients reported that the following symptoms affected their quality of life and day-to-day living: changes in libido, sexual function or fertility, hot flushes, fatigue, low energy, difficulties with urination, loss of appetite, bone or skeletal pain, indigestion, bowel problems, peripheral neuropathy, dizziness, and muscle loss. Patients from the CCS survey noted difficulty travelling to access treatment, costs associated with travelling to appointments, and difficulty managing side effects as some of the issues they expect to be improved. Maintaining quality of life, prolonging life, providing a cure, and reducing side effects from current medications or treatments were some of the expected outcomes that most CCSN survey patients hoped a new drug would address to manage their disease.

While describing the considerations regarding balancing the advantages and disadvantages of a treatment, CCSN survey patients reported life extension and cures, severity of side effects, quality of life, high mental stress, and living a healthy life as important. When asked about disease experience and its impact on day-to-day activities, 14 (67%) patients from the CCS survey mentioned that the ability to engage in sexual activity was most affected, along with the ability to work, to exercise, and to maintain positive mental health being moderately to significantly impacted. On the other hand, respondents from the CCSN survey reported identifying the cause, working toward the cure, avoiding metabolic syndrome, avoiding having metastases progressing to other body locations, preventing or mitigating the spread of cancer in the bones, and avoiding erectile dysfunction (which inhibits intimacy) and incontinence as the most important aspects of their disease to control. While patients from the CCS survey identified transportation costs associated with appointments as the largest barrier while receiving treatments, followed by lack of familiarity with navigating the health care system and long wait times to receive tests or treatments, CCSN survey respondents noted that limited availability in the community, financial hardship due to cost, travel costs associated with accessing therapy, supplies, and challenges with administration were some issues they faced while accessing therapies.

While describing the experience with the current drug under review, the sole patient from the CCSN survey who had taken niraparib reported constipation and decreased appetite as adverse effects. When asked in comparison to other therapies how was their treatment experience with niraparib in treating their prostate cancer, the respondent noted that there was little or no difference in symptom management, side effects, and ease of use. The patient also noted that the experience regarding disease progression was much better compared to other therapies.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of mCRPC.

Unmet Needs

The clinical experts indicated that since mCRPC is a terminal phase of prostate cancer, the unmet needs of patients would be prolonged OS, improved quality of life, and reduced toxicity. Both clinical experts highlighted that the balance between treatment efficacy and quality of life would be important. In addition, the clinical experts noted a need for new treatments since these patients have primary or acquired resistance to offered treatments in the mCRPC setting.

Place in Therapy

Clinical experts agreed that it remains unclear whether niraparib and abiraterone acetate would lead to a shift in the current treatment paradigm. This uncertainty stems from the increased use of ARPis. They noted that niraparib and abiraterone acetate would not be coadministered with systematic treatments except for androgen deprivation therapy. However, it could be administrated with palliative external beam radiotherapy (EBRT). One of the experts highlighted that although there is some biological theory that abiraterone acetate would increase the efficacy of a PARP inhibitor when they are coadministrated, this has not been investigated clinically. While niraparib and abiraterone acetate are used in patients who have been treated with enzalutamide, apalutamide, and darolutamide in the nmCRPC or mCSPC settings, many medical oncologists would favour a change to chemotherapy in patients progressing on an ARPi. They noted that if a treatment was used in mCSPC, it is not likely that the patient would receive it again in mCRPC (with the occasional exception of docetaxel). The clinical experts noted that niraparib and abiraterone acetate may have a limited role as a first-line or later-line treatment in the mCRPC setting due to the decreasing number of patients who are ARPi-naive and the few patients who would be clinically ineligible for docetaxel.

Patient Population

The clinical experts agreed with the BRCA gene–mutated mCRPC population specified in the Health Canada–approved indication. Testing for the BRCA mutation is usually conducted at an early stage for patients with mCRPC. It was noted that most patients with mCRPC, especially those who are otherwise well, would be considered for treatment with cytotoxic chemotherapy. However, it is rare for patients to have an absolute contraindication to chemotherapy. Clinicians may consider alternatives to chemotherapy in patients whose disease is asymptomatic or minimally symptomatic and palliative to minimize the toxic effects of treatments. Niraparib and abiraterone acetate may be a treatment option for those patients with mCRPC who are BRCA-positive and for whom chemotherapy was not a treatment of choice.

Assessing the Response Treatment

The clinical experts indicated that in clinical practice, a combination of radiographic, biochemical, and clinical parameters is used to determine whether a patient with mCRPC is responding to treatment.

Discontinuing Treatment

The clinical experts indicated that treatment with niraparib and abiraterone acetate should be discontinued if treatment is intolerable, if the patient experiences disease progression, or if the patient prefers to discontinue treatment.

Prescribing Considerations

According to the clinical experts consulted by CADTH, PARP inhibitors have the potential to be toxic. Therefore, patients receiving niraparib and abiraterone acetate must be under the care of a medical oncologist to manage toxicity. They noted that to manage toxicity, it is required to involve medical oncologists in the community setting and other oncology professionals in academic settings.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by clinician groups. The full original clinician group input received by CADTH has been included in the Stakeholder section of this report.

Clinician group input on the review of niraparib and abiraterone acetate with prednisone was received from the OH-CCO Genitourinary Cancer Drug Advisory Committee. A total of 8 clinicians provided input on behalf of OH-CCO.

OH-CCO highlighted the need to have therapies in the first-line mCRPC setting that can prolong life, considering there is currently no cure and no targeted treatments available at this setting. They also mentioned the need for treatments that can maximize quality of life. The group noted that niraparib and abiraterone acetate with prednisone would become a SOC in treatment-naive patients with mCRPC with HRR mutation, although the CADTH review team noted that the Health Canada–approved indication is for patients with BRCA mutations only. The group indicated that while PSA will be used to determine the burden of disease and to monitor response to therapy, serial radiographic imaging will also be used to monitor response and to determine progression as per SOC. They also noted they would discontinue treatment in cases of significant side effects or disease progression.

The clinician group highlighted that niraparib and abiraterone acetate with prednisone should be administered by oncologists with experience using PARP inhibitors, as well as with expertise in the management of PARP inhibitor side effects. The clinician group noted that niraparib and abiraterone acetate with prednisone is a novel combination of therapies that would benefit a targeted population of patients with prostate cancer.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

ARAT = androgen receptor axis-targeted; ECOG PS = Eastern Cooperative Oncology Group Performance Status; Gn-RH = gonadotropin-releasing hormone; HRR = homologous recombination repair; mCRPC = metastatic castration-resistant prostate cancer; mCSPC = metastatic castration-sensitive prostate cancer; nmCRPC = nonmetastatic castration-resistant prostate cancer; PAG = CADTH Provincial Advisory Group; pCPA = pan-Canadian Pharmaceutical Alliance; pERC = CADTH pan-Canadian Oncology Drug Review Expert Review Committee; PSA = prostate-specific antigen; vs. = versus.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of niraparib 200 mg and abiraterone acetate 1,000 mg (oral tablet) with prednisone 10 mg once daily for the treatment of adult patients with deleterious or suspected deleterious BRCA gene–mutated (germline and/or somatic) mCRPC who are asymptomatic/mildly symptomatic, and in whom chemotherapy is not clinically indicated. The focus has been placed on comparing niraparib and abiraterone acetate to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of niraparib and abiraterone acetate with prednisone is presented in 2 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. CADTH’s assessment of the certainty of the evidence in this first section using the GRADE approach followed the critical appraisal of the evidence. The second section includes indirect evidence from the sponsor. No long-term extension studies or studies addressing gaps in the systematic review evidence section were submitted by the sponsor.

Included Studies

Clinical evidence from the following is included in the CADTH review and appraised in this document:

• 1 pivotal RCT

• 1 ITC.

Systematic Review

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Description of Studies

The MAGNITUDE study is an ongoing phase III, randomized, double-blind, placebo-controlled, multicentre trial. The aim of the trial is to assess the efficacy and safety of niraparib 200 mg and abiraterone acetate 1,000 mg and prednisone 10 mg administered orally once daily for the treatment of adult patients with mCRPC who had not received prior systemic therapy in the mCRPC setting. Patients were prospectively screened for HRR gene alterations and then enrolled in either cohort 1 if they had presence of HRR gene alterations (either monoallelic or biallelic pathogenic gene alterations in ≥ 1 of the following genes: ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2) or cohort 2 if they did not have HRR gene alterations or if they were patients whose gene testing failed. Cohort 2 enrolment and follow-up was stopped based on the threshold for futility being met in a preplanned futility analysis. Patients from cohort 1 and cohort 2 could continue to a third open-label cohort of patients with HRR gene alterations (cohort 3) to obtain descriptive data on the clinical experience with a fixed-dose combination tablet formulation of niraparib and abiraterone acetate. Cohort 1 was the focus of this review because it aligns with the Health Canada indication and the sponsor’s reimbursement request.

The trial included a screening period of up to 28 days, a treatment period of until disease progression or unacceptable toxicity, and a follow-up period of up to 60 months, until death or loss to follow-up. Following discontinuation of the treatment, patients were followed for survival, initiation of subsequent prostate cancer therapy, and disease progression; patients were followed for up to 5 years or until death, loss to follow-up, withdrawal of consent, or study termination. Characteristics of the MAGNITUDE study are summarized in Table 5.

Given the Health Canada indication for niraparib and abiraterone acetate specifies patients with deleterious or suspected deleterious BRCA gene–mutated mCRPC and that patients must have confirmation of BRCA mutation before treatment is initiated, this review will report on a subgroup of patients from cohort 1 with BRCA gene alterations.

Table 5: Details of Studies Included in the Systematic Review

AAP = abiraterone acetate with prednisone; ANC = absolute neutrophil count; AR = androgen receptor; BP = blood pressure; BPI-SF = Brief Pain Inventory (Short Form); DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; Gn-RH = gonadotropin-releasing hormone; HRR = homologous recombination repair; mCRPC = metastatic castration-resistant prostate cancer; ORR = objective response rate; OS = overall survival; PARP = poly-(ADP [adenosine diphosphate]-ribose) polymerase; PCWG3 = Prostate Cancer Clinical Trials Working Group 3; PFS2 = progression-free survival on first subsequent therapy; PSA = prostate-specific antigen; RCT = randomized controlled trial; rPFS = radiographic progression-free survival; TCC = time to initiation of cytotoxic chemotherapy; TEAE = treatment-emergent adverse event; TPP = time to pain progression; TPSA = time to prostate-specific antigen progression; TSP = time to symptomatic progression.

Note: Details from Table 5 have been taken from the sponsor’s Summary of Clinical Evidence.¹⁴

^aTo align with the Health Canada indication for niraparib and abiraterone acetate with prednisone, the population of the MAGNITUDE study that was considered herein was patients with a BRCA gene alteration who were randomized to receive niraparib and abiraterone acetate with prednisone or placebo and abiraterone acetate with prednisone (a subgroup of cohort 1, which consisted of patients positive for HRR gene alterations).

Sources: MAGNITUDE Second Interim Analysis Clinical Study Report⁴³ and ClinicalTrials.gov entry.⁴⁴

A total of 765 patients were enrolled in the MAGNITUDE study; of these, 423 patients had HRR gene alterations and were enrolled in cohort 1. Of the 423 patients with HRR alterations, 225 patients were enrolled in the BRCA subgroup. Patients enrolled in cohort 1 were randomized 1:1 at 205 sites across 26 countries, including Canada (5 sites), to receive niraparib 200 mg and abiraterone acetate 1,000 mg and prednisone 10 mg daily (N = 113 in the BRCA subgroup) or placebo and abiraterone acetate 1,000 mg and prednisone 10 mg (N = 112 in the BRCA subgroup). Randomization was balanced using randomly permuted blocks and stratified by past taxane-based chemotherapy exposure (yes versus no), past AR-targeted therapy exposure (yes versus no), and prior abiraterone acetate with prednisone use (yes versus no). For cohort 1, stratification by gene alteration group (i.e., BRCA1 or BRCA2 versus all other HRR gene alterations) was also performed. The MAGNITUDE study was initiated on February 5, 2019. This study is ongoing, with results available from 2 prespecified interim analyses with data cutoff dates of April 5, 2022, and June 17, 2022.

Populations

Inclusion and Exclusion Criteria

A detailed description of the inclusion and exclusion criteria for the MAGNITUDE trial is provided in Table 5. Patients eligible for enrolment in cohort 1 were adults with mCRPC and positive for HRR gene alteration, including BRCA mutation, and had an ECOG PS score grade of 0 or 1. Patients were excluded if they had had prior treatment with a PARP inhibitor, systemic therapy (i.e., novel second-generation AR targeted therapy such as enzalutamide, apalutamide, or darolutamide; taxane-based chemotherapy; or more than 4 months of abiraterone acetate with prednisone before randomization) in the mCRPC setting; or abiraterone acetate with prednisone outside of the mCRPC setting. Patients who had previously been treated and progressed on an ARPi in the mCSPC and nmCRPC settings were eligible for the MAGNITUDE trial. Patients who had received 2 months to 4 months of abiraterone acetate with prednisone before randomization for the treatment of mCRPC should have had no evidence of progression by PSA during screening (i.e., required to have 2 PSA values during the prescreening and screening phases) or had uncontrolled hypertension.

Interventions

Patients received niraparib 200 mg and abiraterone acetate 1,000 mg with prednisone 10 mg or placebo and abiraterone acetate 1,000 mg with prednisone 10 mg taken orally daily. Treatment began at cycle 1, day 1, in the treatment phase and continued in 28-day cycles until the study treatment was discontinued.¹⁵ Placebo for niraparib was provided as a capsule formulation and was matched in size, colour, and shape to maintain the study blind. Study treatments were administered together, except for prednisone, which was taken twice daily. Treatments were to be discontinued for unequivocal clinical progression, unacceptable toxicity, death, or sponsor termination of the study.

In the MAGNITUDE trial, dose interruptions and modifications of niraparib and abiraterone acetate and placebo and abiraterone acetate were generally done if patients experienced GRADE 3 or higher toxicities. Treatment was also interrupted before procedures that required hospitalization. Grade 1 or grade 2 toxicities were managed symptomatically without requiring dose adjustments or dose interruptions. The dose of prednisone remained unchanged with dose modifications of niraparib, placebo, or abiraterone acetate.

If either study drug (i.e., niraparib/placebo or abiraterone acetate) was permanently discontinued due to toxicity, the other study drug could be continued. Prednisone was discontinued (with a taper if clinically indicated) if abiraterone acetate was permanently discontinued.

Supportive concomitant therapies (e.g., endocrine therapy, analgesics, antihypertensives, antacids, antibacterials) were allowed. The following concomitant treatments were prohibited: investigational drugs other than the study treatments; other anticancer therapies; other drugs that targeted the androgen axis (e.g., antiandrogens such as enzalutamide and apalutamide, CYP17 inhibitors such as ketoconazole); testosterone; radiotherapy for tumour progression (patients may have received palliative radiotherapy in selected cases after discussion with the sponsor); chemotherapy; immunotherapy; diethylstilbestrol or similar estrogen receptor agonists; pomegranates and pomegranate juice; spironolactone; radiopharmaceuticals such as radium-223, strontium, or samarium; and strong inducers of CYP3A4 (e.g., rifampin). Concomitant treatment with substrates of CYP2D6 and CYP2C8 were restricted due to the potential for drug-drug interactions.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 6, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence¹⁴ as well as any outcomes identified as important to this review according to the clinical experts consulted by CADTH and stakeholder input from patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected end points that were considered to be most relevant to inform CADTH’s expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing CADTH’s expert committee deliberations were also assessed using GRADE.

Table 6: Efficacy Outcomes Summarized From the Study Included in the Systematic Review

BICR = blinded independent central review; FACT-P = Functional Assessment of Cancer Therapy–Prostate; OS = overall survival; rPFS = radiographic progression-free survival; TPP = time to pain progression; TSP = time to symptomatic progression.

Note: Details included in Table 6 are from the sponsor’s Summary of Clinical Evidence.¹⁴

^aStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchal testing).

Sources: MAGNITUDE Second Interim Analysis Clinical Study Report¹⁵ and ClinicalTrials.gov entry.⁴⁴

Efficacy Outcomes

Overall Survival

The secondary outcome of OS was defined as the time from date of randomization to date of death from any cause. Patients alive at the time of analysis would be censored on the last date the patient was known to be alive.

rPFS by BICR

The primary end point for this study was rPFS as assessed by BICR. This outcome was defined as the time interval from the date of randomization to the first date of radiographic progression or death due to any cause, whichever occurred first. Radiographic progression was determined by the first occurrence of progression by bone scan (according to PCWG3 criteria) or progression of soft tissue lesions by CT or MRI scan (according to RECIST 1.1 criteria), both assessed by BICR.

Time to Symptomatic Progression

The secondary end point of TSP was defined as the date of randomization to the date of the first of any of the following:

• EBRT for skeletal symptoms

• tumour-related orthopedic surgical intervention

• other cancer-related procedures (e.g., nephrostomy insertion, bladder catheter insertion, EBRT, surgery for tumour symptoms other than skeletal)

• cancer-related morbid events (e.g., fracture [symptomatic and/or pathologic], cord compression, urinary obstructive events)

• initiation of a new systemic anticancer therapy because of cancer pain.

Time to Pain Progression

The exploratory end point of TPP was defined as the time from the date of randomization to the date of the first observation of pain progression. Pain progression was defined as an average increase by 2 points from baseline in the Brief Pain Inventory (Short Form) tool, worst pain intensity (item 3), observed at 2 consecutive evaluations 3 or more weeks apart.

FACT-P Questionnaire

FACT-P was an exploratory end point evaluating prostate cancer–specific HRQoL. A summary of its measurement properties is in Table 7. FACT-P consists of the 27 items from the Functional Assessment of Cancer Therapy–General (FACT-G), of which 10 items are prostate cancer–specific concerns. This questionnaire assesses physical, social/family, emotional, and functional well-being. Patients respond by selecting 1 of 5 response categories ranging from “not at all” to “very much.” Decreasing scores indicate worsening and/or deterioration (i.e., worse HRQoL). The MID for total score was estimated at 10.¹⁵

Table 7: Summary of Outcome Measures and Their Measurement Properties

BPI = Brief Pain Inventory; BPI-SF = Brief Pain Inventory (Short Form); CRPC = castration-resistant prostate cancer; FACT-G = Functional Assessment of Cancer Therapy–General; FACT-P = Functional Assessment of Cancer Therapy–Prostate; HRQoL = health-related quality of life; ICC = intraclass correlation coefficient; mCRPC = metastatic castration-resistant prostate cancer; MID = minimal important difference; PCS = prostate cancer subscale; PPI = Present Pain Intensity; PSA = prostate-specific antigen.

Harms Outcomes

TEAEs included any untoward medical occurrence that occurred or worsened on or after the first dose of study treatment through 30 days after the last dose of study treatment and are included in the analysis in the MAGNITUDE trial. SAEs were defined as an untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, was persistent or a significant disability, was a congenital anomaly or birth defect, or was medically important per medical and scientific judgment. WDAEs were defined as events related to discontinued study treatment due to TEAEs in the MAGNITUDE trial. Deaths that occurred within 30 days of the last dose of study treatment in the MAGNITUDE trial were reported.

Statistical Analysis

Sample Size and Power Calculation

It was estimated that for cohort 1 of the MAGNITUDE study, approximately 400 patients with mCRPC and HRR gene alterations were to be randomized 1:1 to receive niraparib and abiraterone acetate with prednisone or placebo and abiraterone acetate with prednisone. A target subgroup within cohort 1, the BRCA subgroup, would consist of patients with BRCA1 or BRCA2 mutations; this subgroup was planned to consist of at least 50% of patients from cohort 1 who would undergo randomization.

The target sample size for cohort 1 was event-driven, with approximately 220 rPFS events required to provide 87% power in detecting an HR of 0.65 for rPFS in patients with mCRPC and HRR gene alterations (median rPFS of 13 months for the placebo and abiraterone acetate with prednisone treatment group versus 20 months for the niraparib and abiraterone acetate with prednisone treatment group) at a 2-tailed level of significance of 0.05. With a 21-month accrual period and an additional 7 months of follow-up, the study duration to reach the required number of rPFS events would be approximately 28 months. Assuming that approximately 50% of patients in cohort 1 belonged to the BRCA subgroup, with the proposed sample size and study duration, approximately 102 rPFS events were planned to be observed in the BRCA subgroup to provide 93% power to detect an HR of 0.5 (median 13 months versus 26 months) at a 2-tailed level of significance of 0.05.

Statistical Testing and Sensitivity Analysis

A summary of statistical analysis appears in Table 8. The primary end point (rPFS by BICR) was tested using stratified log-rank test at the overall 2-tailed significance level of 0.05. The Kaplan-Meier product limit method and a stratified Cox model were used to estimate the median rPFS and to obtain the HR along with the associated 95% CIs, respectively. Sensitivity analyses were carried out using a nonstratified log-rank test, using an investigator-assessed radiographic progression, and having no censoring for subsequent therapy.

A post hoc covariate-adjusted sensitivity analysis was conducted for rPFS and OS using a propensity-based method because of the observed differences in baseline characteristics despite randomization. The inverse probability treatment weighting method with an estimate of average treatment effect was used as the statistical approach for comparing outcomes between the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone acetate with prednisone group to adjust for imbalances in the population characteristics. Propensity score weighting was performed to obtain adjusted estimates of treatment effects and to limit the potential confounding effect of unbalanced patient characteristics between the 2 groups in the MAGNITUDE study. Propensity scores (i.e., based on the probability of receiving treatment) were used to obtain weights after adjustment by relevant covariates.

Table 8: Statistical Analysis of Efficacy End Points

IPCW = inverse probability of censoring weighting; NR = not reported; OS = overall survival; rPFS = radiographic progression-free survival; TPP = time to pain progression; TSP = time to symptomatic progression.

Note: Details included in Table 8 are from the sponsor’s Summary of Clinical Evidence.¹⁴

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

The final analysis of the primary end point rPFS was performed when approximately 220 rPFS events were observed in cohort 1 and approximately 102 rPFS events were observed in the BRCA subgroup within cohort 1. The second preplanned interim analysis of secondary end points was performed on June 17, 2022, after observing 179 OS events. Prespecified sensitivity analyses were performed in accordance with the statistical analysis plan. The efficacy analysis began by testing rPFS in the BRCA subgroup of cohort 1 using a 2-sided alpha level of 0.05. If statistical significance was met in the BRCA subgroup, then rPFS in all of cohort 1 was to be tested, also at a 2-sided alpha level of 0.05 based on the predefined testing hierarchy. If rPFS in cohort 1 was statistically significant, then the secondary end points were to be tested using a group sequential method with 2 interim analyses and the final analysis. After testing for the primary end point of rPFS in the BRCA subgroup and cohort 1, an alpha of 0.05 was split between the secondary end points, which were analyzed for all of cohort 1 with an alpha of 0.025 allocated to OS and an alpha of 0.0125 allocated to time to initiation of cytotoxic chemotherapy (TCC) and TSP separately. The alpha for the secondary end points was further subdivided between the 2 planned interim analyses and the final analysis. For the secondary end points, the O’Brien-Fleming boundaries as implemented by the Lan-DeMets alpha spending method were used, and interim boundary cutoffs were calculated using the information fraction for the OS end point. Given that the study met the primary end point of rPFS by BICR and the results of the first interim analysis were publicly presented, a change in the prescribing pattern of subsequent therapies was possible; hence, a revised alpha spending function for TCC and TSP at the second interim analysis was prospectively implemented before the database lock for the second interim analysis. This revision was designed to minimize the impact on secondary end points based on the likely increased use of subsequent anticancer therapy with a PARP inhibitor (essentially a crossover for patients treated with SOC therapy). The preplanned analysis of OS, including the alpha spending for OS, remained unchanged from the originally planned O’Brien-Fleming boundaries for the second interim analysis and the final analysis. The overall study wise type I error rate remained adequately controlled at the 2-sided level of 0.05 with the revised alpha spending function for TCC and TSP, and the original alpha spending function for OS. As per the preplanned testing procedure, the initial statistical significance boundaries at the second interim analysis were 0.012 for both TSP and TCC, and 0.0067 for OS (based on 179 observed OS events at the second interim analysis). If either TCC or TSP met statistical significance, its alpha would be recycled, with the significance boundary for the other of TCC or TSP at the second interim analysis becoming 0.0183; as described earlier, the significance boundary for OS would remain at 0.0067.

Data Imputation Methods

Data for which quality issues were detected were excluded, when deemed necessary, from the sensitivity analysis for efficacy and safety. The strength of association between rPFS and OS was evaluated for the BRCA subgroup using the iterative multiple imputation approach when data were missing. Missing data for patient-reported outcomes were analyzed by accounting for change from baseline with a mixed model of repeated measures and using a pattern-mixture model as a sensitivity analysis.

Subgroup Analyses

Subgroup analyses were conducted only for the HRR study population in the MAGNITUDE study. Per the Health Canada indication and sponsor’s reimbursement request, this review was limited to the prespecified BRCA subgroup.

Secondary Outcomes

The testing of the key secondary efficacy end points (TSP and OS) was based on the stratified log-rank test. These end points were summarized using the Kaplan-Meier method. Cox proportional hazard models were used to estimate the HR and its 95% CI. A sensitivity analysis using a nonstratified log-rank test was performed for each end point. For OS, an additional sensitivity analysis censoring death due to COVID-19 was performed. The multiplicity of testing secondary outcomes was carried out.

For other efficacy end points (e.g., TPP), estimates of the time-to-event end points were obtained using the Kaplan-Meier estimates and stratified log-rank test of the survival distributions and a stratified Cox model was used to obtain the HR along with the associated 95% CIs. A sensitivity analysis using a nonstratified log-rank test was performed for each end point.

A prespecified multivariate Cox regression analysis, adjusting for important selected prognostic factors, was performed for OS. Each baseline prognostic factor from a predefined list was assessed individually for the prognostic value (P < 0.05) using a univariate Cox regression model. The selected factors with a prognostic value were included as covariates in a multivariate Cox regression model to assess their significance in the presence of the other factors. Backward selection methods were used to identify the final set of prognostic factors (exit P value = 0.10). The treatment group was then added to the final multivariate Cox proportional hazards model to assess the effect of treatment when adjusted for the selected prognostic factors. For OS in the BRCA population, PSA (P = 0.079), lactate dehydrogenase (P = 0.017), the ECOG PS score (0 versus 1) at baseline (P = 0.0103), the number of bone lesions at baseline (≤ 10 versus > 10) (P = 0.003), and the presence of visceral disease (yes versus no) (P = 0.002) were included as covariates in the final multivariate Cox regression model.

Analysis Populations

The analysis population is summarized in Table 9. The efficacy outcomes were analyzed based on the randomized analysis set for cohort 1. The safety analysis set included all randomized patients who received at least 1 dose of study treatment in cohort 1. The safety analysis was performed separately by cohort.

Results

Patient Disposition

A summary of patient disposition for the second interim analysis (data cut-off date of June 17, 2022) is presented in Table 10. Overall, 946 patients were screened, and 423 patients with HRR gene alterations were randomized to cohort 1. The reasons for screening failure specifically for the cohort 1 BRCA subgroup were not reported. Of the 423 patients with HRR alterations, 225 patients were enrolled in the BRCA subgroup. In the BRCA subgroup, 113 patients were randomized to the niraparib and abiraterone acetate with prednisone group and 112 patients to the placebo and abiraterone acetate with prednisone group. At the second interim analysis, 47 (41.6%) patients in the niraparib and abiraterone acetate with prednisone group and 29 (25.9%) patients in the placebo and abiraterone acetate with prednisone group were still receiving treatment. The rate of treatment discontinuation was higher in the placebo and abiraterone acetate with prednisone group compared to the niraparib and abiraterone acetate with prednisone group. The most common reason for discontinuation in both groups was disease progression (niraparib and abiraterone acetate with prednisone = 41.6%; placebo and abiraterone acetate with prednisone = 67.9%).

Table 9: Analysis Populations of MAGNITUDE Study

Note: Details included in Table 9 are from the sponsor’s Summary of Clinical Evidence.¹⁴

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Table 10: Summary of Patient Disposition of Cohort 1 BRCA Subgroup — MAGNITUDE Study, Second Interim Analysis

FAS = full analysis set; NR = not reported; PP = per-protocol.

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Baseline Characteristics

A summary of baseline patient demographics and disease characteristics of the cohort 1 BRCA subgroup are in Table 11. The baseline characteristics outlined in Table 11 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. There are some important imbalances in the baseline characteristics between the 2 treatment groups. Some of those important imbalances included, between the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone acetate with prednisone group, respectively, a tumour stage of T3 at initial diagnosis (|||||versus |||||), a metastasis stage of M0 (33.6% versus 50%) and M1 (61.9% versus 44.6%), a Gleason score of 7 (14.4% versus 24.1%) and a score of 8 or more (74.1% versus 64.3%), having surgery as a prior prostate cancer therapy |||||| |||||| ||||||, an ECOG PS score of 0 (61.1% versus 71.4%) and a score of 1 (38.9% versus 28.6%), and extent of disease in nodal at baseline (54.9% versus 44.6%). The study population was predominately white (72%), with an approximate mean age of 68 years. Most patients had a tumour stage of T3 (|||||), a Gleason score of 8 or more (69.2%), and an ECOG PS score of 0 (66.2%). A similar proportion of patients in both groups had prior prostate cancer therapy, in which hormone therapy was the most common therapy (approximately 95%), followed by surgery (approximately ||||).

Exposure to Study Treatments

A summary of treatment exposure is presented in Table 12. The median duration of treatment observed by the second interim data cut-off date (June 17, 2022) was longer in the niraparib and abiraterone acetate with prednisone group (|| months) compared to the placebo and abiraterone acetate with prednisone group (|||| months). More patients received 24 or more cycles of treatment in the niraparib and abiraterone acetate with prednisone group ||||||| compared to the placebo and abiraterone acetate with prednisone group (16.1%).

Table 11: Summary of Baseline Characteristics of Cohort 1 BRCA Subgroup — MAGNITUDE Study, Second Interim Analysis

AAP = abiraterone acetate with prednisone; ECOG PS = Eastern Cooperative Oncology Group Performance Status; M0 = metastasis stage 0; M1 = metastasis stage 1; NR = not reported; PSA = prostate-specific antigen; SD = standard deviation; T0 = tumour stage 0; T1 = tumour stage 1; T2 = tumour stage 2; T3 = tumour stage 3; T4 = tumour stage 4.

Note: Details included in Table 11 are from the sponsor’s Summary of Clinical Evidence.¹⁴

^aPatients having multiple lesions within each category are counted only once in the category but may be represented in more than 1 category.

^bIncludes lymph nodes not specified as pelvic or nonpelvic.

^cProstate local recurrence or progression.

^dIncludes patients with no bone lesions.

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Table 12: Summary of Patient Exposure of Cohort 1 BRCA Subgroup — MAGNITUDE Study, Second Interim Analysis

AA = abiraterone acetate; SD = standard deviation.

Note: Details included in Table 12 are from the sponsor’s Summary of Clinical Evidence.¹⁴

^aTreatment duration is defined as the following: (duration from the date of the first dose of study drug to the date of the last dose of study drug + 1) ÷ 30.4375. The study is ongoing.

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Concomitant Medications and Subsequent Therapies

Concomitant medications taken by more than 10% of patients in the BRCA subgroup of the MAGNITUDE trial are presented in Table 13. Most patients (|||||| took 1 or more concomitant medications during study treatment. Endocrine therapy was the most common concomitant treatment (|||||| in the niraparib and abiraterone acetate with prednisone group versus ||||| in the placebo and abiraterone acetate with prednisone group). Other anticancer therapies were prohibited during the study.

Of those patients who discontinued study treatment as of the second data cut-off date, more patients had received subsequent therapy for prostate cancer in the placebo and abiraterone acetate with prednisone group (66 [58.9%] patients) compared to the niraparib and abiraterone acetate with prednisone group (35 [31%] patients). The most common type of subsequent therapy was chemotherapy, with 28 (24.8%) patients in the niraparib and abiraterone acetate with prednisone group versus 44 (39.3%) patients in the placebo and abiraterone acetate with prednisone group. The most common chemotherapy used was docetaxel (15.9% versus 32.1%) followed by cabazitaxel (7.1% versus 11.6%) for the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone acetate with prednisone group, respectively. There were some imbalances between the groups in terms of subsequent therapies. In general, a higher percentage of patients in the placebo and abiraterone acetate with prednisone group received subsequent therapy compared to those in the niraparib and abiraterone acetate with prednisone group (58.9% versus 31%). The most prominent therapy was PARP inhibitor therapy in the placebo and abiraterone acetate with prednisone group — 22 of 66 (19.6%) patients, compared with 1 such patient in the niraparib and abiraterone acetate with prednisone group.

Table 13: Summary of Subsequent Treatment and Concomitant Medication of Cohort 1 BRCA Subgroup — MAGNITUDE Study, Second Interim Analysis

AR = androgen receptor; NR = not reported; PARP = poly-(ADP [adenosine diphosphate]-ribose) polymerase.

Note: Details included in Table 13 are from the sponsor’s Summary of Clinical Evidence.¹⁴

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Efficacy

Only those efficacy outcomes identified as important to this review are reported. The main findings presented for the BRCA subgroup of cohort 1 in the MAGNITUDE trial are from the second interim analysis (with a June 17, 2022, data cut-off date). Table 14 provides a summary of the efficacy results.

Overall Survival

The median follow-up time was 24.80 months for all patients in the BRCA subgroup. The median duration of follow-up was 20.18 months in the niraparib and abiraterone acetate with prednisone group and 19.98 months in the placebo and abiraterone acetate with prednisone group. Overall, 92 deaths occurred in both groups. The median OS was 29.27 months in the niraparib and abiraterone acetate with prednisone group and 28.55 months in the placebo and abiraterone acetate with prednisone group, with an adjusted HR of 0.68 (95% CI, 0.445 to 1.046) and stratified HR of 0.881 (95% CI, 0.58 to 1.33). The probability of OS at 12 months was 84.1% (95% CI, 75.9% to 89.7%) and 83.9% (95% CI, 75.7% to 89.5%), and the probability of OS at 24 months was 65.6% (95% CI, 55.4% to 74.1%) and 56.6% (95% CI, 45.5% to 66.3%) in the niraparib and abiraterone acetate with prednisone group and in the placebo and abiraterone acetate with prednisone group, respectively. Kaplan-Meier curves for OS are shown in Figure 1. The results from the nonstratified sensitivity analysis of OS for the BRCA subgroup were consistent with the stratified analysis.

Figure 1: MAGNITUDE Study, Kaplan-Meier Plot of OS — Cohort 1 BRCA Subgroup, FAS, Second Interim Analysis

AAP = abiraterone acetate with prednisone; FAS = full analysis set; OS = overall survival.

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Radiographic Progression-Free Survival

As rPFS was found to be statistically significant at the first interim analysis, no formal statistical testing was performed at the second interim analysis. By the time of the second interim analysis, 135 events had occurred overall. The median rPFS was 19.52 months in the niraparib and abiraterone acetate with prednisone group and 10.87 months in the placebo and abiraterone acetate with prednisone group, with a stratified HR of 0.55 (95% CI, 0.39 to 0.78) favouring niraparib and abiraterone acetate with prednisone. The probability of being event-free at 12 months was ||||| ||||||| ||||| || |||||| and ||||| |||||| || ||||||, and the probability of being event-free at 24 months was ||||| |||| ||| ||||| || |||||| and ||||| |||| ||| ||||| || |||||| in the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone acetate with prednisone group, respectively. Kaplan-Meier curves for rPFS are shown in Figure 2.

Figure 2: MAGNITUDE Study, Kaplan-Meier Plot of rPFS — Cohort 1 BRCA Subgroup, FAS, Second Interim Analysis

AAP = abiraterone acetate with prednisone; FAS = full analysis set; rPFS = radiographic progression-free survival.

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Time to Symptomatic Progression

Overall, 82 events had occurred by the time of the second interim analysis. The median TSP in the niraparib and abiraterone acetate with prednisone group was not estimated while the median TSP was 23.56 months in the placebo and abiraterone acetate with prednisone group, with a between-group HR of 0.54 (95% CI, 0.35 to 0.85; P = 0.0071). The probability of being event-free at 12 months was 83.4% (75% to 89.2%) and 75.1% (65.7% to 82.2%), and the probability of being event-free at 24 months was 68% (95% CI, 57.3% to 76.6%) and 47.8% (95% CI, 36.1% to 58.5%) in the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone acetate with prednisone group, respectively. Kaplan-Meier curves for TSP are shown in Figure 3.

Figure 3: MAGNITUDE Study, Kaplan-Meier Plot of TSP — Cohort 1 BRCA Subgroup, FAS, Second Interim Analysis

AAP = abiraterone acetate with prednisone; FAS = full analysis set; TSP = time to symptomatic progression.

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Time to Pain Progression

Overall, 74 events had occurred in both groups. The median TPP in the niraparib and abiraterone acetate with prednisone group was not estimated while the median TPP was 22.11 months in the placebo and abiraterone acetate with prednisone group, with a stratified HR of 0.70 (95% CI, 0.44 to 1.12; P = 0.133). The probability of being event-free at 12 months was 72.90% (62.9% to 80.6%) and 69.4% (59.3% to 77.5%), and the probability of being event-free at 24 months was 66.9% (95% CI, 55.9% to 75.8%) and 49.9% (95% CI, 36.2% to 61.3%) in the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone acetate with prednisone group, respectively. Kaplan-Meier curves for TPP are shown in Figure 4.

Figure 4: MAGNITUDE Study, Kaplan-Meier Plot of TPP — Cohort 1 BRCA Subgroup, FAS, Second Interim Analysis

AAP = abiraterone acetate with prednisone; FAS = full analysis set; TPP = time to pain progression.

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Change From Baseline in FACT-P Total Score

Results for the change from baseline in the FACT-P total score observed at cycle 25 (exploratory end point) are presented in Table 14 and Figure 5. The change from baseline in the FACT-P total score was an exploratory end point. The mean difference in absolute change from baseline in the FACT-P total score at cycle 25 between the 2 treatment groups was |||| |||| ||| ||||| || ||||| ||||||||| |||||.

Table 14: Summary of Key Efficacy Results of Cohort 1 BRCA Subgroup — MAGNITUDE Study, Second Interim Analysis

AAP = abiraterone acetate with prednisone; BICR = blinded independent central review; CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FACT-P = Functional Assessment Cancer Therapy–Prostate; HR = hazard ratio; LSM = least squares mean; NE = not estimable; NR = not reported; OS = overall survival; PFS2 = progression-free survival on first subsequent therapy; PSA = prostate-specific antigen; rPFS = radiographic progression-free survival; SE = standard error; TPP = time to pain progression; TSP = time to symptomatic progression; vs. = versus.

Note: Details included in Table 14 are from the sponsor’s Summary of Clinical Evidence.¹⁴

^aBased on a multivariate analysis, which accounted for PSA, lactate dehydrogenase, ECOG PS grade (0 vs. 1), number of bone lesions at baseline (≤ 10 vs. > 10), and the presence of visceral disease (yes vs. no).

^bThe P value was from a log-rank test stratified by stratification factors and was part of multiplicity adjustment.

^cThe P value was from a log-rank test stratified by stratification factors.

^dLSMs were derived based on the mixed-effects model with baseline, visit, treatment, and visit by treatment interaction as fixed effects, and individual patient as a random effect.

^eBased on an F-test comparing niraparib and AAP vs. placebo and AAP. For the fixed-effects test, the P value was used for testing the significance of the main fixed effects.

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Figure 5: Least Squares Mean Change from Baseline in FACT-P (Total Score) to Cycle 25, Mixed Model of Repeated Measures — Cohort 1 BRCA Subgroup, Randomized Analysis Set, Second Interim Analysis [Redacted]

AAP = abiraterone acetate with prednisone; FACT-P = Functional Assessment Cancer Therapy–Prostate.

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Harms

Harms data were reported for the safety analysis set from the second interim analysis (data cut-off date of June 17, 2022). The key harms results for the cohort 1 BRCA subgroup are presented in Table 15. Any AE occurring at or after the initial administration of study medication through the day of the last dose plus 30 days was considered treatment-emergent.

Adverse Events

Almost all patients in the study reported at least 1 TEAE (99.1% of patients in the niraparib and abiraterone acetate with prednisone group; 97.3% of patients in the placebo and abiraterone acetate with prednisone group). The most common TEAEs in the niraparib and abiraterone acetate with prednisone group versus the placebo and abiraterone acetate with prednisone group, respectively, were anemia (46.9% versus 25.9%), constipation (33.6% versus 19.6%), hypertension (32.7% versus 24.1%), and nausea (32.7% versus 20.5%). A larger proportion of patients in the niraparib and abiraterone acetate with prednisone group experienced at least 1 TEAE at a level of grade 3 and grade 4 compared to the placebo and abiraterone acetate with prednisone group (68.1% versus 50.9%).

Serious Adverse Events

At least 1 treatment-emergent SAE was reported in 40.7% of patients in the niraparib and abiraterone acetate with prednisone group, and in 25% of patients in the placebo and abiraterone acetate with prednisone group. Anemia and COVID-19 were the most common SAEs in the niraparib and abiraterone acetate with prednisone group (4.7%). In the placebo and abiraterone acetate with prednisone group, COVID-19 was the most frequent SAE (2.7%).

Withdrawals Due to Adverse Events

Study treatment withdrawal due to a TEAE was reported in 15% of patients in the niraparib and abiraterone acetate with prednisone group, and in 5.4% of patients in the placebo and abiraterone acetate with prednisone group. The most common TEAEs that led to treatment discontinuation in both treatment groups was COVID-19 (13.3% in the niraparib and abiraterone acetate with prednisone group versus 8.9% in the placebo and abiraterone acetate with prednisone group).

Mortality

In the niraparib and abiraterone acetate with prednisone group, deaths were reported for ||||| of patients on study treatment and ||||| in follow-up. In the placebo and abiraterone acetate with prednisone group, deaths were reported for || of patients on study treatment and ||||| of patients in follow-up. The majority of deaths coded as AEs in both groups was attributed to progressive disease in follow-up (||||| in the niraparib and abiraterone acetate with prednisone group; ||||| in the placebo and abiraterone acetate with prednisone group).

Notable Harms

Notable harms were selected based on serious warnings and precautions in the Health Canada product monograph for niraparib and abiraterone acetate with prednisone.³⁹ Anemia occurred in ||||| of patients treated with niraparib and abiraterone acetate with prednisone and ||||| of patients treated with placebo and abiraterone acetate with prednisone. The incidence of hypertension was ||||| in the niraparib and abiraterone acetate with prednisone group and ||||| in the placebo and abiraterone acetate with prednisone group. The percentage of patients who experienced fatigue in the niraparib and abiraterone acetate with prednisone group versus the placebo and abiraterone acetate with prednisone group was ||||| and ||||| respectively. Other notable harms reported in at least 1% of patients in the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone acetate with prednisone group, respectively, were the following: asthenia (||||| versus |||||), fluid retention (||||| versus |||||), neutropenia (||||| versus ||||), and hypokalemia (||||| versus ||||).

Table 15: Summary of Harms Results — MAGNITUDE Study, Cohort 1 BRCA Subgroup, Safety Analysis Set, Second Interim Analysis

AA = abiraterone acetate; AE = adverse event; SAE = serious adverse event.

^aThere was a frequency of 15% or greater in at least 1 treatment group.

^bThere was a frequency of 2% or greater in at least 1 treatment group.

^cAggregated data were from BRCA Clinical Study Report: supplement.⁴³

^d“On–study treatment death” was defined as death that occurs within 30 days of the last dose of the study drug.

^e“Follow-up death” was defined as death that occurs more than 30 days after the last dose of the study drug.

^fThis was from the product monograph on niraparib and abiraterone acetate with prednisone.³⁹

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.¹⁵

Critical Appraisal

Internal Validity

The MAGNITUDE study is an ongoing phase III, double-blind, multicentre RCT in which randomization has been performed using an Interactive Web Response System and stratification has been based on relevant prognostic factors. However, despite randomization, several key baseline factors were imbalanced between the 2 treatment groups, such as (but not limited to) body location of metastases, metastasis stage, and ECOG PS score. Differences in the baseline characteristics reduce the benefits of randomization and increase the probability that these measured and unmeasured factors would confound the results and make it difficult to determine the true effects of the treatments. In addition, there were imbalances in subsequent treatment between the 2 groups, which clinical experts noted could potentially confound the results. However, a multivariate Cox regression analysis was not performed to adjust for important prognostic factors within the BRCA subgroup, except for the OS outcome. For OS, an analysis was conducted to control for the following factors based on a stepwise approach: treatment (niraparib versus placebo), PSA levels, lactate dehydrogenase levels, ECOG PS grade (0 versus 1), number of bone lesions at baseline (≤ 10 versus > 10), and the presence of visceral disease (yes versus no). Therefore, imbalanced baseline characteristics may have introduced confounding effects on the remaining outcomes. The clinical experts consulted by CADTH indicated that the differences in baseline characteristics signalled the niraparib and abiraterone acetate group had more serious disease than the control group. Therefore, CADTH reviewers determined that any potential bias arising from the imbalances would go toward the null (i.e., against niraparib and abiraterone acetate with prednisone). There were major protocol deviations both in the first and second interim analyses, including enrolling patients in the study without satisfying the eligibility criteria, receiving disallowed concomitant treatments, administering the wrong treatment or incorrect doses, missing planned tumour assessments related to COVID-19, and having unblinded patients. The number of patients affected by protocol deviations in the BRCA subgroup specifically was not reported; therefore, it is unclear how the protocol deviations could influence the interpretation of the study results or pose a safety risk to the patients in this subgroup. Therefore, the magnitude and direction of potential bias cannot be determined.

To minimize the risk of differential measurement error, the trial performed tumour assessments using RECIST 1.1 criteria and radiographic scans were assessed by a BICR. There was low selective reporting bias, as the data were analyzed in accordance with the prespecified statistical plan. All interim analyses conducted were planned a priori with appropriately specified alpha spending methods, and secondary outcomes were adjusted for multiplicity. A number of patients were unblinded in both groups before the data cut-off date at the second interim analysis (11 [9.7%] patients in the niraparib and abiraterone acetate with prednisone group versus 21 [19%] patients in the placebo and abiraterone acetate with prednisone group), which could potentially increase the risk of detection bias, particularly for subjective assessment of patient-reported outcomes (i.e., TSP, TPP, FACT-P, and AEs). However, there was no apparent evidence that this biased the results in favour of niraparib and abiraterone acetate.

Furthermore, the niraparib and abiraterone acetate with prednisone group received more treatment cycles than the placebo and abiraterone acetate with prednisone group (33.0% versus 23. 7%), which can lead to biased or misleading conclusions about the effectiveness of the intervention. The longer treatment duration in the experimental group could lead to a larger observed effect because participants have been receiving the treatment for a longer period. This could artificially inflate the perceived effectiveness of the niraparib and abiraterone acetate with prednisone. However, it may also increase the likelihood of reporting AEs with additional treatments. The clinical experts noted that this also could indicate that patients stopped the treatment due to disease progression. CADTH reviewers could not determine whether the efficacy and safety results were influenced by this imbalance based on the available information, although it is anticipated to have had a limited effect, if any.

In terms of statistical analyses, all statistical analyses and interim analyses were prespecified in the MAGNITUDE study protocol and all planned outcomes were reported for the BRCA subgroup. Although the utility of the few sensitivity analyses is uncertain, they generally supported the results of the primary rPFS analysis. Interim analyses were prespecified in the protocol. However, the use of the group sequential design can potentially lead to operational bias in cases where knowledge of the interim analysis exists. O'Brien-Fleming boundaries were employed in the trial as a strategy wherein the level of statistical significance becomes progressively smaller in each analysis, while still reserving the majority of the alpha allocation for the concluding analysis.⁵³ However, the alpha spending only applied to the secondary outcomes (OS and TSP) and the primary objective related to rPFS was still considered to have been met at the first interim analysis. While the rPFS results appeared to have been maintained at the second interim, no formal statistical comparisons or thresholds were set. While the trial appears to have met its primary objective, given that there was limited supporting evidence from secondary outcomes — notably a lack of OS benefit for niraparib and abiraterone acetate with prednisone versus placebo and abiraterone acetate with prednisone — longer follow-up for the rPFS analyses would have been preferred to determine the clinical value of treatment with niraparib and abiraterone acetate with prednisone.

External Validity

The clinical experts consulted by CADTH considered the eligibility criteria and baseline characteristics of the MAGNITUDE trial generalizable to adult patients with mCRPC in the Canadian setting, although they identified some differences and the CADTH review team identified limitations to the external validity in comparison to the Health Canada–indicated population. The dosing and administration of niraparib and abiraterone acetate with prednisone in the MAGNITUDE trial was consistent with the Health Canada–approved product monograph. The experts also noted that abiraterone acetate with prednisone, an approved treatment option for patients with mCRPC in Canada, was an appropriate comparator.

The drug under review is indicated for “the treatment of adult patients with deleterious or suspected deleterious BRCA mutated (germline and/or somatic) mCRPC, who are asymptomatic/mildly symptomatic, and in whom chemotherapy is not clinically indicated.” Patients in the cohort 1 BRCA subgroup of the MAGNITUDE trial all had BRCA mutations confirmed before being enrolled in the trial, which aligns with the indicated population and reimbursement request. However, there were potential gaps and implementation challenges related to the evidence from the MAGNITUDE trial versus the population of patients included in the approved indication. First, CADTH noted that the indication is line-agnostic, whereas no patients in the MAGNITUDE trial had received prior systemic therapy in the mCRPC setting (i.e., received niraparib and abiraterone acetate with prednisone or placebo and abiraterone acetate with prednisone as first-line treatment in this setting). As a result, there is no direct comparative evidence for the use of niraparib and abiraterone acetate in the second-line, third-line, and later-line settings. Additionally, the clinical experts indicated that although asymptomatic patients can be easily identified, determining whether a patient is “mildly symptomatic” is a subjective judgment and may vary between clinicians. It is unclear if patients enrolled in the MAGNITUDE trial would be classified as asymptomatic or mildly symptomatic because the trial did not have eligibility criteria or report baseline characteristics directly related to this. Likewise, the clinical experts indicated that there is no objective definition for patients “in whom chemotherapy is not clinically indicated.” Health Canada reported that this component of the indication is based on the clinical judgment of the treating physician and was included to reflect the MAGNITUDE study exclusion criteria, where no prior chemotherapy in the mCRPC setting was allowed. However, the clinical experts consulted by CADTH for this review noted that any patient with mCRPC who is well enough for cytotoxic chemotherapy could be interpreted as having a clinical indication for it, although they and/or their clinicians may not wish to treat these patients with chemotherapy due to the associated adverse effects.

The clinical experts consulted by CADTH noted that excluding patients from the MAGNITUDE trial who previously received a novel second-generation AR targeted therapy, taxane-based chemotherapy, or more than 4 months of abiraterone acetate with prednisone before randomization in the mCRPC setting was appropriate in terms of establishing a purely mCRPC treatment-naive population to evaluate the efficacy of niraparib and abiraterone acetate with prednisone. However, they noted that the exclusion criteria reduce the generalizability of the trial results to the current population of patients with mCRPC in Canada as many patients would have received a second-generation AR targeted therapy in an earlier stage of the disease. The clinical experts noted that this might impact the choice of niraparib and abiraterone acetate with prednisone in the mCRPC setting because there would be a small population of these patients that would not be considered for taxane chemotherapy as first-line mCRPC treatment. Therefore, the CADTH review team noted that the trial population may reflect a relatively small population in clinical settings based on treatment history and eligibility. But, as also mentioned, implementing conditions to define the exact population may be difficult because of the lack of objective criteria for defining the characteristics aligned with the indication and MAGNITUDE trial eligibility.

Outcomes measured in the MAGNITUDE trial are those recommended by PCWG3¹¹ (i.e., OS, rPFS, and patient-reported outcomes such as symptoms and HRQoL) and some are clinically relevant and important to patients, based on the input received from stakeholders for this review. According to clinical experts, although rPFS is a relevant end point for assessing efficacy in trials, it is not an ideal primary outcome to assess the primary efficacy. This is because the emphasis on radiographic results to determine disease progression and treatment benefit in the mCRPC setting does not adequately reflect clinical practice, which involves a broader and more holistic assessment of determining treatment benefit. While there are data emerging that rPFS is a predictor of OS,^54-56 CADTH reviewers concluded that the association was difficult to interpret at the time of this review because of the varying definitions of rPFS used, relatively short follow-up periods used for the comparisons, and lack of prospective evidence. The clinical experts agreed that given the advancements in therapies and understanding of the natural history of prostate cancer, OS remains the most clinically relevant outcome.

Although abiraterone acetate with prednisone is an appropriate comparator as per the clinical experts consulted by CADTH, there are additional clinically relevant comparators used to treat patients with mCRPC in Canada. The clinical experts indicated that the treatment paradigm in the mCRPC setting has changed substantially since the MAGNITUDE trial began to become chemotherapy-focused in recent years due to emerging evidence and because most patients have received an ARPi in the mCSPC setting. The clinical experts consulted by CADTH for this review noted that they would not offer an alternate ARPi in the first-line setting in mCRPC if the patient received an ARPi in the nmCRPC or mCSPC settings, and they reported that almost every patient could theoretically receive chemotherapy in the mCRPC setting unless patients preferred not to receive it. Therefore, the absence of head-to-head evidence between niraparib and abiraterone acetate with prednisone versus chemotherapy represents an evidence gap.

The CADTH review team identified some aspects of the MAGNITUDE trial that may reduce its generalizability. First, clinical experts noted that the subsequent anticancer therapies patients received after their first-line treatment failed in this study are not fully representative of currently Canadian clinical practice. They indicated that in recent years, docetaxel has become the most common first-line treatment for mCRPC. Moreover, the MAGNITUDE trial did not include patients with a poor ECOG PS while clinical experts noted that enrolling patients with only an ECOG PS score of 0 and 1 is not entirely representative of patients with mCRPC as they expect to find patients with higher ECOG PS scores in Canadian practice. Additionally, based on the baseline characteristics of patients enrolled in the MAGNITUDE trial, the CADTH review team noted that Black and African American individuals may be underrepresented.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^12,13

• “High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word ‘likely’ for evidence of moderate certainty (e.g., ’X intervention likely results in Y outcome’).

• Low certainty: Our confidence in the effect estimate is limited — The true effect may be substantially different from the estimate of the effect. We use the word ‘may’ for evidence of low certainty (e.g., ‘X intervention may result in Y outcome’).

• Very low certainty: We have very little confidence in the effect estimate — The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as ’very uncertain.’”

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The reference points for the certainty of evidence assessment for OS was set according to the presence or absence of an important effect based on thresholds informed by the clinical experts consulted for this review. Although 1 clinical expert suggested a reference point for the certainty of evidence assessment for rPFS could be 25%, both clinical experts were uncertain of what the exact threshold for clinical importance would be; therefore, the target of the certainty of evidence assessment for rPFS was the presence or absence of any (non-null) effect. The reference point for the certainty of the evidence assessment for the FACT-P total score was set according to the presence or absence of an important effect based on thresholds identified in the literature. The target of the certainty of evidence assessment was the presence or absence of any (non-null) effect for the TSP and TPP due to the lack of a formal MID estimate; for harms events, due to the unavailability of the absolute difference in effects, the certainty of evidence was summarized narratively.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for niraparib and abiraterone acetate with prednisone versus placebo and abiraterone acetate with prednisone.

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor.

Indirect Evidence

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Objectives for the Summary of Indirect Evidence

The MAGNITUDE pivotal trial provides a head-to-head comparison between niraparib and abiraterone acetate with prednisone versus placebo and abiraterone acetate with prednisone in adult male patients with mCRPC with a BRCA gene alteration. However, direct evidence with respect to the comparative effectiveness of niraparib and abiraterone acetate with prednisone versus other mCRPC treatments in this population is currently unavailable. Therefore, an ITC is warranted to address this evidence gap.

Description of Indirect Comparison(s)

One ITC¹⁷ — described as an unanchored MAIC — was determined feasible by the sponsor. In the analysis, IPD from patients treated with niraparib and abiraterone acetate with prednisone in the MAGNITUDE pivotal trial was compared with the IPD from patients with first-line treatment mCRPC in the CAPTURE study.

The CAPTURE trial (Figure 6) was an observational, multiple-cohort database study focusing on Spanish patients with localized prostate cancer, mCSPC, or first-line treatment mCRPC (defined as patients who received any treatment after interrupting continuous androgen deprivation therapy with a luteinizing hormone-releasing hormone agonist, gonadotropin-releasing hormone agonist, or those who were not surgically castrated)⁵⁷ to describe the trajectory of the disease and explore clinical management and outcomes based on the HRR mutation status.

The data source for patients with first-line treatment mCRPC in the CAPTURE trial included the PROREPAIR-B trial (NCT03075735; a start date of January 2013 and actual completion date of December 2018), the PROSTAC trial (NCT02362620; a start date of May 2014 and estimated completion date of December 2020), the PROSABI trial (NCT02787837; a start date of May 2014 and estimated completion date of December 2020), and the PROSENZA trial (NCT02922218; a start date of June 2016 and estimated completion date of December 2020).⁵⁷

Figure 6: Schema of the CAPTURE Study [Redacted]

HRR = homologous recombination repair; LPC = localized prostate cancer; mCRPC = metastatic castration-resistant prostate cancer; mCSPC = metastatic castration-sensitive prostate cancer; PCa = prostate cancer.

Source: Protocol of the CAPTURE study.⁵⁷

ITC Design

Objectives

The objective of the unanchored MAIC was to determine the efficacy and safety of niraparib and abiraterone acetate with prednisone relative to other therapies in addition to placebo and abiraterone acetate with prednisone for the treatment of first-line adult patients with mCRPC and BRCA gene alterations.

Study Selection Methods

A systematic literature review of RCTs investigating niraparib and abiraterone acetate and other potentially relevant treatments was conducted by the sponsor. Details on the study selection criteria and methods are shown in Table 16. In total, 32 RCTs were identified. An assessment evaluating the feasibility of conducting an ITC with data from these trials was carried out.

Table 16: Study Selection Criteria and Methods for ITC Submitted by the Sponsor

AE = adverse event; EBRT = external beam radiotherapy; mCRPC = metastatic castration-resistant prostate cancer; nmCRPC = nonmetastatic castration-resistant prostate cancer; OS = overall survival; PARP = poly-(ADP [adenosine diphosphate]-ribose) polymerase; PFS =  progression-free survival; PFS2  =  progression-free survival on first subsequent therapy; RCT = randomized controlled trial; rPFS = radiographic progression-free survival; SAE = serious adverse event; TCC = time to initiation of cytotoxic chemotherapy; TPP = time to pain progression; TPSA = time to prostate-specific antigen progression; TSP = time to symptomatic progression.

^aThe latest literature search was conducted on March 14, 2023.

Source: Sponsor’s indirect treatment comparison report.¹⁷

ITC Analysis Methods

It was determined by the sponsor that neither a network meta-analysis nor an anchored MAIC with identified RCTs was feasible due to high between-study heterogeneity or lack of a common comparator. Only an unanchored MAIC using IPD from the MAGNITUDE trial and IPD from the CAPTURE study (i.e., a retrospective observational database study that involved the Spanish patient population with first-line treatment mCRPC)⁵⁷ was potentially feasible after examining patient populations (including eligibility criteria and baseline characteristics), interventions, and comparators, as well as outcomes (e.g., definitions, frequency of assessment) between the BRCA populations from the MAGNITUDE trial and those from the CAPTURE study.

In the unanchored MAIC, the population selected from the MAGNITUDE trial was the patient subgroup with mCRPC and BRCA1 or BRCA2 mutations. Based on different eligibility criteria, 3 populations were selected from the CAPTURE study, including:

• patients with first-line treatment mCRPC and BRCA1 or BRCA2 mutations (scenario 1)

• patients with first-line treatment mCRPC and BRCA1 or BRCA2 mutations, and having an ECOG PS of 1 or less (scenario 2)

• patients with first-line treatment mCRPC and BRCA1 or BRCA2 mutations, having an ECOG PS of 1 or less, having an absolute neutrophil count of 1.5 or greater multiplied by 10⁹/L, having hemoglobin of 9.0 g/dL or greater and being independent of transfusions for at least 30 days, having serum albumin of 3.0 g/dL or greater, having creatinine clearance of 30 mL per minute or greater, and having serum total bilirubin of 1.5 or less multiplied by the upper limit of normal (ULN) or direct bilirubin of 1 or less multiplied by the ULN (scenario 3).

In the unanchored MAIC, niraparib and abiraterone acetate with prednisone from the MAGNITUDE trial was compared with 3 treatments from the CAPTURE study, including enzalutamide only (160 mg once daily as continuous); a physician’s choice of either abiraterone acetate, cabazitaxel, docetaxel, or enzalutamide; and novel hormone therapy which referred to abiraterone, enzalutamide, darolutamide, or apalutamide.

The following issues were of note:

• Although the scenario 2 and scenario 3 populations were more similar to the patient cohort from the MAGNITUDE study, evidence in these 2 populations was not presented by CADTH because the additional restriction criteria in these 2 populations were not specified in the proposed indication for reimbursement, and because there was a lack of information regarding the 2 scenario populations. For example, the number of patients in the scenario 2 and scenario 3 populations was not even reported.

• Evidence regarding the comparators — a physician’s choice of either abiraterone acetate, cabazitaxel, docetaxel, or enzalutamide and novel hormone therapy — was not presented or appraised in the CADTH reimbursement review because these 2 comparators were referring to a group or category of treatments considered to be noninformative for the CADTH reimbursement review.

Table 17: List of Treatment Effect Modifiers and Prognostic Factors Identified by the Sponsor

Source: Sponsor’s indirect treatment comparison report.¹⁷

The sponsor identified a list of treatment effect modifiers and prognostic factors from literature (Table 17). From those reported in both the MAGNITUDE study and the CAPTURE study, 9 effect modifiers and prognostic factors were selected for weighting adjustment by the clinical experts consulted by the sponsor and shown as follows (ordered by rank of adjustment importance):

1. alkaline phosphatase (≤ ULN, > ULN)

2. lactate dehydrogenase (≤ ULN, > ULN)

3. age

4. baseline ECOG PS (0, 1)

5. number of bone lesions at baseline (≤ 10, > 10)

6. metastasis stage M1 at diagnosis (yes, no)

7. baseline PSA (log)

8. Gleason score at initial diagnosis (≤ 7, > 7)

9. presence of visceral metastasis (yes, no).

The rank of adjustment importance of each covariate was determined by a combination of opinions of clinical experts consulted by the sponsor, by its association with treatment assignment, and by its association with the outcome. The association between each covariate and treatment assignment was assessed in a univariate logistic regression model, where treatment was regressed against each covariate separately.

The propensity scores were determined with a logistic regression model fitted to the combined MAGNITUDE and CAPTURE study data, where treatment was regressed against the main effects of included covariates. Three assumptions were evaluated to determine the valid use of propensity score, including the positivity assumption (which required all participants to be eligible to receive niraparib and abiraterone acetate with prednisone or the relevant comparators), the overlap assumption (which required the distributions of propensity scores between the niraparib and abiraterone acetate with prednisone and comparator groups to be similar), and the balance assumption (which required the populations of the niraparib and abiraterone acetate with prednisone and comparator groups to be sufficiently balanced). To assess the positivity assumption, all patients were assessed to determine if they were contraindicated to niraparib and abiraterone acetate with prednisone or the comparators. Histograms and density plots were visually inspected to evaluate the overlap assumption. Covariate balance was assessed via the change in SMD between the niraparib and abiraterone acetate with prednisone and comparator groups before and after adjustment; SMDs greater than 0.2 were indicative of unacceptable balance.

For each scenario and treatment comparator, base-case analyses (i.e., covariates number 1 to number 6 were adjusted) and sensitivity analyses (i.e., covariates number 1 to number 9 were adjusted) in combination with different methods dealing with missing data (i.e., simple imputation or complete case analysis) were carried out. In other words, the sponsor carried out base-case adjustment with simple imputation (presented as primary analysis by the sponsor), base-case adjustment with complete case analysis, sensitivity adjustment with simple imputation, and sensitivity adjustment with complete case analysis. Additionally, an analysis without adjustment of any covariate was also conducted.

OS, rPFS (by BICR), time to PSA progression, time to second progression on next line (progression-free survival on first subsequent therapy), time to subsequent therapy, and time to treatment discontinuation were used to determine the relative efficacy or safety. The comparative effectiveness was summarized as HR (95% CI). The summary of outcomes measured in the MAGNITUDE trial and the CAPTURE trial database were presented in Table 18. The HR was estimated using a weighted Cox proportional hazards model, where the coefficient of the treatment coefficient informed the log-HR of niraparib and abiraterone acetate with prednisone versus the comparator. The corresponding standard error (SE) was estimated using a robust sandwich variance estimator to account for the uncertainty in the weights. A log-rank test was also conducted to test the null hypothesis that there was no difference in the survival observed between the niraparib and abiraterone acetate with prednisone and comparator groups.

Table 18: Summary of Outcomes Measured in MAGNITUDE and CAPTURE Studies

BICR = blinded independent central review; OS = overall survival; PCWG2 = Prostate Cancer Working Group 2; PCWG3 = Prostate Cancer Clinical Trials Working Group 3; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; rPFS = radiographic progression-free survival.

^aThe exact definition of disease progression (and therefore rPFS) may vary across data sources and studies included in the CAPTURE trial.

Source: Sponsor’s indirect treatment comparison report.¹⁷

Summary of Included Studies

The distribution of baseline characteristics before and after weighting the scenario 1 population (i.e., patients, selected from the CAPTURE study, with first-line treatment mCRPC and BRCA1 or BRCA2 mutations) is provided in Table 19. After weighting, characteristics such as age, baseline PSA, the Gleason score at initial diagnosis, and the presence of visceral metastases in the base-case analysis were still unbalanced between the MAGNITUDE study population and the CAPTURE study population.

Results

The median follow-up time for patients in the MAGNITUDE trial was 26.8 months while in the CAPTURE trial, the median follow-up time was 25.2 months. Efficacy and safety results from the primary analyses (i.e., base-case adjustment with simple imputation) in the scenario 1 population (i.e., patients, selected from the CAPTURE trial, with first-line treatment mCRPC and BRCA1 or BRCA2 mutations) are presented in Table 20. The results of all sensitivity analyses (data not shown) in the scenario 1 population favoured niraparib and abiraterone acetate with prednisone over comparators, with the majority showing statistical significance.

Overall Survival

The HR for OS among patients receiving enzalutamide only was |||| ||||| || ||||| (Table 20). However, the Kaplan-Meier curves crossed, indicating that the proportional hazards assumption did not hold (Figure 7).

Table 19: Baseline Characteristics of MAGNITUDE and CAPTURE Studies Before and After Reweighting

AAP = abiraterone acetate with prednisone; ALP = alkaline phosphatase; ECOG PS = Eastern Cooperative Oncology Group Performance Status; LDH = lactate dehydrogenase; M1 = metastasis stage 1; PSA = prostate-specific antigen; SD = standard deviation; SMD = standardized mean difference; ULN = upper limit of normal; vs. = versus.

Notes: Table 19 presents scenario 1, where all patients in the CAPTURE study with BRCA mutations were included.

SMDs with an absolute value of more than 0.2 are bolded.

Missing covariates were simply imputed in adjustments.

^aOne patient from the MAGNITUDE trial imputed to have LDH ≤ ULN, 1 MAGNITUDE patient imputed to have LDH > ULN .

^bThree patients from the MAGNITUDE trial imputed to have “no” Stage M1 at diagnosis, 2 MAGNITUDE patients imputed to have “yes” Stage M1 at diagnosis.

^cSix patients from the MAGNITUDE trial imputed to have Gleason score at initial diagnosis of > 7.

Source: Sponsor’s indirect treatment comparison report.¹⁷

Table 20: Efficacy and Safety Results of the Sponsor-Submitted ITC

CI = confidence interval; ITC = indirect treatment comparison; NE = not estimable; OS = overall survival; rPFS = radiographic progression-free survival; vs. = versus.

Note: Results were obtained from the base-case model with simple imputation in the scenario 1 population, where all patients in the CAPTURE study with BRCA mutations were included.

Source: Sponsor’s indirect treatment comparison report.¹⁷

Figure 7: Kaplan-Meier Curves of OS (Niraparib and Abiraterone Acetate With Prednisone vs. Enzalutamide, Scenario 1 Population, Base-Case Adjustment With Simple Imputation) [Redacted]

AAP = abiraterone acetate with prednisone; CI = confidence interval; Enza = enzalutamide; HR = hazard ratio; NE = not estimable; Nira = niraparib; OS = overall survival; sATT = average treatment effect on the treated in the sample; SE = standard error; vs. = versus.

Source: Sponsor’s indirect treatment comparison report.¹⁷

Radiographic Progression-Free Survival

The HR for rPFS among patients receiving enzalutamide only was |||| ||||| || ||||| (Table 20). The Kaplan-Meier curves are shown in Figure 8.

Time to Treatment Discontinuation

The HR (95% CI) for time to treatment discontinuation among patients receiving enzalutamide only was |||| ||||| || ||||| (Table 20). The Kaplan-Meier curves are shown in Figure 9.

Figure 8: Kaplan-Meier Curves of rPFS (Niraparib and Abiraterone Acetate With Prednisone vs. Enzalutamide, Scenario 1 Population, Base-Case Adjustment With Simple Imputation) [Redacted]

AAP = abiraterone acetate with prednisone; CI = confidence interval; Enza = enzalutamide; HR = hazard ratio; NE = not estimable; Nira = niraparib; rPFS = radiographic progression-free survival; sATT = average treatment effect on the treated in the sample; SE = standard error; vs. = versus.

Source: Sponsor’s indirect treatment comparison report.¹⁷

Figure 9: Kaplan-Meier Curves of Time to Treatment Discontinuation (Niraparib and Abiraterone Acetate With Prednisone vs. Enzalutamide, Scenario 1 Population, Base-Case Adjustment With Simple Imputation) [Redacted]

AAP = abiraterone acetate with prednisone; CI = confidence interval; Enza = enzalutamide; HR = hazard ratio; NE = not estimable; Nira = niraparib; sATT = average treatment effect on the treated in the sample; SE = standard error; vs. = versus.

Source: Sponsor’s indirect treatment comparison report.¹⁷

Critical Appraisal of the Sponsor-Submitted ITC

The sponsor assessed the feasibility of conducting ITCs and determined that only an unanchored MAIC was feasible. However, CADTH noted that the ITC analysis carried out by the sponsor was not a typical unanchored MAIC based on comparing IPD from 1 study with aggregate-level data from the other study. The analysis submitted to CADTH was more like a single exposure cohort (i.e., the niraparib and abiraterone acetate with prednisone group of the MAGNITUDE study) compared with an external comparator (e.g., enzalutamide-only group from the CAPTURE study) using population adjustment methods based on IPD from both groups.

Regardless of the study design, to reduce bias in the estimation of relative effectiveness, it is essential to make the cohort of patients treated with enzalutamide comparable to the cohort of patients treated with niraparib and abiraterone acetate with prednisone in terms of patient characteristics such as prognostic and effect modifying factors. The propensity score weighting adopted by the sponsor was considered an appropriate method to adjust for patient characteristics. However, there were still concerns regarding patient comparability. First, in the sponsor-submitted ITC analysis, more than 20 potential prognostic and effect modifying factors were identified from the literature (Table 17) that were considered relevant and comprehensive by the clinical experts consulted by CADTH. However, of the identified factors, only 9 factors (6 factors adjusted for the base-case analysis and an additional 3 factors for the sensitivity analysis) were involved in the propensity score weighting. It is understandable that many prognostic and effect modifying factors identified were not reported in the MAGNITUDE or CAPTURE trials, which made it impossible to adjust. Yet, with many relevant factors unadjusted, it is likely that the differences unaccounted for would bias the results, although the degree of the bias remains unknown. Second, the sponsor prespecified that it would be indicative of unacceptable imbalance in patient characteristics between groups if the absolute values of the SMDs between the weighted means or prevalence proportions of niraparib and abiraterone acetate with prednisone and comparator groups were greater than 0.2. After adjustment in the base-case analysis, the absolute values of the SMDs greater than 0.2 were identified for several prognostic factors such as age (SMD = 0.269), baseline PSA (SMD = 0.250), Gleason score at initial diagnosis (SMD = 0.460), and the presence of visceral metastases (SMD = 0.513), which suggested the existence of insufficient balance. Third, the sponsor attempted to use results from the scenario 2 and scenario 3 populations, which were more similar to the patient cohort from the MAGNITUDE study in terms of patient characteristics, to corroborate the findings from the scenario 1 population. However, evidence generated from these 2 scenario populations was not considered informative due to a lack of information (e.g., the number of patients in the scenario 2 and scenario 3 populations was not even reported).

There were other concerns that also increased CADTH’s uncertainty on the ITC estimates. First of all, the extent to which the discrepancy in the definitions of disease progression between the MAGNITUDE and CAPTURE studies would impact the ITC estimates was unclear (Table 18). The sponsor stated that “(t)he exact definition of disease progression (and therefore rPFS) may vary across data sources and studies included in CAPTURE” but “there are no meaningful differences in the definitions and assessments used in MAGNITUDE and CAPTURE that would lead to considerable bias in an ITC.”¹⁷ However, due to a lack of information, the potential bias due to differences in outcome definitions could not be ruled out. In addition, the sponsor-submitted ITC did not provide clear information on whether data from the CAPTURE trial was temporally relevant to the data from the MAGNITUDE trial. For instance, 1 data source of the CAPTURE study for the enzalutamide-only group (i.e., the PROSENZA study) started on June 2016 and was expected to be completed in December 2020 (no update on the ClinicalTrials.gov website has appeared since January 2020), while the MAGNITUDE trial started in February 2019 and is expected to be complete in 2027. The clinical experts consulted by CADTH noted that in the enzalutamide-only group, the proportion of patients with OS events (93.35% [18 of 19] of patients) or rPFS events (89.7% [17 of 19] of patients) was higher than 1 would find in clinical practice in recent years. In other words, the prognosis (e.g., survival) of the patients with mCRPC has been improving over time, according to the clinical experts consulted by CADTH. As a result, due to the potential difference in time periods between the MAGNITUDE and CAPTURE studies, it was possible that the treatment effect of enzalutamide was underestimated. Similarly, the discrepancy in geographic regions between the MAGNITUDE study (26 countries) and the CAPTURE study (1 country only [Spain]) might also result in biased ITC estimates due to the potential differences in the pattern of care and other factors (e.g., access to care) across regions. Finally, there was no assessment or discussion provided in the ITC report with respect to treatment-related factors (e.g., treatment adherence, concomitant treatments) in the MAGNITUDE and CAPTURE trials, which might threaten the validity of the treatment estimates of the ITC.

Lastly, findings from the ITC focused on the comparison between niraparib and abiraterone acetate with prednisone versus enzalutamide in the first-line treatment setting only. Therefore, there remains a gap in the indirect comparative evidence related to later lines of therapy.

Studies Addressing Gaps in the Systematic Review Evidence

No studies addressing gaps in the systematic review evidence were submitted by the sponsor.

Discussion

Summary of Available Evidence

The evidence included in this review consisted of 1 pivotal phase III, double-blind RCT and 1 ITC submitted by the sponsor.

One trial, the MAGNITUDE study (N = 423), met the inclusion criteria for the systematic review conducted by the sponsor, and a subgroup of patients in cohort 1 of the MAGNITUDE trial who had BRCA mutation (N = 225) enrolled in the study. The objective of the MAGNITUDE trial was to evaluate the efficacy and safety of niraparib and abiraterone acetate with prednisone versus placebo and abiraterone acetate with prednisone in adult patients with mCRPC who had not received prior systemic therapy in the mCRPC setting except for androgen deprivation therapy and had a potentially limited exposure (≤ 4 months) to abiraterone acetate with prednisone. Eligible patients were randomized to receive niraparib 200 mg and abiraterone acetate 1,000 mg with 10 mg prednisone taken orally once daily, or placebo and abiraterone acetate 1,000 mg with prednisone 10 mg daily administration. The primary outcome was rPFS assessed by BICR, and secondary outcomes were OS, TSP, and safety. HRQoL measured by the FACT-P questionnaire was assessed as an exploratory outcome. Despite randomization, there were some baseline patient characteristics that were imbalanced between treatment groups, including the metastasis stage at initial diagnosis, Gleason score at initial diagnosis, and ECOG PS score at baseline. The population was predominately white (72%), with an approximate mean age of 68 years. Most patients had a tumour stage of T3 and a Gleason score of 8 or more (69.2%). A similar proportion of patients in both groups had prior prostate cancer therapy, in which hormone therapy was the most common therapy (approximately 95%), followed by surgery (approximately 63.6%).

The sponsor-submitted ITC provided comparative evidence of niraparib and abiraterone acetate with prednisone versus enzalutamide. The analysis used IPD from patients with mCRPC treated with niraparib and abiraterone acetate with prednisone in the MAGNITUDE pivotal trial (N = 113) with the IPD from patients with mCRPC treated with first-line enzalutamide in the CAPTURE observational study (N = 19). Patients from the CAPTURE study were reweighted using propensity score weighting in an attempt to match the distribution of patient characteristics of the patient cohort from the MAGNITUDE study. Outcomes presented in the analysis included OS, rPFS, and time to treatment discontinuation.

Interpretation of Results

Efficacy

Preventing or delaying disease progression as well as prolonging life were identified as being important to patients. OS and rPFS were captured in the MAGNITUDE study, which corresponds with these patient needs. Managing symptoms that affect patients’ HRQoL and reducing skeletal pain were also highlighted by patient group input. In the MAGNITUDE trial, these outcomes were assessed by TSP, TPP, and FACT-P.

Outcomes assessed at given time points for OS, rPFS, TSP, TPP, and HRQoL (FACT-P total score) were mostly affected by concerns for imprecision (i.e., the 95% CIs crossed a threshold of clinical important benefit to include the potential for both benefit and harm) and study limitation (e.g., imbalanced baseline characteristics between the 2 treatment groups). As of the second interim analysis, there was no difference between the treatment groups for OS ([stratified HR = 0.88; 95% CI, 0.58 to 1.33] and [adjusted HR = 0.68; 95% CI, 0.44 to 1.04]). An empirically validated MID for OS has not been submitted to CADTH, but clinical experts suggested the clinical importance threshold of a 5% absolute difference between groups for OS rates at 12 months and 24 months. The probability of OS at 12 months was 84.1% for the niraparib and abiraterone acetate with prednisone group compared with 83.9% for the placebo and abiraterone acetate with prednisone group, with a 0.2% difference. The difference between the 2 groups for the probability of OS at 24 months was 9%, with a 95% CI that included both harm and benefit. It was noted that the OS results are still likely immature since they were based on 2 interim analyses and not on the final clinical cut-off. Health Canada issued a Notice of Compliance with conditions in part because of the immature nature of the OS data, although the regulator only had the results from the first interim analysis for its review. The Health Canada review report states the following: “…at Interim Analysis 1 with a BRCA subgroup specific OS HR = 0.96 [95% CI: 0.57, 1.63]), where the upper bound of the 95% CI exceeded 1. Given the uncertainty in the magnitude of survival benefit in the overall BRCA population, a Notice of Compliance with Conditions QN was recommended.”⁵⁹ Despite the additional follow-up time included with the second interim analysis (from median 18.6 months to 24.8 months) for this reimbursement review, there remains a low degree of certainty regarding the OS effects of treatment with niraparib and abiraterone acetate with prednisone versus placebo and abiraterone acetate with prednisone at both 12 months and 24 months. The 95% CI for the HR for OS between niraparib and abiraterone acetate with prednisone versus placebo and abiraterone acetate with prednisone was wide and the upper limit still crossed 1 at the later time point. Therefore, there is considerable imprecision in the OS estimates. The clinical experts consulted by CADTH agreed that there was a high degree of uncertainty in the OS estimates and that a longer follow-up time for the outcome is needed.

The MAGNITUDE trial determined that niraparib and abiraterone with prednisone were superior to placebo and abiraterone acetate with prednisone for the primary outcome of rPFS, particularly in the BRCA subgroup. The stratified HR for rPFS at the second interim analysis was 0.553 (95% CI, 0.392 to 0.782) in favour of niraparib and abiraterone acetate with prednisone, with a median of nearly 20 months versus 11 months for the placebo and abiraterone acetate with prednisone group. The difference in probabilities of being event-free for rPFS between the 2 treatment groups was ||| ||| ||||| at 12 months and at 24 months, respectively. An empirically validated MID for absolute differences in rPFS has not been submitted to CADTH. The clinical experts consulted by CADTH suggested the clinical importance threshold of rPFS could be a 25% difference between groups, although they were uncertain what the exact threshold of clinical importance would be. Based on using the null as a threshold, CADTH determined there was moderate certainty for clinical benefit in rPFS at 12 months and 24 months when comparing niraparib and abiraterone acetate with prednisone to placebo and abiraterone acetate with prednisone. Since any potential bias arising from the imbalances in baseline characteristics would go toward the null according to the clinical experts consulted by CADTH, and considering that the findings showed benefit for rPFS, there was less concern with regard to risk of bias. The GRADE assessment of the evidence demonstrated niraparib and abiraterone acetate with prednisone likely increases rPFS at both 12 months and 24 months compared to placebo and abiraterone acetate with prednisone, although the clinical importance of the difference between the groups is unknown. Furthermore, the clinical importance of rPFS as an outcome was unclear. The clinical experts consulted by CADTH indicated that rPFS is not an ideal primary outcome to assess efficacy of new treatments for mCRPC in terms of clinical practice, due to the emphasis on radiographic results to define disease progression. The clinical expert reported that in regular practice, disease progression is assessed using a combination of biochemical, symptom, and radiological assessments.

Furthermore, it is unclear if benefits in rPFS would translate into improvements in OS. For many new drugs that reported improvement in progression-free survival, further analysis has demonstrated no improvement in OS.⁶⁰ On the other hand, some studies have reported the correlation coefficient between rPFS and OS ranges from 0.72⁵⁴ to 0.3 between progression-free survival and OS in patients with mCRPC,⁶¹ which demonstrates inconsistent evidence on establishing the relationship between OS and rPFS. Therefore, CADTH reviewers concluded the association between rPFS and OS was difficult to interpret at the time of this review. This is due to different factors, including the varying definitions of rPFS used, the relatively short follow-up periods used for the comparisons, and a lack of prospective evidence. The clinical experts agreed that given the advancements in therapies and understanding of the natural history of prostate cancer, OS remains the most clinically relevant outcome.

Although Health Canada indicated that the primary efficacy results were supported by results suggesting TSP favoured niraparib and abiraterone acetate with prednisone,⁵⁹ there was low certainty for an increase in TSP at 12 months, and the evidence was very uncertain about the effect of niraparib and abiraterone acetate with prednisone on TPP at 12 months in comparison to placebo and abiraterone acetate with prednisone. A serious risk of bias due to a lack of balanced baseline characteristics between the 2 groups and concern for serious imprecision due to the 95% CI encompassing both important harm and important benefit decreased the certainty of the results. The clinical experts noted that differences between the 2 groups was not likely clinically meaningful for TSP and TPP; however, they considered the results for TSP and TPP to align with the direction of the results for the primary outcome (i.e., rPFS).

HRQoL was assessed based on the least squares mean change from baseline in the FACT-P total score. The trials demonstrated a trivial difference between the 2 groups in FACT-P total score at cycle 25. The established MID in the literature for the FACT-P total score is 10.⁵² Hence, certain concerns arose regarding risk of bias due to the presence of imbalanced baseline characteristics and relatively wide 95% CIs that crossed the null effect. These factors led to a downgrade of the certainty of evidence to moderate. The HRQoL outcomes were exploratory and as such, this evidence cannot support firm conclusions for this end point.

One concern noted by clinical experts consulted by CADTH was that the exclusion criteria might be restrictive and exclude a large number of patients in the mCRPC setting. Niraparib and abiraterone acetate with prednisone or prednisolone has a Health Canada–approved indication “for the treatment of adult patients with deleterious or suspected deleterious BRCA mutated (germline and/or somatic) mCRPC, who are asymptomatic/mildly symptomatic, and in whom chemotherapy is not clinically indicated.”³⁹ The participating drug programs and the CADTH review team identified potential gaps and implementation challenges related to the evidence from the MAGNITUDE trial versus the population of patients included in the approved indication. First, CADTH noted that the indication is line-agnostic, whereas no patients in the MAGNITUDE trial had received prior systemic therapy in the mCRPC setting (i.e., study treatment was first-line in this setting). As a result, there was no direct comparative evidence for the use of niraparib and abiraterone acetate with prednisone in the second-line, third-line, and later-line settings. Second, the clinical experts consulted by CADTH noted that determining whether a patient is mildly symptomatic is a subjective clinical decision and likely varies between clinicians and patients. Lastly, the clinical experts consulted by CADTH noted that it may be challenging to identify patients in whom chemotherapy is not clinically indicated. According to Health Canada, the “in whom chemotherapy is not clinically indicated” component of the indication is defined based on the clinical judgment of the treating physician, and this component of the indication was included to reflect the exclusion criteria of the MAGNITUDE study, which prohibited any prior chemotherapy in the mCRPC setting. However, the clinical experts consulted by CADTH noted that, in current practice, any patient who is well enough to receive cytotoxic chemotherapy would be considered clinically indicated for that type of treatment, but that chemotherapy may not be the patient’s therapy of choice. The clinical experts noted that if patients are not well enough to receive chemotherapy, they also may not be well enough to receive treatment with a PARP inhibitor such as niraparib. Overall, the clinical experts reported that there is no clear definition to identify patients in whom chemotherapy is not clinically indicated in clinical practice. Both the clinical experts and Health Canada agreed that it is defined based on the clinical judgment of the treating physicians. The sponsor noted that the language “not clinically indicated for chemotherapy” in the indication was a decision made at the regulatory level. Regarding the definition, the sponsor notes that chemotherapy being not clinically indicated does not mean chemotherapy-ineligible, but rather that it is a physician’s choice where the physician applies their clinical judgment to determine the right treatment option for their patient. The sponsor highlighted that the MAGNITUDE study did not specify inclusion criteria concerning chemotherapy ineligibility.

Although abiraterone acetate was an appropriate comparator when the MAGNITUDE trial was designed and started recruitment, the clinical experts highlighted that the treatment paradigm has substantially shifted since then toward the use of chemotherapy as the most common first-line treatment for patients with mCRPC. However, the evidence comparing niraparib and abiraterone acetate with prednisone and chemotherapy was not included in the submission to CADTH, which represents a gap in the available evidence, given the shared place in therapy for mCRPC. Of note, the clinician group noted that the drug under review would become a SOC in treatment-naive patients with mCRPC. In contrast, the clinical experts consulted by CADTH noted that while niraparib and abiraterone acetate with prednisone is used in patients with mCRPC who have been treated with enzalutamide, apalutamide, and darolutamide in the mCSPC setting, many medical oncologists would favour a change to chemotherapy for the first-line mCRPC in patients progressing on an ARPi. Therefore, the clinical experts indicated that niraparib and abiraterone acetate with prednisone would be positioned as a second-line and beyond treatment due to the decreasing number of patients who are ARPi-naive and considering the current evidence that does not show an improvement in OS or disease-specific outcomes. In contrast, clinician group input noted that niraparib and abiraterone acetate with prednisone would become a SOC in treatment-naive patients with mCRPC with HRR mutation, although the CADTH review team noted that the Health Canada–approved indication is for patients with BRCA mutations only. The CADTH review team notes that differences in the clinical expert input and clinician group input signals that there could be regional differences in clinical practice across Canada.

Findings from the sponsor-conducted ITC were considered of high uncertainty due to several limitations. First, as discussed in the Critical Appraisal of the Sponsor-Submitted ITC section, there was a comparability concern between the cohort of patients treated with enzalutamide only from the CAPTURE trial and the cohort of patients treated with niraparib and abiraterone acetate with prednisone from the MAGNITUDE trial. Second, the Kaplan-Meier curves for OS, which was considered as the most clinically relevant end point for patients with mCRPC, signalled that the proportional hazards assumption was violated, and no further analyses addressing the nonproportional hazard issue were found. Third, there was a lack of information in the sponsor-submitted ITC report for CADTH to determine, for example, whether the discrepancy in the definitions of disease progression (and therefore rPFS) between the MAGNITUDE and CAPTURE studies would impact the ITC estimates and whether data from the CAPTURE study was temporally relevant to the data from the MAGNITUDE study.

Harms

The overall frequency of TEAEs was different between the niraparib and abiraterone acetate with prednisone group and the placebo and abiraterone with prednisone group in the MAGNITUDE trial. Almost all patients experienced at least 1 TEAE in both treatment groups, with the most frequently reported TEAEs being anemia, constipation, hypertension, and nausea. A greater proportion of patients in the niraparib and abiraterone acetate with prednisone group experienced grade 3 or grade 4 AEs compared to those in the placebo and abiraterone acetate with prednisone group (68% versus 51%, respectively).

The frequency of deaths was nearly 12% in the niraparib and abiraterone acetate with prednisone group and 8% in the placebo and abiraterone with prednisone group; the majority of deaths in both groups was attributed to disease progression. Likewise, the frequencies of SAEs and WDAEs was approximately 2 to 3 times higher with the niraparib and abiraterone acetate with prednisone group than the placebo and abiraterone acetate with prednisone group. Assessment of the certainty of evidence also revealed it is likely that niraparib and abiraterone acetate with prednisone results in an increase in the proportion of patients who experience WDAEs and SAEs. There are a number of serious warnings and precautions in the Health Canada product monograph,³⁹ some of which were considered as notable harms in the CADTH review, including anemia, hypertension, fatigue, thrombocytopenia, asthenia, and fluid retention. In addition, the frequency of all notable harms was higher in the niraparib and abiraterone acetate with prednisone group. The patient groups that provided input for this review highlighted that there is a need for reducing side effects with treatments for mCRPC. However, the MAGNITUDE study harms results suggest that niraparib and abiraterone acetate with prednisone results in more clinically important AEs compared to placebo and abiraterone acetate with prednisone since a higher incidence of TEAEs, grade 3 or grade 4 AEs, SAEs, deaths, AEs leading to treatment discontinuation, and notable harms were reported with the niraparib and abiraterone acetate with prednisone group. This also signals a likely increase in the resources required to manage the AEs.

In the ITC, time to treatment discontinuation was defined in the MAGNITUDE trial as “time from treatment commencement to the date of treatment discontinuation due to any cause including death,” while it was defined in the CAPTURE trial as “time from the date of first dose to the date of the last dose/discontinuation of the treatment regimen or death.” Given that 18 of 19 patients in the enzalutamide group had OS events, there was only 1 patient who discontinued enzalutamide due to reasons other than death. However, the results showed that 43 of 113 patients in the niraparib and abiraterone acetate with prednisone group had OS events while 66 patients discontinued treatment due to any cause, including death, which indicated that 23 additional patients discontinued treatment due to nonfatal reasons. Therefore, due to a lack of further information, evidence regarding time to treatment discontinuation remained highly uncertain. Overall, there was a great deal of uncertainty as to the comparative safety of niraparib and abiraterone acetate with prednisone versus other treatments for mCRPC beyond what was observed in the MAGNITUDE trial.

Conclusion

mCRPC is an advanced stage of prostate cancer, and there is an unmet need for new treatments to prolong life, prevent disease progression, improve HRQoL, and reduce AEs. The MAGNITUDE trial is an ongoing, double-blind, phase III RCT, evaluating the efficacy and safety of first-line treatment with niraparib and abiraterone acetate with prednisone in patients with mCRPC. The trial did not demonstrate a benefit with niraparib and abiraterone acetate with prednisone compared to placebo and abiraterone acetate with prednisone on OS or HRQoL, which were identified as important outcomes by patients and clinical experts. Moderate certainty of evidence shows niraparib and abiraterone acetate with prednisone likely resulted in an increase in rPFS when compared with placebo and abiraterone acetate with prednisone; however, the clinical importance of this difference was uncertain. Results for TSP and TPP suggested that niraparib and abiraterone acetate with prednisone were favoured over placebo and abiraterone acetate with prednisone but the results for these efficacy outcomes were affected by concerns for imprecision and limitations in the trial, such as imbalanced baseline characteristics between treatment groups. Niraparib and abiraterone acetate with prednisone appeared to be associated with a higher frequency of TEAEs, grade 3 or grade 4 AEs, SAEs, WDAEs, and notable harms compared with placebo and abiraterone acetate with prednisone. Findings from the sponsor-conducted indirect comparison with enzalutamide were considered of high uncertainty due to several major limitations, such as the fact that many relevant prognostic and effect modifying factors were not adjusted as well as the fact that the proportional hazards assumption was likely violated for OS.

References

1.Canadian Cancer Society. What is Prostate Cancer? 2020; https://www.cancer.ca/en/cancer-information/cancer-type/prostate/prostate-cancer/?. Accessed by sponsor, no date provided.

2.Malone S, Shayegan B, Basappa NS, et al. Management algorithms for metastatic prostate cancer. Can Urol Assoc J. 2019;14(2):50-60. PubMed

3.So AI, Chi KN, Danielson B, et al. Update: Canadian Urological Association-Canadian Urologic Oncology Group guideline on metastatic castration-naive and castration-sensitive prostate cancer. Can Urol Assoc J. 2022;Sep 26 Epub ahead of print.

4.Fizazi K, Jenkins C, Tannock IF. Should docetaxel be standard of care for patients with metastatic hormone-sensitive prostate cancer? Pro and contra. Ann Oncol. 2015;26(8):1660-1667. PubMed

5.Jenkins V, Solis-Trapala I, Payne H, et al. Treatment experiences, information needs, pain and quality of life in men with metastatic castrate-resistant prostate cancer: results from the EXTREQOL study. Clin Oncol (R Coll Radiol). 2019;31(2):99-107. PubMed

6.Saad F, Ivanescu C, Phung D, et al. Skeletal-related events significantly impact health-related quality of life in metastatic castration-resistant prostate cancer: data from PREVAIL and AFFIRM trials. Prostate Cancer Prostatic Dis. 2017;20(1):110-116. PubMed

7.Antonarakis ES, Gomella LG, Petrylak DP. When and how to use PARP inhibitors in prostate cancer: a systematic review of the literature with an update on on-going trials. Eur Urol Oncol. 2020;3(5):594-611. PubMed

8.Canadian Cancer Society. Survival statistics for prostate cancer. 2023; https://www.cancer.ca/en/cancer-information/cancer-type/prostate/prognosis-and-survival/survival-statistics/. Accessed by sponsor, no date provided.

9.Francini E, Gray KP, Shaw G, et al. Impact of new systemic therapies on overall survival (OS) of patients (pts) with metastatic castration resistant prostate cancer (mCRPC) in a hospital-based registry. J Clin Oncol. 2018;36(6_suppl):203-203.

10.Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. PubMed

11.Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402-1418. PubMed

12.Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of clinical epidemiology. 2011;64(4):401-406. PubMed

13.Santesso N, Glenton C, Dahm P, et al. GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions. Journal of clinical epidemiology. 2020;119:126-135. PubMed

14.AKEEGA™ for the Treatment of mCRPC BRCA Patients [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: niraparib and abiraterone acetate with prednisone, 200 mg niraparib and 1000 mg abiraterone acetate, oral tablets. Toronto (ON): Jassen Inc.; June 6, 2023.

15.Clinical Study Report: JNJ-64091742. Second Interim Analysis of Secondary and Other Endpoints (IA2). A Phase 3, Randomized, Placebo-controlled, Double-blind Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for Treatment of Subjects With Metastatic Prostate Cancer [internal sponsor's report]. Toronto (ON): Janssen Inc.; 2023 Jan 05.

16.Janssen Inc. response to August 15, 2023 CADTH request for additional information regarding Akeega review: providing the absolute differences in Kaplan-Meier survival probabilities for time to event outcomes [internal sponsor's report]. Ottawa (ON): Janssen Inc.; 2023 Aug 15.

17.Indirect treatment comparisons of niraparib in combination with abiraterone acetate and prednisone in patients with first-line BRCA+ metastatic castration-resistant prostate cancer [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: niraparib/abiraterone acetate, 200 mg/1000 mg, oral Toronto (ON): Janssen Inc Canada; 2023 Jun 7.

18.Brenner DR, Weir HK, Demers AA, et al. Projected estimates of cancer in Canada in 2020. Can Med Assoc J. 2020;192(9):E199. PubMed

19.Canadian Cancer Society. Canadian Cancer Statistics. A 2022 Special Report of Cancer Prevalence. 2022; https://cancer.ca/en/research/cancer-statistics/canadian-cancer-statistics. Accessed 2023 Mar 27.

20.Shore N, Oliver L, Shui I, et al. Systematic literature review of the epidemiology of advanced prostate cancer and associated homologous recombination repair gene alterations. J Urol. 2021;205(4):977-986. PubMed

21.Canadian Cancer Statistics 2022. Canadian Cancer Society; 2022. https://cancer.ca/en/research/cancer-statistics. Accessed 2023 Mar 27. Accessed by sponsor, no date provided.

22.Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513-1520. PubMed

23.Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512. PubMed

24.Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-naive metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71(2):151-154. PubMed

25.Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65(11):1180-1192. PubMed

26.Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160. PubMed

27.Warner EW, Yip SM, Chi KN, Wyatt AW. DNA repair defects in prostate cancer: impact for screening, prognostication and treatment. BJU international. 2019;123(5):769-776. PubMed

28.S S, KA S, MP K, al e. Recommendations for the implementation of genetic testing for metastatic prostate cancer patients in Canada. Can Urol Assoc J. 2022;16(10):321-332. PubMed

29.Shaheen M, Allen C, Nickoloff JA, Hromas R. Synthetic lethality: exploiting the addiction of cancer to DNA repair. Blood. 2011;117(23):6074-6082. PubMed

30.Janssen Inc. response to July 10, 2023 CADTH request for additional information regarding Akeega review: perspective on the anticipated place in therapy for AKEEGA [internal sponsor's report]. Ottawa (ON): Janssen Inc.; 2023 Jul 10. City (PROV): Sponsor name.

31.Provisional Funding Algorithms. 2023; https://www.cadth.ca/cadth-provisional-funding-algorithms. Accessed 2023 Mar 27.

32.Tran K, McGill S. CADTH Health Technology Review: Treatment Sequences of Androgen-Targeted Agents for Prostate Cancer. Can J Health Technol. 2021;1(3):1-29.

33.Advanced/Metastatic Prostate Cancer. Clinical Practice Guideline GU-010 – Version 3. Edmonton (AB): Cancer Care Alberta; 2021: https://www.albertahealthservices.ca/assets/info/hp/cancer/if-hp-cancer-guide-gu010-met-prostate.pdf. Accessed by sponsor, no date provided.

34.Sandhu S, Attard G, Olmos D, et al. Gene-by-gene analysis in the MAGNITUDE study of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2022;40(16 Suppl):5020.

35.So AI, Chi K, Danielson B. 2022 UPDATE: Canadian Urological Association-Canadian Urologic Oncology Group guideline: metastatic castration-naive and castration-sensitive prostate cancer. Can Urol Assoc J. 2022;16(12):E581-E589. PubMed

36.Parker C, Castro E, Fizazi K, et al. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(9):1119-1134. PubMed

37.Mottet N, Cornford P, Van den Bemt RCN, al. e. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Eur Urol. 2022;79(2):243-262. PubMed

38.Schaeffer E, Srinivas S, Antonarakis ES, et al. NCCN Guidelines Insights: Prostate Cancer, Version 1.2021. J Natl Compr Canc Netw. 2021;19(2):134-143. PubMed

39.AKEEGA (niraparib/abirarterone acetate): 100 mg niraparib (as niraparib tosylate)/500 mg abiraterone acetate oral tablets [Product Monograph]. Toronto (ON): Janssen Inc.; 2023 Jun 7.

40.ZYTIGA® (abiraterone acetate): Abiraterone acetate tablets, 250 mg uncoated tablets, 500 mg film-coated tablets [Product Monograph]. Toronto (ON): Janssen Inc.; 2018 Mar 9.

41.XTANDI® (enzalutamide) Enzalutamide capsules, 40mg [Product monograph]. Markham (ON): Astellas Pharma Canada, Inc; 2019 Jan 14.

42.Chi KN, Rathkopf D, Smith MR, et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023:JCO.22.01649.

43.Clinical Study Report (CSR): 64091742PCR3001, Supplement. A Phase 3, Randomized, Placebo-controlled, Double-blind Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for Treatment of Subjects With Metastatic Prostate Cancer - MAGNITUDE [internal sponsor's report]. Toronto (ON): Janssen Research & Development LLC; 2023.

44.Janssen Research & Development LLC. NCT03748641: A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for Treatment of Participants With Metastatic Prostate Cancer (MAGNITUDE). ClinicalTrials.gov. Bethesda (MD): US National Library of Medicine 2023: https://clinicaltrials.gov/ct2/show/NCT03748641. Accessed by sponsor, no date provided.

45.Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994;23(2):129-138. PubMed

46.Robinson DW, Jr., Zhao N, Dawkins F, Qi M, Revicki D. Pain questionnaire performance in advanced prostate cancer: comparative results from two international clinical trials. Qual Life Res. 2013;22(10):2777-2786. PubMed

47.Gater A, Abetz-Webb L, Battersby C, et al. Pain in castration-resistant prostate cancer with bone metastases: a qualitative study. Health Qual Life Outcomes. 2011;9:88. PubMed

48.Logothetis CJ, Basch E, Molina A, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012;13(12):1210-1217. PubMed

49.Kuppen MCP, Westgeest HM, van den Eertwegh AJM, et al. Health-related Quality of Life and Pain in a Real-world Castration-resistant Prostate Cancer Population: Results From the PRO-CAPRI Study in the Netherlands. Clin Genitourin Cancer. 2020;18(3):e233-e253. PubMed

50.Esper P, Mo F, Chodak G, Sinner M, Cella D, Pienta KJ. Measuring quality of life in men with prostate cancer using the functional assessment of cancer therapy-prostate instrument. Urology. 1997;50(6):920-928. PubMed

51.Yount S, Cella D, Banik D, Ashraf T, Shevrin D. Brief assessment of priority symptoms in hormone refractory prostate cancer: the FACT Advanced Prostate Symptom Index (FAPSI). Health Qual Life Outcomes. 2003;1:69. PubMed

52.Cella D, Nichol MB, Eton D, Nelson JB, Mulani P. Estimating Clinically Meaningful Changes for the Functional Assessment of Cancer Therapy—Prostate: Results from a Clinical Trial of Patients with Metastatic Hormone-Refractory Prostate Cancer. Value Health. 2009;12(1):124-129. PubMed

53.Adaptive and Novel Trial Designs: An Overview of Key Methodologies and Issues in Critical Appraisal. Ottawa (ON): CADTH; 2018 https://www.cadth.ca/sites/default/files/pdf/CP0008_Novel_Trial_Designs_Report.pdf. Accessed by sponsor, no date provided.

54.Morris MJ, Molina A, Small EJ, et al. Radiographic progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302 results. J Clin Oncol. 2015;33(12):1356-1363. PubMed

55.Rathkopf DE, Beer TM, Loriot Y, et al. Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial. JAMA Oncol. 2018;4(5):694-701. PubMed

56.Lorente D, Castro E, Lozano R, et al. Correlation between time to PSA progression (TTPP), radiographic progression-free survival (rPFS) and overall survival (OS) in first-line abiraterone/enzalutamide (Abi/Enza) and docetaxel (Doc) treated patients in a prospective cohort study. J Clin Oncol. 2019;37(7_suppl):267-267.

57.Drug Reimbursement Review sponsor submission: niraparib/abiraterone acetate, 200 mg/1000 mg, oral [internal sponsor's package]. Toronto (ON): Janssen Inc.; 2023.

58.Cochrane Handbook for Systematic Reviews of Interventions. 2022; https://training.cochrane.org/handbook. Accessed by sponsor, no date provided.

59.Health Canada reviewer's report: Akeega (niraparib and abiraterone acetate) [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: niraparib and abiraterone acetate with prednisone, 200 mg niraparib and 1000 mg abiraterone acetate oral tablets. Toronto (ON): Janssen Inc; 2023 Jun 7. Toronto (Ontario): Janssen Inc.; 2023.

60.Tannock IF, Pond GR, Booth CM. Biased Evaluation in Cancer Drug Trials—How Use of Progression-Free Survival as the Primary End Point Can Mislead. JAMA Oncology. 2022;8(5):679-680. PubMed

61.Halabi S, Vogelzang NJ, Ou SS, Owzar K, Archer L, Small EJ. Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer. J Clin Oncol. 2009;27(17):2766-2771. PubMed

Appendix 1: Detailed Outcome Data

Note that this appendix has not been copy-edited.

As rPFS was found to be statistically significant at first interim analysis, no formal statistical testing was performed at second interim analysis Figure 10 shows the Kaplan-Meier curves of rPFS for the cohort 1 BRCA subgroup at the first interim analysis.

Figure 10: Kaplan-Meier Plot of Radiographic Progression-Free Survival by Central Review — Cohort 1 BRCA Subgroup

AAP = abiraterone acetate plus prednisone.

Source: MAGNITUDE Second Interim Analysis Clinical Study Report.⁴³

Pharmacoeconomic Review

Executive Summary

The executive summary comprises 2 tables (Table 1 and Table 2) and a conclusion.

Table 1: Submitted for Review

mCRPC = metastatic castration-resistant prostate cancer; NOC = Notice of Compliance.

Table 2: Summary of Economic Evaluation

ICER = incremental cost-effectiveness ratio; LY = life-year; mCRPC = metastatic castration-resistant prostate cancer; OS = overall survival; QALY = quality-adjusted life-year; RDI = relative dose intensity; vs. = versus.

Conclusions

Based on the CADTH clinical review of the MAGNITUDE trial, moderate certainty of evidence shows niraparib and abiraterone acetate with prednisone resulted in little improvement in radiographic progression-free survival (rPFS) when compared with abiraterone acetate with prednisone, although the findings are slightly below the clinically important threshold of a 25% difference suggested by clinical experts consulted by CADTH. CADTH’s clinical review reported that treatment with niraparib and abiraterone acetate with prednisone did not demonstrate a benefit in overall survival (OS) compared to abiraterone acetate with prednisone. Given the lack of direct comparative evidence, the sponsor submitted an indirect treatment comparison (ITC) using data from the CAPTURE study to estimate the relative clinical efficacy of niraparib and abiraterone acetate with prednisone versus enzalutamide. The CADTH clinical review reported that the results of this analysis were highly uncertain due to several major limitations, including patient comparability across studies, violation of the proportional hazards (PHs) assumption, outcome definitions, and the temporal relevance of the CAPTURE study.

In addition to these clinical limitations, CADTH identified several limitations with the sponsor’s economic submission that could be addressed through reanalysis. For the CADTH base-case analysis, CADTH revised the assumptions about OS, which led to more plausible estimates of survival benefit; applied a more realistic health state utility value in the progression-free health state; assumed that patients were treated until progression for all treatments; and removed relative dose intensity (RDI) assumptions. In CADTH’s base-case analysis, the incremental cost-effectiveness ratio (ICER) of niraparib and abiraterone acetate with prednisone compared to abiraterone acetate with prednisone was $271,803 per quality-adjusted life-year (QALY) gained (incremental costs = $133,835; incremental QALYs = 0.49). The probability of being cost-effective at a $50,000 per QALY gained threshold was 0%. For niraparib and abiraterone acetate with prednisone to be considered cost-effective at a $50,000 per QALY gained threshold compared to abiraterone acetate with prednisone, the price of niraparib and abiraterone acetate would need to be $3,213 per 28-day cycle, reflecting a price reduction of 61%. Given the limitations in the comparative clinical efficacy data for enzalutamide, a high degree of uncertainty remained in estimating the cost-effectiveness of niraparib and abiraterone acetate with prednisone versus enzalutamide. This comparison was explored through scenario analysis only.

CADTH identified key considerations regarding the alignment of the trial population, the reimbursement request, and the indicated population. First, the evidence generated by the MAGNITUDE trial was in patients receiving first-line treatment for metastatic castration-resistant prostate cancer (mCRPC), whereas the Health Canada indication does not specify treatment line. Clinical experts consulted by CADTH also indicated that a limited number of patients would meet the inclusion criteria of the MAGNITUDE trial, as they would have experienced prior exposure to abiraterone acetate with prednisone and enzalutamide in the castration-sensitive stage of their disease. In addition to the limitations in trial population alignment, there remains uncertainty regarding how “in whom chemotherapy is not clinically indicated” would be defined in clinical practice. Clinical experts consulted by CADTH noted that any patient with mCRPC fit enough for cytotoxic chemotherapy should be considered eligible for it, and that any decision that a patient is not indicated for chemotherapy is therefore based on the judgment of the treating physician rather than on consistent clinical criteria.

Consequently, CADTH was unable to estimate the cost-effectiveness of niraparib and abiraterone acetate with prednisone for the full population in which the treatment is likely to be used. CADTH’s estimates of the ICER and the price reduction needed to reach cost-effectiveness at a given willingness-to-pay threshold only apply to the narrow subset of patients meeting the MAGNITUDE trial’s inclusion criteria (i.e., first-line treatment in patients without prior exposure to abiraterone acetate or enzalutamide, and who had not been previously treated with chemotherapy in the mCRPC setting). The cost-effectiveness of niraparib and abiraterone acetate with prednisone as a subsequent therapy or in patients for whom chemotherapy is clinically indicated remains unknown.

Stakeholder Input Relevant to the Economic Review

This section is a summary of the feedback received from the patient groups, registered clinicians, and drug plans that participated in the CADTH review process. Patient input was received from the Canadian Cancer Society; it collected input from 24 patients and caregivers, the majority of whom were living in Canada, via an anonymous online survey. The majority of respondents (n = 21) identified as a person who has or has had mCRPC, and the remaining 3 identified as caregivers. No respondents had experience with niraparib and abiraterone acetate with prednisone. Patients with disease experience reported that they had experienced several physical and psychosocial struggles that impacted their quality of life. With regard to treatment experiences, the majority of patients had undergone 3 or more lines of therapy since their initial diagnosis with prostate cancer, with varying levels of side effects that impacted their daily life. The most common side effects reported by respondents were changes in libido, sexual function, or fertility, followed by hot flashes and fatigue. Patient input noted that there is a need for new therapies with fewer or less severe side effects.

Clinician input was received from the Ontario Health (Cancer Care Ontario) Genitourinary Cancer Drug Advisory Committee. The clinician input highlighted that first-line therapy for mCRPC is aimed at prolonging life and maximizing quality of life given that there is no available cure. Current treatment options were noted to include abiraterone acetate, enzalutamide, docetaxel, and radium-223, all given concurrently with androgen deprivation therapy (ADT). The input noted that in treatment-naive patients with mCRPC with BRCA mutations, niraparib and abiraterone acetate with prednisone would become a standard of care, as there are no other combination therapies for first-line treatment of patients in this setting.

Drug plan input noted that first-line treatment of mCRPC in Canada includes abiraterone acetate with prednisone, enzalutamide, taxane-based chemotherapy (i.e., docetaxel), or radium-223 (used for a small group of patients). Drug plan input also noted that in Ontario, olaparib may be a relevant comparator used as a first-line treatment of patients with mCRPC with a BRCA mutation if the patient was previously treated with abiraterone acetate or enzalutamide in the nonmetastatic castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer (mCSPC) setting; however, it is not currently reimbursed. Drug plan input raised questions regarding the eligibility of niraparib and abiraterone acetate with regard to defining “mildly symptomatic,” and whether patients who are not clinically indicated for chemotherapy or patients who decline chemotherapy despite clinical eligibility should be considered for treatment with niraparib and abiraterone acetate.

Several of these concerns were addressed in the sponsor’s model.

• The sponsor’s submitted model accounted for quality of life and length of life.

• The sponsor’s submitted model incorporated treatment-related adverse events (AEs).

CADTH was unable to address the following concerns raised from stakeholder input.

• The inclusion of olaparib as a comparator was not considered as it is not currently reimbursed for the relevant indication.

Economic Review

The current review is for niraparib and abiraterone acetate (Akeega) with prednisone for the treatment of adults with deleterious or suspected deleterious BRCA-mutated (germline and/or somatic) mCRPC who are asymptomatic or mildly symptomatic, and in whom chemotherapy is not clinically indicated.

Economic Evaluation

Summary of Sponsor’s Economic Evaluation

Overview

The sponsor submitted a cost-utility analysis (CUA) comparing costs and outcomes for niraparib and abiraterone acetate with prednisone with abiraterone acetate with prednisone, and enzalutamide.¹ The model population comprised adults with deleterious or suspected deleterious BRCA-mutated (germline and/or somatic) mCRPC who are asymptomatic or mildly symptomatic, and in whom chemotherapy is not clinically indicated.

Niraparib and abiraterone acetate consists of niraparib, a selective poly-(ADP [adenosine diphosphate])-ribose polymerase inhibitor and abiraterone acetate, a CYP17 inhibitor. Niraparib and abiraterone acetate is available in 2 strengths: a 100 mg niraparib/500 mg abiraterone acetate tablet or a 50 mg niraparib/500 mg abiraterone acetate tablet.² The recommended dose of niraparib and abiraterone acetate is 200 mg niraparib with 1,000 mg abiraterone acetate (i.e., two 100 mg/500 mg tablets) daily, to be taken with 10 mg prednisone or prednisolone. The cost per niraparib and abiraterone acetate tablet (regardless of strength) is $147.10, resulting in a daily cost of $294.20 and a corresponding annual cost of $107,457. The comparators in this analysis included abiraterone acetate with prednisone and enzalutamide, with corresponding annual per-patient costs of $11,186 and $42,654, respectively. The annual cost of prednisone is $16, to be taken with niraparib and abiraterone acetate, and abiraterone acetate. The sponsor applied RDI assumptions of 87.5% for niraparib and abiraterone acetate, 96% for abiraterone acetate, and 87.5% for enzalutamide, which resulted in the following annual treatment costs (including prednisone costs as indicated) in the submitted model: $94,039 for niraparib and abiraterone acetate, $10,754 for abiraterone acetate, and $37,323 for enzalutamide.¹

The model used a 1-week cycle length and simulated costs, life-years (LYs), and QALYs for each treatment over a lifetime time horizon (10 years). The analysis was undertaken from the perspective of Canada’s publicly funded health care system. Costs and QALYs were discounted at a rate of 1.5% per annum and a half-cycle correction was applied.¹

Model Structure

The sponsor submitted a partitioned survival model with the following health states: progression-free, progressed disease (PD), and death (Figure 1). All patients entered the model in the progression-free state, at which time it was assumed they initiated first-line treatment for mCRPC. Patients could remain in the progression-free state or transition to the PD or death health states each cycle. Patients in the PD health state could remain in the PD state or transition to the death state. The proportion of patients who were progression-free, had PD, or were dead at any time was derived from survival extrapolations informed by rPFS and OS data from the MAGNITUDE trial and from an ITC. The proportion of patients in the PD health state was estimated as the difference between the proportion of living patients (estimated using the OS curve) and the proportion of progression-free patients (estimated from the rPFS curve).

Model Inputs

The baseline population characteristics used to inform the model were based on the MAGNITUDE trial and Institut national d’excellence en santé et en services sociaux (INESSS) Drug Submission Guidelines normative values for males.^1,3 The mean age applied in the model was 67.9 years (standard deviation [SD] = 8.9 years`), informed by the MAGNITUDE trial. The normative values for males from the INESSS Drug Submission Guidelines informed the mean weight (84.0 kg [SD = 8.4 kg]) and body surface area (1.98 m² [SD = 0.2 m²]).³

Clinical efficacy for niraparib and abiraterone acetate with prednisone and abiraterone acetate with prednisone was informed by the MAGNITUDE trial (second interim analysis), which had a median duration of follow-up of 24.8 months. Evidence for abiraterone acetate with prednisone was generated alongside placebo. Parametric survival modelling was used to extrapolate rPFS, OS, and time to treatment discontinuation (TTTD). The submitted model used jointly fitted models for rPFS because the PHs assumption was not violated. The sponsor chose the Weibull distribution for the base-case analysis based on clinical plausibility and statistical assessment. For OS, the sponsor fitted models individually for niraparib and abiraterone acetate with prednisone and abiraterone acetate with prednisone, using the gamma distribution and Gompertz distribution, respectively, because the PHs assumption was considered to be violated. Similarly, the PHs assumption was considered violated for TTTD and thus the sponsor fitted individual models for niraparib and abiraterone acetate with prednisone and abiraterone acetate with prednisone, choosing the Gompertz and gamma models, respectively.

Clinical efficacy for enzalutamide was incorporated into the model via a hazard ratio (HR) approach, with values obtained from ITCs using patient-level data from both the MAGNITUDE study and the CAPTURE study (a real-world database study). The CAPTURE study was an observational study in Spanish patients that analyzed the disease trajectory in patients with prostate cancer, including patients with mCRPC who were treated with enzalutamide. The submitted model applied covariate-adjusted HRs for rPFS and OS of 2.78 (95% confidence interval [CI], 1.49 to 5.26) and 1.67 (95% CI, 0.78 to 3.33), respectively. It was assumed that patients were treated with enzalutamide until they experienced disease progression (i.e., TTTD was equal to rPFS). All parametric distributions (rPFS, OS, and TTTD) were limited by the general population mortality statistics derived from Statistics Canada life tables.⁴

A health state utility value of 0.93 was used for the progression-free health state, which was derived from the EQ-5D-5L analysis of MAGNITUDE trial data using the value set from Andrade et al. (2020).⁵ The postprogression utility value applied in the sponsor’s base-case analysis (0.60) was derived from an observational study conducted in Europe (n = 602) that used the EQ-5D-3L instrument.⁶ The selected utility value represented patients with mCRPC who were post–chemotherapy treatment.⁶

The submitted model included costs associated with drug acquisition, treatment administration, diagnostic testing, end-of-life, medical resource use, AEs, and subsequent treatments. Drug acquisition and administration costs were estimated for both preprogression treatments (i.e., niraparib and abiraterone acetate with prednisone, abiraterone acetate with prednisone, and enzalutamide) and subsequent treatments, and incorporated RDI assumptions as follows: 87.5% for niraparib and abiraterone acetate with prednisone and enzalutamide, 96% for abiraterone acetate with prednisone, and 100% for all subsequent treatments. Disease management costs included physician visits, laboratory tests, imaging, and procedures, and were calculated using a micro-costing approach informed by published literature, expert opinion, and relevant schedules of benefits.^7-15 The submitted model included a 1-time cost of diagnostic testing for all patients of $1,300, applied in the first cycle of the model. A 1-time cost of $31,319 at the time of death was applied.¹⁶

The model included grade 3 to grade 5 AEs with an incidence of 5% or greater in both the preprogression and postprogression (i.e., subsequent therapies) settings. The AE frequencies for niraparib and abiraterone acetate with prednisone and abiraterone acetate with prednisone were obtained from the MAGNITUDE trial. Preprogression AEs for enzalutamide were obtained from the PREVAIL trial, a double-blind phase III study of enzalutamide versus placebo in patients with metastatic prostate cancer.¹⁷ Postprogression AEs were sourced from pivotal trial publications for the corresponding subsequent therapies available in the model.^18-23 A per-cycle disutility was applied based on the type, frequency, and duration of AE for each treatment. The disutility values were derived from the literature and the duration was informed by expert opinion solicited by the sponsor.^24-27 Costs associated with AEs were obtained from the Ontario Case Costing Initiative Analysis Tool.²⁸ Preprogression AE costs were applied as a 1-time cost in the first cycle, and postprogression AE costs were applied as a 1-time cost at the time of disease progression.

In the submitted model, patients could receive up to 3 lines of subsequent therapy in the PD health state, which were dependent on the first-line treatment received. Subsequent treatments were modelled as a mix of treatments and costs were estimated using median treatment durations and completion rates, which were applied as a lump sum during the first incident cycle in the PD health state. Only costs related to subsequent therapies were captured in the submitted model, and not postprogression survival benefits.

Summary of Sponsor’s Economic Evaluation Results

All analyses were run probabilistically (1,000 iterations for the base case and scenario analyses). The deterministic and probabilistic results were similar. The probabilistic findings are presented as follows.

Base-Case Results

In the sponsor’s base-case analysis, compared with abiraterone acetate with prednisone, treatment with niraparib and abiraterone acetate with prednisone was associated with an incremental QALY gain of 0.92 and an incremental cost of $136,932, resulting in an ICER of $149,066 per QALY gained. Compared with enzalutamide, niraparib and abiraterone acetate with prednisone was associated with an incremental QALY gain of 0.87 and an incremental cost of $114,894, resulting in an ICER of $131,972 per QALY gained (Table 3). The probability of niraparib and abiraterone acetate with prednisone being cost-effective at a $50,000 per QALY gained threshold compared to abiraterone acetate with prednisone and enzalutamide was 0% for both comparisons. In the niraparib and abiraterone acetate with prednisone arm of the model, 2% of patients were alive at the end of the 10-year time horizon. Approximately 27% of the incremental QALYs in the sponsor’s base case were accrued beyond 36.8 months, the median follow-up time in the MAGNITUDE trial.

The sponsor’s model predicted that treatment with niraparib and abiraterone acetate with prednisone would result in a longer duration of life (i.e., LYs) compared to abiraterone acetate with prednisone and enzalutamide by 1.01 years and 0.84 years, respectively.

Table 3: Summary of the Sponsor’s Economic Evaluation Results, Pairwise

ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Note: The submitted analysis is based on the publicly available prices of the comparator treatments.

Source: Sponsor’s pharmacoeconomic submission.¹

Sensitivity and Scenario Analysis Results

The sponsor conducted several scenario and sensitivity analyses testing alternative parameter values and assumptions. These included alternative parametric distributions for rPFS, OS, and TTTD, subsequent treatment assumptions, and alternative utility values. The sponsor’s base case was most influenced by assumptions relating to the OS parametric distributions, with the ICER for niraparib and abiraterone acetate with prednisone compared to abiraterone acetate with prednisone ranging from $101,367 to $662,526 per QALY gained, depending on what distributions were individually fit to the treatment groups (with the other remaining as the base-case selection).

CADTH Appraisal of the Sponsor’s Economic Evaluation

CADTH identified several key limitations to the sponsor’s analysis that have notable implications for the economic analysis.

• The submitted model does not align with the indicated population. The approved indication for niraparib and abiraterone acetate with prednisone is for all adult patients with BRCA-deficient mCRPC, irrespective of the line of treatment. The MAGNITUDE trial was restricted to patients receiving their first line of treatment. As a result, there is no direct comparative evidence for the use of niraparib and abiraterone acetate in the second-line, third-line, and later-line settings. Clinical experts consulted by CADTH indicated that niraparib and abiraterone acetate with prednisone may be used in subsequent treatment lines due to the decreasing number of patients who are androgen receptor pathway inhibitor (ARPi)–naive (i.e., have received treatment with abiraterone acetate with prednisone, or enzalutamide).

  • CADTH was unable to address this limitation within the submitted model. As the trial only included patients receiving first-line mCRPC treatment, CADTH notes that the cost-effectiveness of niraparib and abiraterone acetate with prednisone used as a subsequent line of therapy is unknown.

• Unclear definition of chemotherapy eligibility in clinical practice. The indication for niraparib and abiraterone acetate with prednisone specifies that it is for use in patients “in whom chemotherapy is not clinically indicated.” However, there is uncertainty regarding how chemotherapy eligibility would be defined in clinical practice. Clinical experts consulted by CADTH noted that any patient with mCRPC fit enough for cytotoxic chemotherapy should be considered eligible for it, and that any decision that a patient is not indicated for chemotherapy is therefore based on the judgment of the treating physician rather than on consistent clinical criteria. Clinical experts consulted by CADTH indicated that there are 2 groups of patients that may be deemed ineligible for chemotherapy. The first group is patients who are too sick for chemotherapy, who clinical experts consulted by CADTH also indicated may mean they are not well enough for treatment with niraparib and abiraterone acetate with prednisone. The second group is patients who are considered too well for chemotherapy; these patients may express a preference to delay chemotherapy and avoid the associated AEs. It is uncertain how these groups of ineligible patients are distributed in the Canadian context, and evidence from the MAGNITUDE trial does not provide comparative evidence for niraparib and abiraterone acetate with prednisone in those subgroups.

  • CADTH notes that given this uncertainty, the cost-effectiveness results may not be generalizable to the patient population that is most likely to receive niraparib and abiraterone acetate with prednisone in Canada.

• The extrapolation of OS is uncertain. The submitted model predicted a gain in LYs such that treatment with niraparib and abiraterone acetate with prednisone would result in a longer duration of life compared to abiraterone acetate with prednisone and enzalutamide by 1.01 years and 0.84 years, respectively, despite finding no significant difference in OS during the trial period. At the time of the second interim analysis (with a data cut-off date of June 17, 2022) of the MAGNITUDE trial, the median OS was estimated to have a between-group HR of 0.88; however, the 95% CI was found to cross 1 (95% CI, 0.58 to 1.33). When fitting parametric distributions to support the long-term extrapolation of OS data, the sponsor selected parametric distributions based primarily on goodness-of-fit criteria and clinical plausibility. The sponsor chose different distributions for niraparib and abiraterone acetate with prednisone and abiraterone acetate with prednisone, selecting the gamma and Gompertz distributions, respectively. However, in the case where separate parametric models are fitted to individual treatment groups, it is best practice to select the same type of model unless substantial justification is provided, allowing the treatment effect to act on both the shape and scale parameters of the distribution.²⁹ While CADTH acknowledges that the sponsor chose OS models largely based on best fit statistics, it is important to consider that these tests assess the internal validity of the fitted models, but not the extrapolated time period. In light of this, CADTH had clinical experts assess the survival estimates predicted by several parametric distributions for each treatment strategy at specified time points over the modelled time horizon to validate survival curves in accordance with biological plausibility, with particular consideration of the extrapolated period.

  • The CADTH reanalysis used the gamma distribution for both niraparib and abiraterone acetate with prednisone and abiraterone acetate with prednisone, based on advice from clinical experts consulted by CADTH.

  • CADTH conducted a scenario analysis assuming equivalent OS for niraparib and abiraterone acetate with prednisone and abiraterone acetate with prednisone.

• The comparative efficacy of niraparib and abiraterone acetate with prednisone versus enzalutamide is highly uncertain. In the absence of head-to-head evidence for niraparib and abiraterone acetate with prednisone versus enzalutamide, the sponsor estimated comparative effectiveness using an ITC. CADTH’s clinical review team noted several methodological limitations with the ITC, including that the patient cohorts in the CAPTURE study and MAGNITUDE trial were not comparable, the PHs assumption for OS had been violated, there was uncertainty with regard to the definitions of disease progression, and the temporal relevance of data from CAPTURE was in question. Given the use of HRs derived from this ITC to inform the clinical efficacy of enzalutamide relative to niraparib and abiraterone acetate with prednisone, substantial uncertainty exists in the pairwise comparison between these treatments.

  • Given the inability to draw conclusions from the ITC, CADTH presented the pairwise comparison of niraparib and abiraterone acetate with prednisone versus enzalutamide as a scenario analysis.

• The health state utility values are uncertain and lack face validity. Clinical experts consulted by CADTH agreed that the utility values used in the sponsor’s submission lack face validity. Based on the Canadian utility norms from the 2013 Canadian Community Health Survey, the reported utility for those age 60 years to 70 years is 0.842.³⁰ The sponsor applied a baseline utility value of 0.929 to patients in the progression-free health state, implying that people with mCRPC have a higher level of well-being than the Canadian norm for people of a similar age to the modelled population. This utility value was derived from the MAGNITUDE trial data, collected using the EQ-5D-5L instrument. The health state utility value for the PD health state is derived from the literature: an observational study of patients with mCRPC in Germany and utilities that were derived using the EQ-5D-3L instrument. Based on this study, the sponsor applied a utility of 0.60 for the PD health state, which reflects patients with mCRPC who were post–chemotherapy treatment. CADTH recommends that all utilities used to populate models be derived from 1 source — that is, from the same population, assessed using the same instrument, and valued with the same preference weights.³¹ While clinical experts consulted by CADTH indicated that there would be a decline in quality of life for each line of subsequent therapy, it is unclear if the population included by Diels et al. (2015)⁶ appropriately captures all patients in the PD health state. Additional uncertainty arises with regard to the treatment landscape over time and across jurisdictions, which may not be reflective of Canadians with mCRPC.

  • To address the use of different instruments to estimate utility values for health states, the CADTH reanalysis used utility estimates derived from the EQ-5D-3L analysis of the MAGNITUDE trial data for the progression-free health state.

  • CADTH maintained the sponsor’s utility estimate for the PD health state; however, CADTH notes that there is a high degree of uncertainty with regard to the patient population included in the post–chemotherapy treatment group and timing of disease. Given that the progressed disease health state is made up of patients on multiple lines of treatment who clinical experts consulted by CADTH indicated would have different utility values, significant uncertainty remains with regard to a utility value that is representative of patients in this health state.

• TTTD was modelled inconsistently. In the submitted model, the sponsor fitted distributions to TTTD data from the MAGNITUDE trial to model time on treatment for niraparib and abiraterone acetate with prednisone and abiraterone acetate with prednisone, and assumed that treatment with enzalutamide would continue until disease progression. The sponsor capped time on treatment at progression-free survival such that patients would stop treatment at the time of disease progression regardless of the estimate of the TTTD curve. The TTTD data were not included as part of CADTH’s clinical review and thus have not been appraised. Further, clinical experts consulted by CADTH indicated that, with the exception of ADT (which is continued throughout the entire disease trajectory), oral treatments are typically discontinued at the time of disease progression, or when the next line of treatment is being initiated. In the sponsor’s base-case analysis, the selected distribution for abiraterone acetate with prednisone resulted in patients being treated until progression; however, niraparib and abiraterone acetate with prednisone was discontinued before progression, resulting in patients accruing health outcomes in the progression-free health state with no treatment cost. The inconsistent discontinuation timing as modelled does not align with the expectations of clinical experts who indicated that treatment-free intervals are not standard practice in the mCRPC setting.

  • CADTH assumed that all treatments were continued until the time of disease progression.

• The use of RDI underestimated drug acquisition costs. In the sponsor’s base-case analysis, the mean RDI observed in the MAGNITUDE trial was used to derive the drug acquisition cost (i.e., expected versus observed doses). The inclusion of RDI may underestimate the total treatment costs in real-world clinical practice as the dose received by patients may be different from the planned dose for several reasons. For oral therapies, Canadian pharmacies are likely to fill and dispense prescriptions in full. Therefore, it is unlikely that any unused tablets would result in lower prescription costs as unused tablets are unlikely to be recuperated.

  • In the CADTH reanalysis, RDI was assumed to be 100% for all treatments.

• Companion diagnostic tests were modelled inappropriately. The sponsor assumed that all patients in the submitted model accrued the cost of 1 diagnostic test. However, of the modelled treatments, only niraparib and abiraterone acetate with prednisone is reliant upon the results of the diagnostic test; therefore, the sponsor’s approach did not adequately capture the difference in costs associated with requiring germline-confirmed and/or somatically confirmed BRCA mutation for treatment with niraparib and abiraterone acetate with prednisone. In fact, it is likely that for each BRCA mutation identified, multiple patients had to be tested, which increases the potential costs associated with niraparib and abiraterone acetate with prednisone without accruing any health benefit since those patients would go on to be treated with a comparator treatment. Further, the sponsor’s approach did not incorporate relevant diagnostic test parameters, including test sensitivity and specificity. By not accounting for the possibility of false-positive results, the efficacy of niraparib and abiraterone acetate with prednisone may be overestimated if it is being used for patients without a BRCA mutation. The Specific Guidance for Treatments With Companion Diagnostics appendix of CADTH’s Guidelines for the Economic Evaluation of Health Technologies indicates that “the consequences of a false-positive companion diagnostic result should be fully modelled” due to the potential reduction in treatment effectiveness, harm from treatment, and associated resource consumption.³²

  • With the sponsor’s assertion that 10% of patients with mCRPC have either germline-confirmed or somatically confirmed BRCA mutation,³³ CADTH conducted a scenario analysis that assumed each modelled patient being treated with niraparib and abiraterone acetate accrued the cost of 10 diagnostic tests (i.e., approximately 10 tests conducted to identify 1 patient with a BRCA mutation).

• Poor modelling practices were employed. The sponsor’s submitted model included numerous IFERROR statements, which lead to situations in which the parameter value is overwritten with an alternative value without alerting the user to the automated overwriting. The systematic use of IFERROR statements makes thorough auditing of the sponsor’s model impractical and it remains unclear whether the model is running inappropriately by overriding errors.

  • CADTH was unable to address this limitation and notes that a thorough validation of the sponsor’s model was not possible.

Additionally, the following key assumptions were made by the sponsor and have been appraised by CADTH (refer to Table 4).

Table 4: Key Assumptions of the Submitted Economic Evaluation (Not Noted as Limitations to the Submission)

ADT = androgen deprivation therapy; mCRPC = metastatic castration-resistant prostate cancer.

CADTH Reanalyses of the Economic Evaluation

Base-Case Results

The CADTH base case was derived by making changes in model parameter values and assumptions in consultation with clinical experts. These changes, summarized in Table 5, included using alternative OS extrapolations, changing the utility value in the progression-free health state, assuming that patients were treated until progression, and removing RDI assumptions. The reanalysis is based on publicly available prices of the comparator treatments.

Table 5: CADTH Revisions to the Submitted Economic Evaluation

OS = overall survival; RDI = relative dose intensity; TTTD = time to treatment discontinuation; RAMQ = Régie de l'assurance maladie du Québec.

The CADTH base case focuses on the comparison of niraparib and abiraterone acetate with prednisone versus abiraterone acetate with prednisone, the only comparison for which head-to-head trial data were available. The CADTH base case resulted in an ICER of $271,803 per QALY gained for niraparib and abiraterone acetate with prednisone versus abiraterone acetate with prednisone (incremental cost = $133,835; incremental QALYs = 0.49) with a 0% probability of being cost-effective at a willingness-to-pay threshold of $50,000 per QALY gained. Cost-effectiveness was driven by the higher treatment cost of niraparib and abiraterone acetate with prednisone compared to abiraterone acetate with prednisone and longer progression-free survival, leading to patients remaining on therapy longer. The results of the stepped analysis are presented in Table 6.

Table 6: Summary of the Stepped Analysis of the CADTH Reanalysis Results (Deterministic)

ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year.

Given the magnitude of uncertainty surrounding the sponsor’s ITC and the long-term extrapolation of clinical benefits, CADTH was unable to derive a robust base-case estimate of the cost-effectiveness of niraparib and abiraterone acetate with prednisone versus enzalutamide. CADTH conducted an additional scenario analysis to estimate the cost-effectiveness versus enzalutamide (Appendix 4).

Scenario Analysis Results

A price reduction analysis based on the CADTH base case indicated that, at a willingness-to-pay threshold of $50,000 per QALY gained, niraparib and abiraterone acetate with prednisone would be considered cost-effective compared to abiraterone acetate with prednisone with a 61% price reduction (Table 7).

Table 7: CADTH Price Reduction Analyses

ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Additionally, CADTH conducted scenario analyses to determine the impact of alternative assumptions on the cost-effectiveness of niraparib and abiraterone acetate with prednisone. In the scenario assuming that OS is equivalent between niraparib and abiraterone acetate with prednisone and abiraterone acetate with prednisone, the ICER increased to $1,033,787 per QALY gained. Including the higher companion diagnostic tests for niraparib and abiraterone acetate with prednisone resulted in an ICER of $345,453 per QALY gained for niraparib and abiraterone with prednisone compared to abiraterone acetate with prednisone.

Issues for Consideration

• Drug plan input and feedback received from clinical experts consulted by CADTH noted changes in the treatment landscape for patients with prostate cancer in recent years. In many Canadian treatment settings, patients with mCSPC are receiving treatment intensification such that they are being treated with ARPis, including abiraterone acetate and enzalutamide. As a result, patients who progress to mCRPC have largely already received ARPi treatment and are unlikely to be treated with them again. For these patients, the most common approach to first-line mCRPC treatment is taxane-based chemotherapy (i.e., docetaxel). Both Health Canada and the clinical experts consulted by CADTH noted that determining chemotherapy eligibility is based on clinical judgment. The clinical experts consulted by CADTH indicated that, technically, all patients with mCRPC have an indication for chemotherapy and that it may be difficult to exclude patients in whom chemotherapy is not clinically indicated from treatment with niraparib and abiraterone acetate with prednisone. Given this, it is important to note that there is no direct comparative efficacy data for niraparib and abiraterone acetate with prednisone compared to docetaxel, and the cost-effectiveness and budgetary impact is unknown.

• At the time of writing this report, olaparib (Lynparza) in combination with abiraterone acetate and prednisone is under review for the first-line treatment of adult patients with deleterious or suspected deleterious germline and/or somatic BRCA-mutated mCRPC, for whom chemotherapy is not clinically indicated.³⁴ Given that this indication significantly overlaps with that being reviewed for niraparib and abiraterone acetate, olaparib may be a relevant comparator that could not be included in the present analysis. The cost-effectiveness of niraparib and abiraterone acetate with prednisone compared to olaparib with abiraterone acetate and prednisone is unknown. Additionally, it is uncertain how the introduction of olaparib with abiraterone acetate and prednisone would impact market share expectations and, subsequently, the estimated 3-year budget impact.

• To receive treatment with niraparib and abiraterone acetate with prednisone, patients must have a germline-confirmed or somatically confirmed BRCA mutation. As this will be the first first-line treatment for mCRPC that is dependent on genetic testing results, it is anticipated that there will be an increase in the overall number of genetic tests in patients with prostate cancer. Drug plan input noted that while some provinces may already test for BRCA mutations to treat with olaparib monotherapy as a subsequent therapy, genetic testing at diagnosis (i.e., before first-line treatment) is not standard practice in all CADTH-participating jurisdictions. The increase in genetic testing of patients with prostate cancer represents an added cost to the health care system. Further, the actual cost of companion diagnostic tests is uncertain due to the use of different platforms and testing methods (e.g., multipanel somatic gene testing, next-generation sequencing).

• The pan-Canadian Pharmaceutical Alliance concluded negotiations with a letter of intent for enzalutamide for multiple indications: mCSPC, nonmetastatic castrate-resistant prostate cancer, and first-line and subsequent-line mCRPC.^35-38 As such, enzalutamide has a confidential negotiated price and is currently funded by jurisdictional cancer formularies.^39,40 The CADTH reanalyses are based on the publicly available price of enzalutamide, which may be different than the confidential price and may influence the results of the cost-effectiveness and budget impact analyses (BIAs).

• The pan-Canadian Pharmaceutical Alliance concluded negotiations with a letter of intent for abiraterone acetate for the treatment of mCRPC and as such, abiraterone acetate has a confidential negotiated price and is currently funded by jurisdictional cancer formularies.^39-41 The CADTH reanalyses are based on the publicly available price of abiraterone acetate, which may be different than the confidential price and may influence the results of the cost-effectiveness and BIAs.

Overall Conclusions

Based on the CADTH clinical review of the MAGNITUDE trial, moderate certainty of evidence shows niraparib and abiraterone acetate with prednisone resulted in little improvement in rPFS when compared with abiraterone acetate with prednisone, although the findings are slightly below the clinically important threshold of a 25% difference suggested by clinical experts consulted by CADTH. CADTH’s clinical review reported that treatment with niraparib and abiraterone acetate with prednisone did not demonstrate a benefit in OS compared to abiraterone acetate with prednisone. Given the lack of direct comparative evidence, the sponsor submitted an ITC using data from the CAPTURE study to estimate the relative clinical efficacy of niraparib and abiraterone acetate with prednisone versus enzalutamide. The CADTH clinical review reported that the results of this analysis were highly uncertain due to several major limitations, including patient comparability across studies, a violation of the PHs assumption, outcome definitions, and the temporal relevance of the CAPTURE study.

In addition to these limitations, CADTH identified several limitations with the sponsor’s economic submission that could be addressed through reanalysis. For the CADTH base-case analysis, CADTH revised the assumptions about OS, which led to more plausible estimates of survival benefit; applied a more realistic health state utility value in the progression-free health state; assumed that patients were treated until progression for all treatments; and removed RDI assumptions. In CADTH’s base-case analysis, the ICER of niraparib and abiraterone acetate with prednisone compared to abiraterone acetate with prednisone was $271,803 per QALY gained (incremental costs = $133,835; incremental QALYs = 0.49). The probability of being cost-effective at a $50,000 per QALY gained threshold was 0%. Based on CADTH’s base-case analysis, for niraparib and abiraterone acetate with prednisone to be considered cost-effective at a $50,000 per QALY gained threshold compared to abiraterone acetate with prednisone, the price of niraparib and abiraterone acetate would need to be $3,213 per 28-day cycle, reflecting a price reduction of 61%. Given the limitations in the comparative clinical efficacy data for enzalutamide, a high degree of uncertainty remained in estimating the cost-effectiveness of niraparib and abiraterone acetate with prednisone versus enzalutamide; this comparison was explored through scenario analysis only.

CADTH identified key considerations regarding the alignment of the trial population, the reimbursement request, and the indicated population. First, the evidence generated by the MAGNITUDE trial was in patients receiving first-line treatment for mCRPC, whereas the Health Canada indication does not specify a treatment line. Clinical experts consulted by CADTH also indicated that a limited number of patients would meet the MAGNITUDE trial’s inclusion criteria, as they would have experienced prior exposure to abiraterone acetate with prednisone and enzalutamide in the castration-sensitive stage of their disease.

In addition to the limitations in trial population alignment, there remained uncertainty regarding how “in whom chemotherapy is not clinically indicated” would be defined in clinical practice. Clinical experts consulted by CADTH noted that any patient with mCRPC fit enough for cytotoxic chemotherapy should be considered eligible for it, and that any decision that a patient is not indicated for chemotherapy is therefore based on the judgment of the treating physician rather than on consistent clinical criteria. Consequently, CADTH was unable to estimate the cost-effectiveness of niraparib and abiraterone acetate with prednisone for the full population in which the treatment is likely to be used. CADTH’s estimates of the ICER and the price reduction needed to reach cost-effectiveness at a given willingness-to-pay threshold only apply to the narrow subset of patients meeting the MAGNITUDE trial’s inclusion criteria (i.e., patients without prior exposure to abiraterone or enzalutamide, and who had not been previously treated with chemotherapy in the mCRPC setting). The cost-effectiveness of niraparib and abiraterone acetate with prednisone as a subsequent therapy or in patients for whom chemotherapy is clinically indicated remains unknown.

References

1.Pharmacoeconomic evaluation [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Niraparib and abiraterone acetate, 100 mg and 50 mg tablets. Burlington (ON): Janssen Inc.; 2023 Jun 5.

2.Akeega (niraparib and abiraterone acetate): 100 mg and 50 mg tablet [product monograph]. Burlington (ON): Janssen Inc.; 2023.

3.INESSS Drug Submission Guidelines. Quebec (QC): Institut natioinal d'excellence en sante et en services sociaux (INESSS); 2022: https://www.inesss.qc.ca/fileadmin/doc/INESSS/Inscription_medicaments/Fiches_inscription/en/Submission_guidance_document.pdf. Accessed 2023 Jun 2.

4.Table: 13-10-0114-01. Life expectancy and other elements of the life table, Canada, all provinces except Prince Edward Island. Ottawa (ON): Statistics Canada; 2022: https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1310011401. Accessed 2023 Jun 30.

5.Andrade LF, Ludwig K, Goni JMR, Oppe M, de Pouvourville G. A French value set for the EQ-5D-5L. Pharmacoeconomics. 2020;38(4):413-425. PubMed

6.Diels J, Hamberg P, Ford D, Price PW, Spencer M, Dass RN. Mapping FACT-P to EQ-5D in a large cross-sectional study of metastatic castration-resistant prostate cancer patients. Qual Life Res. 2015;24(3):591-598. PubMed

7.Chi K. Professor, Department of Medicine, University of British Columbia. 2023.

8.Gotto G. Associate Professor, Departments of Surgery and Oncology, University of Calgary. 2023.

9.Saad F. Professor, Department of Urology, Université de Montréal. 2023.

10.Shayegan B. Associate Professor, Division of Urology, McMaster University. 2023.

11.Ontario Ministry of Health, Long Term Care. Schedule of Benefits, Physician Services Under the Health Insurance Act. 2022; https://www.health.gov.on.ca/en/pro/programs/ohip/sob/physserv/sob_master.pdf. Accessed 2022 Jul 22.

12.Ontario Ministry of Health, Long Term Care. Schedule of Benefits for Laboratory Services. 2020; https://www.health.gov.on.ca/en/pro/programs/ohip/sob/lab/lab_mn2020.pdf. Accessed 2022 Jul 20.

13.Saskatchewan Medical Association. SMA Fee Guide (uninsured services). 2022; https://www.sma.sk.ca/wp-content/uploads/2022/06/2022.06.01-SMA-Fee-Guide-April-1-2022-complete.pdf. Accessed 2023 Jun 2.

14.Ontario Ministry of Health, Long Term Care. Ontario Case Costing Initiative (Web Page) Costing Analysis Tool. 2017; https://hsimi.ca/occp/occpreports/. Accessed 2022 Jun 30.

15.Imaging Bone Metastases in Breast, Prostate, and Lung Cancers. Ottawa (ON): CADTH; 2012: https://www.cadth.ca/imaging-bone-metastases-breast-prostate-and-lung-cancers. Accessed 2023 Jun 30.

16.Krahn MD, Bremner KE, Zagorski B, et al. Health care costs for state transition models in prostate cancer. Med Decis Making. 2013;34(3):366-378. PubMed

17.Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424-433. PubMed

18.de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. PubMed

19.de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005. PubMed

20.Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197. PubMed

21.Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512. PubMed

22.de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-1154. PubMed

23.Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223. PubMed

24.Barqawi YK, Borrego ME, Roberts MH, Abraham I. Cost-effectiveness model of abiraterone plus prednisone, cabazitaxel plus prednisone and enzalutamide for visceral metastatic castration resistant prostate cancer therapy after docetaxel therapy resistance. J Med Econ. 2019;22(11):1202-1209. PubMed

25.Swinburn P, Lloyd A, Nathan P, Choueiri TK, Cella D, Neary MP. Elicitation of health state utilities in metastatic renal cell carcinoma. Curr Med Res Opin. 2010;26(5):1091-1096. PubMed

26.Tolley K, Goad C, Yi Y, Maroudas P, Haiderali A, Thompson G. Utility elicitation study in the UK general public for late-stage chronic lymphocytic leukaemia. Eur J Health Econ. 2013;14(5):749-759. PubMed

27.Tam VC, Ko YJ, Mittmann N, et al. Cost-effectiveness of systemic therapies for metastatic pancreatic cancer. Curr Oncol. Vol 202013:90-106. PubMed

28.Ontario Case Costing Initiative (OCCI). Toronto (ON): Ontario Health and Long-Term Care; 2017: https://data.ontario.ca/dataset/ontario-case-costing-initiative-occi. Accessed 2023 Jun 2.

29.Latimer N. Survival Analysis for Economic Evaluations Alongside Clinical Trials - Extrapolation with Patient-Level Data. (NICE DSU Technical Support Document 14). Sheffield, UK: Decision Support Unit, ScHARR, University of Sheffield; 2011: https://www.ncbi.nlm.nih.gov/books/NBK395885/pdf/Bookshelf_NBK395885.pdf. Accessed 2023 Jul 17.

30.Guertin JR, Feeny D, JE T. Age- and sex-specific Canadian utility norms, based on the 2013–2014 Canadian Community Health Survey. CMAJ. 2018;190(6):E155-161. PubMed

31.Guidelines for the economic evaluation of health technologies: Canada. 4th ed. Ottawa (ON): CADTH; 2017: https://www.cadth.ca/guidelines-economic-evaluation-health-technologies-canada-4th-edition. Accessed 2023 Jun 30.

32.Appendix - Specific Guidance for Treatments with Companion Diagnostics in Guidelines for the Economic Evaluation of Health Technologies: Canada - 4th Edition. Ottawa (ON): CADTH; 2019: https://www.cadth.ca/sites/default/files/pdf/cp0008-guidelines-for-economic-evaluation-of-health-technologies.pdf. Accessed 2023 Jun 30.

33.Abida W, Armenia J, Gopalan A, et al. Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making. JCO Precis Oncol. 2017;2017.

34.Olaparib Reimbursement Review. Ottawa (ON): CADTH; 2023: https://www.cadth.ca/olaparib-0. Accessed 2023 Aug 24.

35.pan-Canadian Pharmaceutical Alliance. Xtandi (enzalutamide). 2015; https://www.pcpacanada.ca/negotiation/20809. Accessed 2023 Aug 21.

36.pan-Canadian Pharmaceutical Alliance. Xtandi (enzalutamide). 2020; https://www.pcpacanada.ca/negotiation/21112. Accessed 2023 Aug 21.

37.pan-Canadian Pharmaceutical Alliance. Xtandi (enzalutamide). 2021; https://www.pcpacanada.ca/negotiation/21298. Accessed 2023 Aug 21.

38.pan-Canadian Pharmaceutical Alliance. Xtandi (enzalutamide). 2013; https://www.pcpacanada.ca/negotiation/20762. Accessed 2023 Aug 21.

39.Saskatchewan Cancer Agency. Drug Formulary. 2023; http://www.saskcancer.ca/health-professionals-article/drug-formulary. Accessed 2023 Aug 21.

40.Cancer Care Ontario: funded evidence-informed regimens. 2022; https://www.cancercareontario.ca/en/drugformulary/regimens. Accessed 2023 Aug 23.

41.pan-Canadian Pharmaceutical Alliance. Zytiga (abiraterone). 2014; https://www.pcpacanada.ca/negotiation/20774. Accessed 2023 Aug 21.

42.Shore N, Oliver L, Shui I, et al. Systematic literature review of the epidemiology of advanced prostate cancer and associated homologous recombination repair gene alterations. J Urol. 2021;205(4):977-986. PubMed

43.Shayegan B, Wallis CJD, Malone S, et al. Real-world use of systemic therapies in men with metastatic castration resistant prostate cancer (mCRPC) in Canada. Urol Oncol. 2022;40(5):192 e191-192 e199.

44.Chi KN, Sandhu S, Smith MR, et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol. 2023;01.

45.Canadian Cancer Statistics: A 2022 special report on cancer prevalence. Toronto (ON): Canadian Cancer Society; 2022: https://cdn.cancer.ca/-/media/files/research/cancer-statistics/2022-statistics/2022-special-report/2022_prevalence_report_final_en.pdf. Accessed 2023 Mar 30.

46.Uncovering the hidden costs of take-home cancer drugs. Ottawa (ON): PDCI Market Access; 2021: https://cdn.cancer.ca/-/media/files/about-us/media-releases/2022/thcd-report/uncovering-the-hidden-costs-of-take-home-cancer-drugs_08-11-21-2.pdf. Accessed 2023 Aug 21.

47.Ontario Ministry of Long-Term Care. Get coverage for prescription drugs. 2023; https://www.ontario.ca/page/get-coverage-prescription-drugs. Accessed 2023 Aug 23.

48.Nova Scotia Health Authority. Take-Home Cancer Drug Fund. 2022; https://www.nshealth.ca/financial-support-take-home-cancer-drug-fund. Accessed 2023 Aug 24.

49.Health PEI. Catastrophic Drug Program. 2023; https://www.princeedwardisland.ca/en/information/health-pei/catastrophic-drug-program. Accessed 2023 Aug 23.

Appendix 1: Cost Comparison Table

Note that this appendix has not been copy-edited.

The comparators presented in the following table have been deemed to be appropriate based on feedback from clinical experts and CADTH-participating drug plans. Comparators may be recommended (appropriate) practice or actual practice. Existing Product Listing Agreements are not reflected in the table and as such, the table may not represent the actual costs to public drug plans.

Table 8: CADTH Cost Comparison Table for Treatment of mCRPC

Note: All prices are wholesale from IQVIA DeltaPA (accessed June 2023), unless otherwise indicated, and do not include dispensing fees.

^aSponsor’s submitted price.¹

Appendix 2: Submission Quality

Note that this appendix has not been copy-edited.

Table 9: Submission Quality

Appendix 3: Additional Information on the Submitted Economic Evaluation

Note that this appendix has not been copy-edited.

Figure 1: Model Structure

Source: Sponsor’s pharmacoeconomic submission.¹

Appendix 4: Additional Details on the CADTH Reanalyses and Sensitivity Analyses of the Economic Evaluation

Note that this appendix has not been copy-edited.

Detailed Results of CADTH Base Case

Table 10: Disaggregated Summary of CADTH’s Economic Evaluation Results

AE = adverse event; ICER = incremental cost-effectiveness ratio; LY = life-year; QALY = quality-adjusted life-year.

Scenario Analyses

Table 11: Summary of CADTH’s Scenario Analysis Results