Reimbursement Review

Talazoparib (Talzenna)

Sponsor: Pfizer Canada ULC

Therapeutic area: Metastatic castration-resistant prostate cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

Introduction

Castration-resistant prostate cancer (CRPC) is defined by disease progression despite castrate levels of testosterone and may present as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of preexisting disease, and/or the appearance of new metastases. A patient may progress to metastatic CRPC (mCRPC) from metastatic castration-sensitive prostate cancer (CSPC) based on biochemical recurrence (characterized by rising PSA levels despite medical or surgical castration) or from nonmetastatic CRPC based on presentation of metastases (assessed radiographically). Progressing to mCRPC is characterized by increased symptomatic burden and reduced health-related quality of life (HRQoL). In Canada, the estimated prevalence of mCRPC is 1.2% to 2.1% of total prostate cancer cases. The expected 5-year survival for males diagnosed with prostate cancer is 91% for all stages combined, and for metastatic disease, the 5-year survival rate is approximately 28%.

According to the clinical experts consulted by Canada’s Drug Agency (CDA-AMC), the main treatment goals for patients with mCRPC are to prolong survival, delay disease progression, improve symptoms, and maintain HRQoL. Systemic therapies for the treatment of patients with mCRPC, and the sequencing of these treatments, depends on patient and disease factors, prior treatments used in the metastatic CSPC setting, and access, which varies across Canada. Docetaxel, cabazitaxel, abiraterone acetate, enzalutamide, radium-223 (for patients with bone-only metastatic disease), lutetium vipivotide tetraxetan, and olaparib, olaparib plus abiraterone acetate plus prednisone (AAP), or niraparib-abiraterone plus prednisone for patients with BRCA1, BRCA2, and/or ATM mutations, are all Health Canada approved, and most are available across the jurisdictions in Canada.

Talazoparib is a potent inhibitor of poly(adenosine diphosphate-ribose) polymerase (PARP) enzymes, which are involved in the homologous recombination repair (HRR) pathway. The approved Health Canada indication for talazoparib is in combination with enzalutamide for the treatment of adult patients with HRR gene-mutated mCRPC. The reimbursement request is aligned with the Health Canada–approved indication. The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of talazoparib 0.5 mg plus enzalutamide 160 mg, taken orally once daily in the treatment of adults with HRR gene-mutated mCRPC.

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups who responded to our call for input and from clinical experts consulted by CDA-AMC for the purpose of this review.

Patient Input

CDA-AMC received input from 2 patient groups, PROCURE and the Canadian Cancer Society (CCS). According to these inputs, the main concerns of patients included distress and treatment decisions, rising PSA levels after treatment, recurrence, hormone therapy and its side effects, as well as metastases. mCRPC mostly impacted patients in sexual activity, followed by the ability to work, maintaining a positive mental health, concentration, travel, exercise, or conducting household chores. Both patient groups clarified that patients' expectations with regard to new treatments included cancer control with fewer side effects, longer-lasting effects, delaying the onset or elimination of metastases, decreasing or maintaining PSA levels over a long period, convenient treatment regimens, prolonging life, and improving quality of life. Patients also expected treatments to be affordable, have better accessibility, better follow-up for long-term issues, and to be heard and taken seriously.

Clinician Input

Input From Clinical Experts Consulted for This Review

The clinical experts indicated that, because mCRPC is a terminal phase of prostate cancer, the unmet needs of patients would be new treatments that would prolong survival and maintain or improve quality of life, while exposing patients to minimal toxicity. Both clinical experts highlighted that the balance between treatment efficacy and quality of life would be important. The clinical experts noted that it remains unclear whether talazoparib plus enzalutamide would lead to a shift in the current treatment paradigm. This uncertainty stems from the increased use of androgen receptor pathway inhibitors (ARPIs) in patients with metastatic CSPC and nonmetastatic CRPC in recent years. They noted that many medical oncologists currently favour prescribing chemotherapy as first-line mCRPC treatment in patients who have previously progressed on an ARPI in the metastatic CSPC and nonmetastatic CRPC settings. They noted that if a treatment was used in metastatic CSPC, it is not likely for the patient to receive it again for first-line mCRPC (with the occasional exception of docetaxel if given at least 1 year prior). The clinical experts noted that talazoparib plus enzalutamide may have a limited role as a first-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; however, it may have a role in subsequent lines of therapy. The clinical experts indicated that patients best suited for talazoparib plus enzalutamide would be those who match the eligibility criteria of the TALAPRO-2 trial, which included first-line treatment for HRR gene-mutated mCRPC, and no contraindications to talazoparib or enzalutamide. The experts indicated that in clinical practice, a combination of radiographic, biochemical (e.g., PSA), and clinical parameters (i.e., decrease in disease-related symptoms) is used to determine whether a patient with mCRPC is responding or progressing while receiving treatment. They noted that, at the very least, assessments should be performed at 3-month intervals. The experts indicated that treatment with talazoparib plus enzalutamide should be discontinued if patients experience disease progression (as defined radiologically or clinically), treatment is intolerable, or if this is the patient’s preference. The experts noted that PARP inhibitors such as talazoparib have the potential to be toxic; therefore, patients receiving talazoparib plus enzalutamide should be under the care of a medical oncologist who can manage toxicity associated with the therapy.

Clinician Group Input

CDA-AMC received 1 input from the Ontario Health (Cancer Care Ontario) (OH [CCO]) Genitourinary Cancer Drug Advisory Committee. According to the clinician group input, the treatment goal is prolonging life and improving quality of life. The group noted that there are no cures currently available for metastatic prostate cancer and there is a need for treatments that prolong life. The group noted that talazoparib in combination with enzalutamide should be used in patients with treatment-naive mCRPC and that treatment with chemotherapy or an ARPI in the metastatic CSPC setting should not preclude eligibility for treatment with talazoparib plus enzalutamide, as per the TALAPRO-2 trial. The group noted that PSA and serial radiographic imaging would be used to monitor response to therapy and that significant side effects and progression of disease on imaging are among the factors for considering discontinuation of the treatment. The clinician group noted that medical oncologists, radiation oncologists, and urologists specialized in prostate cancer care are among the specialists or prescribers that would be required for prescribing the treatment. The OH (CCO) Genitourinary Cancer Drug Advisory Committee added that access to this (and other) combinations in this setting would also require ongoing efforts to ensure equitable, timely access to genomic testing of relevant alterations for all eligible males with prostate cancer living in Canada.

Drug Program Input

Input was obtained from the drug programs that participate in the CDA-AMC reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CDA-AMC recommendation for talazoparib plus enzalutamide:

• relevant comparators

• considerations for initiation of therapy

• considerations for discontinuation of therapy

• considerations for prescribing of therapy

• generalizability

• funding algorithm

• care provision issues.

The clinical experts consulted by CDA-AMC provided advice on the potential implementation issues raised by the drug programs (refer to Table 4).

Testing Procedure Considerations

According to the clinical experts consulted by CDA-AMC, public funding status and clinical practices for somatic or germline HRR mutation testing in patients with mCRPC are not consistent across Canada. Next-generation sequencing (NGS) panels for mutations in BRCA1, BRCA2, and ATM are generally available in jurisdictions. However, there are several other genes that are involved in the HRR pathway, the testing for which is not available or accessible to all patients. Therefore, a small proportion of patients who have mutations in genes other than BRCA1, BRCA2, or ATM may not be identified for eligibility for talazoparib depending on what testing panels are available in their region. There are existing implementation concerns related to testing within health systems, patients, and costs; however, minimal additional impact is anticipated if talazoparib were to be reimbursed.

Clinical Evidence

Systematic Review

Description of Studies

The TALAPRO-2 trial (cohort 2, N = 399) met the inclusion criteria for the systematic review conducted by the sponsor. An objective of the trial was to assess the efficacy and safety of talazoparib 0.5 mg plus enzalutamide 160 mg, taken orally once daily, or matched placebo plus enzalutamide in adult patients with HRR-deficient mCRPC. The trial enrolled adults with asymptomatic or mildly symptomatic mCRPC who had not started systemic cancer treatment after the diagnosis of CRPC (metastatic or nonmetastatic), with the exception of androgen deprivation therapy (ADT) and first-generation antiandrogen drugs. Patients were allowed to have previously received abiraterone acetate or docetaxel for CSPC but were ineligible to participate if they had received any prior treatment with second-generation ARPIs androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide), a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer. Patients were required to have had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1, and progressive disease at study entry. The approved Health Canada indication and reimbursement request aligned with the trial’s HRR-deficient population. The outcomes relevant to this review included the primary outcome of radiographic progression-free survival (rPFS), key secondary outcome of overall survival (OS), and HRQoL outcomes of time to deterioration of pain symptoms measured via the Brief Pain Inventory–Short Form (BPI-SF) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer (EORTC QLQ-PR25) functional and symptom scales and safety. The rPFS data are based on the primary analysis data cut-off date of October 3, 2022, and supportive data from the data cut-off date of September 3, 2024. All other outcomes are based on the data cut-off date of September 3, 2024. Overall, key baseline characteristics were generally balanced between treatment groups. The trial population was predominately white (68%), with a median age of 70 years. Most patients had an ECOG PS score of 0 (approximately 62%), indicating good overall performance; normal or mild renal impairment (approximately 90%); bone and soft tissue disease-site metastasis (approximately 84%); a Gleason score greater than or equal to 8 (approximately 74%); and had prior therapy with surgery or biopsy ██████████████ ████ and first-generation antiandrogens ██████████████ █████ In both groups, the most common detected HRR gene alteration was BRCA2 (33.8%), followed by ATM (21.6%), CDK12 (18.8%), and CHEK2 (17.8%). The talazoparib plus enzalutamide group had a ██████ ████ ████████ █████ ███ █████ ██████ █████ ███ █ ██████ ██████████ ██ ████████ ███ ███ ████████ ██████ █████████ ██████ ██████ ██████. These imbalances were likely due to chance, as ███ █████ ████████ ███████████████ ██ ████████ ████████ ████████ ███████ ███████

Efficacy Results

Only those efficacy outcomes and analyses of subgroups identified as important to this review are reported. The main findings for the efficacy outcomes for the TALAPRO-2 trial are from the data cut-off dates of October 3, 2022, and September 3, 2024. The boundary for statistical significance for the primary outcome of rPFS was met at the data cut-off date of October 3, 2022; therefore, rPFS data were reported descriptively at the September 3, 2024, data cut-off (i.e., not controlled for type I error). All other outcomes are based on the data cut-off date of September 3, 2024.

rPFS by Blinded Independent Central Review

In total, 170 events had occurred in both groups by the data cut-off date of October 3, 2022. The median duration of follow-up for rPFS was 17.5 months (range not reported) for the talazoparib plus enzalutamide group and 16.8 months (range not reported) for the placebo plus enzalutamide group. The median rPFS was not reached (95% confidence interval [CI], 21.9 months to not reached) in the talazoparib plus enzalutamide group and 13.8 months (95% CI, 11.0 months to 16.7 months) for the placebo plus enzalutamide group (log-rank test P < 0.0001), with a between-group hazard ratio (HR) of 0.45 (95% CI, 0.33 to 0.61) in favour of talazoparib plus enzalutamide. The Kaplan-Meier–estimated probability of rPFS at 12 months was ████ █ █████████████ ██████████ ██ █████ ████ ███ ████ ██ ██████ in the talazoparib plus enzalutamide and placebo plus enzalutamide groups, respectively, ████ █ █████████████ ██████████ ██ █████ ████ ███ ████ ██ ██████ The results of sensitivity analyses were consistent with the primary analysis. At the second data cut-off date of September 3, 2024, rPFS descriptive results were consistent with the first data cut-off date. The Kaplan-Meier–estimated probability of rPFS at 48 months was █████ ████ ███ ████ ██ █████ ██████ █████ ████ ███ ███ ██ █████ in the talazoparib plus enzalutamide and placebo plus enzalutamide groups, respectively, ████ █ █████████████ ██████████ ██ █████ ████ ███ ████ ██ █████. The rPFS results were consistent across the subgroup analyses of interest by BRCA alteration status (with or without) and prior treatment with novel hormonal therapy (NHT) or taxane therapy in favour of talazoparib plus enzalutamide.

Overall Survival

In total, 219 events had occurred in both groups by the data cut-off date of September 3, 2024. The median follow-up for OS was 44.2 months for the talazoparib plus enzalutamide group and ████ ██████ for the placebo plus enzalutamide group. The median OS was 45.1 months (95% CI, 35.4 months to not reached) for the talazoparib plus enzalutamide group and 31.1 months (95% CI, 27.3 months to 35.4 months) in the placebo plus enzalutamide group (log-rank test P < 0.0001), with a between-group HR of 0.62 (95% CI, 0.48 to 0.81) in favour of talazoparib plus enzalutamide. The results of sensitivity analyses were consistent with the primary analysis. The Kaplan-Meier–estimated probability of OS at 12 months was █████ ████ ███ ████ ██ █████ ██████ █████ ████ ███ ████ ██ █████ ███████ █████ ███████████ ████ ████ ███ ████ ██ █████; and OS at 48 months was █████ ████ ███ ████ ██ █████ ██████ █████ ████ ███ ████ ██ █████ █████████████ ███████████ █████ ████ ███ ████ ██ ██████ in the talazoparib plus enzalutamide and placebo plus enzalutamide groups, respectively.

Time to Deterioration of Pain by BPI-SF

At the data cut-off date of September 3, 2024, 58 events had occurred in both groups, and the median time to deterioration of pain was not reached in either group. The stratified between-group HR was 0.55 (95% CI, 0.33 to 0.94) in favour of talazoparib plus enzalutamide. The Kaplan-Meier–estimated probability of being free of pain progression at 12 months was █████ ████ ██ ███ █████████ ██████ █████ ████ ██ ███ █████████ █████████████ ███████████ ████ ████ ███ ████ ██ ██████, and at 48 months it ███ █████ ████ ██ ███ █████████ ██████ █████ ████ ██ ███ █████████ █████████████ ███████████ █████ ████ ███ ███ ██ ██████ in the talazoparib plus enzalutamide and placebo plus enzalutamide groups, respectively.

HRQoL by EORTC QLQ-PR25

At the data cut-off date of September 3, 2024, ██ ███ ██ ███ patients in the talazoparib plus enzalutamide group and ██ ███ ██ ███ patients in the placebo plus enzalutamide group contributed to almost all the EORTC QLQ-PR25 functional and symptom scale score analyses up to week 109; the incontinence aid symptoms score was informed by ██ ███ ██ patients, respectively. No comparison was made for the sexual functioning score due to limited data. The sexual activity score and the symptom scale scores were generally maintained and similar in both treatment groups up to week 109. Improvements in urinary and bowel symptoms favoured the talazoparib plus enzalutamide group, with urinary symptoms reaching the minimal important difference (MID) threshold of greater or equal to 5 points. All other scale scores did not reach the clinically important MID threshold.

Harms Results

Harms data reported in this section are from the data cut-off date of September 3, 2024. Almost all patients in both treatment groups reported at least 1 treatment-emergent adverse event (TEAE) (99.5% with talazoparib plus enzalutamide and 97.5% with placebo plus enzalutamide). The most frequently reported TEAEs in the talazoparib plus enzalutamide group were anemia (66.7% versus 18.6% with placebo plus enzalutamide), fatigue (34.8% versus 28.1% with placebo plus enzalutamide), and decreased neutrophil count (34.8% versus 7.0% with placebo plus enzalutamide); a higher proportion of patients in the talazoparib plus enzalutamide group reported these TEAEs than the placebo plus enzalutamide group. The most frequently reported TEAEs in the placebo plus enzalutamide group were fatigue (28.1% versus 34.8% with talazoparib plus enzalutamide), arthralgia (24.6% versus 16.7% with talazoparib plus enzalutamide), and back pain (23.1% versus 24.2% with talazoparib plus enzalutamide). A higher proportion of patients in the talazoparib plus enzalutamide group experienced at least 1 grade 3 or grade 4 TEAE ███████ versus the placebo plus enzalutamide group ████████ The incidence of serious TEAEs was higher in the talazoparib plus enzalutamide group (█████) versus the placebo plus enzalutamide group (██████ In both groups, ██████ █████ ████████ ███ ███████ █████ █████████ █████ ██ █████ were the most frequently reported serious TEAEs. A higher proportion of TEAEs that led to study treatment discontinuation was reported in the talazoparib plus enzalutamide group ██████ versus the placebo plus enzalutamide group ███████ with anemia being the most common reason █████ ███ ██████ Enzalutamide-only treatment discontinuation was reported for ████ of patients in the talazoparib plus enzalutamide group versus ████ in the placebo plus enzalutamide group. A lower proportion of deaths was reported in the talazoparib plus enzalutamide group (46.5%) versus in the placebo plus enzalutamide group (63.3%), with ███████ ███████████ being the primary reason for death in both groups ██████ ██████ ███████ The incidence of notable harms in both treatment groups was comparable and infrequent. Second primary malignancies (other than hematologic) occurred in ████ ███ ████ of patients, and embolic and thrombotic events occurred in 5.6% and 1.0% of patients in the talazoparib plus enzalutamide and placebo plus enzalutamide groups, respectively. There was 1 case of pneumonitis in each group.

Critical Appraisal

TALAPRO-2 was a randomized, double-blind, phase III trial. The patients and investigators were blinded to talazoparib or placebo, but enzalutamide was open label. This design was appropriate because different dosing and oral tablets across the 2 treatment groups may have made blinding to enzalutamide impractical. Randomization procedures, including stratification by prior NHT or taxane therapy for CSPC and HRR gene alteration status (deficient versus nondeficient or unknown), were appropriate and conducted by interactive response technology. The talazoparib plus enzalutamide group had a ██████ ████ ████████ █████ ███ █████ ██████ █████ ███ █ ██████ ██████████ ██ ████████ ███ ███ ████████ ██████ █████████ ██████ ██████ ██████. These imbalances were likely due to chance, as ███ █████ ████████ ███████████████ ██ ████████ ████████ ████████ ███████ ██████ and based on clinical expert feedback, unlikely to have confounded the effect between treatment and outcomes. Sample size and power calculations were based on the primary outcome of rPFS, and the trial was powered to detect significant differences for rPFS, but it was underpowered for the secondary outcome of OS. The analyses were preplanned with adequately justified stopping boundaries and the prespecified analyses of rPFS and OS were appropriately controlled for multiple comparisons. All other analyses were descriptive (i.e., not controlled for type I error). To minimize the risk of bias in the measurement of rPFS, the trial performed tumour assessments using Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1) criteria and radiographic scans were assessed by blinded independent central review (BICR). In addition, the findings of the sensitivity analyses for rPFS were consistent with the primary analysis. Patients were permitted to receive posttreatment anticancer medications after study treatment had been discontinued (36.9% in the talazoparib plus enzalutamide group versus 56.8% in the placebo plus enzalutamide group), which may influence the assessment of OS. Because no sensitivity analyses were performed to test treatment policy strategy for OS (e.g., exclude the effect of subsequent therapies), the estimated effect would be a combination of treatment with talazoparib plus enzalutamide versus placebo plus enzalutamide, plus subsequent treatments. Therefore, survival results might be partially attributable to treatments administered after disease progression rather than the study treatment itself, although without the necessary analysis, the direction and magnitude of bias are unclear. This is a relevant comparison; however, it is reflective of how the intervention and comparator and subsequent therapies would be used in practice in Canada. Based on the Clinical Study Report and statistical analysis plan, the proportional hazards assumption was not assessed or discussed. Despite the absence of these results, visual inspection of the Kaplan-Meier curves for rPFS and OS appear to indicate a clear separation (at approximately 3 months and 8 months, respectively), after which there appeared to be sustained proportionality throughout study treatment. HRQoL was assessed by the BPI-SF and EORTC QLQ-PR25 questionnaires, which have been validated in patients with metastatic prostate cancer with evidence of reliability, responsiveness, and MID. The result of these outcomes was subject to potential bias due to ████ ████ ███ ██ ███████ ████ ██ ████ ██████ ████ █ ██████ ██████████ ██ ███████ ████ ██ ███ ████████████████████ ██████ which could have biased the results in favour of talazoparib plus enzalutamide. For the EORTC QLQ-PR25, no models other than the mixed model for repeated measures were tested that applied alternative imputation methods or sensitivity analyses to assess the impact of missing data.

In general, the population requested for the reimbursement aligns with the approved Health Canada indication, and the dosing and administration of talazoparib plus enzalutamide were consistent with the approved product monograph. However, the trial provided talazoparib plus enzalutamide as first-line treatment only (i.e., patients had not received prior systemic therapy for mCRPC) while the approved Health Canada indication is line agnostic. Therefore, there is no direct comparative evidence for the use of talazoparib plus enzalutamide in later-line settings. The clinical experts consulted by CDA-AMC noted that many medical oncologists currently favour prescribing chemotherapy for the first-line treatment of mCRPC in patients who have previously progressed on an ARPI in the metastatic CSPC and nonmetastatic CRPC settings. Therefore, the clinical experts indicated that most clinicians would likely prescribe talazoparib plus enzalutamide as a second-line and beyond treatment due to the decreasing number of patients who are ARPI naive in the first-line mCRPC setting. According to the clinical experts, the eligibility criteria and baseline characteristics of the TALAPRO-2 trial are generalizable to adult patients with mCRPC in Canada, except that the trial did not include patients with an ECOG PS of greater than 1. The clinical experts indicated that patients with good ECOG PS or a score of 0 to 2 should be eligible for talazoparib plus enzalutamide, if they are able to tolerate the therapy. The experts noted that although enzalutamide was an appropriate comparator when the TALAPRO-2 trial was designed and executed, the current treatment paradigm has shifted since then toward the use of chemotherapy as the most common first-line treatment for patients with mCRPC. The evidence submitted to CDA-AMC did not include head-to-head comparisons between talazoparib plus enzalutamide and chemotherapy, which represents a gap in the available direct evidence given the potential shared place in therapy when used as first-line treatments for mCRPC.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform CDA-AMC expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.

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 rPFS and OS were set according to the presence or absence of an important effect based on thresholds informed by the clinical experts consulted for this review. A threshold could not be determined for time to deterioration of pain by BPI-SF; therefore, the target of certainty appraisal was any effect. The reference point for the certainty of the evidence assessment for EORTC QLQ-PR25 functional and symptom scale scores was set according to the presence or absence of an important effect based on a threshold informed by the literature.

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and 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 (rPFS, OS)

• HRQoL outcomes (time to deterioration of pain by BPI-SF, EORTC QLQ-PR25 functional and symptom scale scores).

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for talazoparib plus enzalutamide versus placebo plus enzalutamide.

Table 2: Summary of Findings for Talazoparib Plus Enzalutamide vs. Placebo Plus Enzalutamide for Patients With HRR Gene-Mutated mCRPC

BPI-SF = Brief Pain Inventory–Short Form; CI = confidence interval; EORTC QLQ-PR25 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer; HRR = homologous recombination repair; ITT = intention to treat; mCRPC = metastatic castration-resistant prostate cancer; NA = not applicable; NE = not estimable; NR = not reported; OS = overall survival; RCT = randomized controlled trial; rPFS = radiographic progression-free survival; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, 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.

^aRated down 1 level for serious imprecision due to the 95% CI for the between-group difference including the possibility of both important benefit and trivial effect; a between-group absolute risk difference of 20% (200 fewer or more events per 1,000 patients) at 12 months was clinically significant according to the clinical experts.

^bRated down 1 level for serious risk of bias due to few patients at risk at 48 months. A between-group absolute risk difference of 5% (50 fewer or more events per 1,000 patients) at 48 months was clinically significant according to the clinical experts. The point estimate and entire CI exceeded the threshold.

^cA between-group absolute risk difference of 10% (100 fewer or more events per 1,000 patients) at 12 months was clinically significant according to the clinical experts. There is no imprecision in the estimate (the point estimate and entire 95% CI for the between-group difference shows little to no difference).

^dA between-group absolute risk difference of 5% (50 fewer or more events per 1,000 patients) at 48 months was clinically significant according to the clinical experts. The point estimate and entire CI exceeded the threshold.

^eRated down 2 levels for very serious imprecision due to the 95% CI for the between-group absolute risk difference including the possibility of benefit and harm. No known minimal important difference so target of certainty appraisal was any effect.

^fRated down 2 levels for very serious risk of bias due to missing outcome data. No known minimal important difference so target of certainty appraisal was any effect. The point estimate and entire CI exceeded the null.

^gRated down 2 levels for very serious risk of bias due to missing outcome data. There is no imprecision in the estimate (the point estimate and entire 95% CI for the between-group difference shows little to no difference); based on literature, a 5-point change from baseline score was considered clinically important.

^hRated down 1 level for serious imprecision due to the 95% CI for the between-group difference including the possibility of both important benefit and little to no difference; based on literature, a 5-point change from baseline score was considered clinically important. Rated down 2 levels for very serious risk of bias due to missing outcome data.

ⁱRated down 1 level for serious imprecision due to the 95% CI for the between-group difference including the possibility of both important harm and little to no difference; based on literature, a 5-point change from baseline score was considered clinically important. Rated down 2 levels for very serious risk of bias due to missing outcome data.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence and additional information provided in the submission.

Long-Term Extension Studies

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

Indirect Comparisons

One sponsor-submitted matching-adjusted indirect comparison (MAIC) was submitted to inform the pharmacoeconomic model and fill gaps in the comparative evidence for other treatments of interest for adults with HRR gene-mutated mCRPC.

Description of Studies

A systematic literature review identified 49 unique RCTs, of which 42 had published results that met the inclusion criteria for first-line treatments in adults with mCRPC. Three trials (TALAPRO-2, PROpel, and MAGNITUDE) reported on survival data for patients with HRR deficiencies receiving relevant first-line treatment for mCRPC, and were included in a feasibility assessment. The TALAPRO-2 study compared talazoparib plus enzalutamide versus enzalutamide, the PROpel study compared olaparib plus AAP versus AAP, and the MAGNITUDE study compared niraparib-abiraterone plus prednisone versus AAP. The feasibility assessment explored potential sources of heterogeneity that included study design, patient eligibility criteria, baseline patient characteristics, outcome characteristics, and efficacy or safety results. ███ ███████ ██ ███ ██████████ ██████████ ████ █████████████ ██████ ███ ███████ but the sponsor assessed them as sufficiently similar to conduct MAICs between the TALAPRO-2 study and each of the PROpel and MAGNITUDE trials. There was no common treatment comparator between the TALAPRO-2 trial and comparator trials; therefore, unanchored MAICs were conducted using individual patient data from the TALAPRO-2 study and summary-level data from the comparator trials. Key treatment effect modifiers and prognostic factors for adjustment were identified and ranked in order of importance based on published analyses on prognostic strength in mCRPC and refined based on external clinical input from a practising clinician experienced in treating mCRPC. Individual patient data from the TALAPRO-2 trial HRR-deficient population were adjusted to match the marginal distribution (e.g., mean, variance) of clinical factors of patients for each comparison between the PROpel (olaparib plus AAP versus AAP) and MAGNITUDE (niraparib-abiraterone plus prednisone versus AAP) trials. Point estimates for rPFS and OS were reported as HRs with 95% CIs.

Efficacy Results

The rPFS HR point estimates and 95% CIs ████████ ████████████████████████ ██████ ████████ ████ ████ █████████ ████ ███ ███ ███ ██████ ███ ███ ███ ███████ ████████ ████████████████████████ ██████ █████████ ████ ███ ███ ███ ██████ ███ ██ █████ ████████ ████████ ████████████████████████ ██████ ████████ ████ ███ ███ ███ ███ ██ ████████ ███ ███████████ ██ ██ ██████████ ██ ████ ███ ██████████ ███ ████████ ██████ ███████ ███ ██████ ███ ████████████ ███████ ██████████ ███ ███ ████████ ██ █████████. The rPFS and OS primary analyses for the MAICs for the PROpel and MAGNITUDE studies adjusted for 5 and 8 treatment effect modifiers and prognostic factors, respectively. However, not all factors could be matched or adjusted; therefore, imbalances remained.

Harms Results

The MAIC did not include harms, and therefore no conclusions could be drawn on the relative safety of talazoparib plus enzalutamide versus relevant comparators.

Critical Appraisal

The methods used to conduct the systematic literature review for the MAIC were a priori registered, and used appropriate criteria to search databases, select studies, extract data, and assess risk of bias of the included studies. The MAIC did not include comparisons between talazoparib plus enzalutamide and chemotherapy, which represents a gap in the available indirect evidence given the shared place in therapy for mCRPC. The MAIC included relevant outcomes identified by the CDA-AMC team (rPFS and OS); however, clinically relevant and patient-relevant outcomes such as pain, HRQoL, and harms were not included in the comparisons. To account for between-study differences in patient baseline characteristics, several potentially relevant treatment effect modifiers and prognostic factors (i.e., clinical factors) were matched in the weighting process for each comparison between the TALAPRO-2 study and comparator trials. The methods used to identify and rank the clinical factors were considered appropriate. For both the PROpel and MAGNITUDE trials, adjustments were limited by how, and if, these variables were reported in both trials, and the highest-ranking factor could not be included in the adjustment for either study. The TALAPRO-2 study stratified by prior NHT or taxane therapy per interactive web response system as a single variable; whereas the PROpel and MAGNITUDE studies reported these variables separately. The PROpel study used the interactive web response system value, whereas the MAGNITUDE study did not specify interactive web response system or electronic data capture. Because interactive web response system values were combined in the TALAPRO-2 study but electronic data capture values were presented separately, electronic data capture values were used to align with reporting of comparator trials. Further, the TALAPRO-2 study stratified by prior therapy in the CSPC stage. The PROpel study reported the proportion of patients who received NHT and taxane-based therapy but did not specify the disease stage. The MAGNITUDE study reported the proportion of patients who received NHT and taxane-based therapy in the metastatic CSPC or nonmetastatic CRPC stage into a single variable. There were important differences in eligibility criteria between the MAGNITUDE and TALAPRO-2 studies. The MAGNITUDE study allowed the use of AAP in the mCRPC setting for 4 months or less, whereas all patients were treatment naive in the mCRPC setting within the TALAPRO-2 trial. Because only summary-level data were available for the MAGNITUDE study, patients who were not truly treatment naive could not be removed when performing analyses. It is possible that these patients had different disease characteristics compared to the rest of the trial population. Overall, the magnitude and direction of potential bias due to imbalances for the rPFS and OS estimates cannot be predicted. Because the unanchored nature of the MAIC requires a stronger assumption (than an anchored MAIC) that all effect modifiers and prognostic factors have been included in the analysis, which was not possible, the effects of talazoparib plus enzalutamide on rPFS and OS compared with relevant comparators are uncertain and definitive conclusions based on these results are not recommended.

Studies Addressing Gaps in the Evidence From the Systematic Review

No additional studies were submitted by the sponsor.

Conclusions

Evidence from 1 phase III, randomized, double-blind trial (TALAPRO-2) reported on outcomes that were important to both patients and clinicians. The trial showed moderate certainty of evidence that treatment with talazoparib plus enzalutamide results in a clinically important increase in rPFS at 12 months and 48 months compared to placebo plus enzalutamide in adults with HRR-deficient mCRPC in the first-line setting. The trial showed high certainty of evidence of a clinically important increase in OS at 48 months, in favour of talazoparib plus enzalutamide. There was low certainty of evidence for a higher probability of being free of pain progression at 12 months and 48 months in favour of talazoparib plus enzalutamide. Up to 109 weeks, no definitive conclusions can be drawn on other HRQoL outcomes due to concerns of imprecision and missing outcome data. There were no new safety signals identified, and the safety of talazoparib plus enzalutamide was consistent with the known safety profiles of the individual drugs, although the trial showed a higher proportion of TEAEs and serious TEAEs when compared with placebo plus enzalutamide. Due to limitations of the indirect treatment comparison, mostly attributed to the heterogeneity across studies and lack of safety assessment, no conclusions can be drawn on the relative efficacy and safety of talazoparib plus enzalutamide compared to relevant comparators, which included olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP alone. The evidence submitted to CDA-AMC did not include direct or indirect comparisons between talazoparib plus enzalutamide and chemotherapy, which represents a gap in the available evidence given the potential shared place in therapy for HRR-deficient mCRPC when used as first-line treatments. The TALAPRO-2 trial and submitted indirect treatment comparison evaluated talazoparib plus enzalutamide as a first-line treatment only; therefore, the efficacy and safety of talazoparib plus enzalutamide as a second-line or later-line treatment for HRR-deficient mCRPC represents a gap in the evidence.

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 talazoparib 0.5 mg plus enzalutamide 160 mg, taken orally once daily in the treatment of adult patients with HRR gene-mutated mCRPC.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CDA-AMC review team.

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, hormone sensitive, or mCRPC.² CRPC is defined by disease progression despite castrate levels of testosterone and may present as either a continuous rise in serum PSA levels, the progression of pre-existing disease, and/or the appearance of new metastases.³ Nonmetastatic CRPC has not spread to other parts of the body (based on bone scans and CT scans); whereas, mCRPC has spread to lymph nodes or other parts of the body, such as the bones.⁴ A patient may progress from metastatic CSPC to mCRPC based on biochemical recurrence (characterized by rising PSA levels despite medical or surgical castration) or from nonmetastatic CRPC based on presentation of metastases (assessed radiographically).^5,6 The mechanisms driving progression from androgen-dependent (hormone sensitive or castration sensitive) prostate cancer to CRPC are still largely unclear, although continued androgen receptor signalling, despite depletion of circulating androgens and androgen receptor blockade, is thought by many to be central to the development of CRPC.⁷

Patients with metastatic prostate cancer typically have declining urinary, sexual, and bowel functions (due to the primary tumour or its treatment) as well as signs and symptoms that are related to the location of the metastasis, which can include bone pain and pathologic fractures, hepatic disorders, neurologic symptoms, weight loss, and fatigue.^3,8 Approximately 90% of mCRPC cases involve bone metastases that may cause significant morbidity.³ Progressing to mCRPC is characterized by increased symptomatic burden and reduced HRQoL.^9-11

Prostate cancer is the most common cancer among males living in Canada, accounting for 11% of cancer-related deaths.¹² It was estimated that in 2022, 24,600 males in Canada were diagnosed with prostate cancer based on an incidence of 117.8 cases per 100,000 population.¹³ As an advanced form of prostate cancer, the prevalence of mCRPC was estimated as 1.2% to 2.1% of total prostate cancer cases.¹⁴ Even though the expected 5-year survival for males diagnosed with prostate cancer in Canada is 91% for all stages combined,¹² for metastatic disease, the 5-year survival rate reduces to approximately 28%.¹⁵

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the review team.

According to the clinical experts consulted by CDA-AMC, the main treatment goals for patients with mCRPC are to prolong survival, delay disease progression, improve symptoms, and maintain HRQoL. Systemic therapies for the treatment of patients with mCRPC, and the sequencing of these treatments, depend on patient and disease factors, prior treatments used in the metastatic CSPC setting, and access, which varies across Canada. Docetaxel, cabazitaxel, abiraterone acetate, enzalutamide, radium-223 (for patients with bone-only metastatic disease), lutetium vipivotide tetraxetan, and olaparib, olaparib plus AAP, or niraparib-abiraterone plus prednisone for patients with BRCA1, BRCA2, and/or ATM mutations, are all Health Canada approved, and most are available across Canada. According to the Canadian Urological Association–Canadian Uro-Oncology Group guideline for the management of mCRPC³ and clinical experts consulted by CDA-AMC, abiraterone acetate, enzalutamide, and docetaxel are treatment options in all lines of therapy for mCRPC. Additionally, cabazitaxel, radium-223, lutetium vipivotide tetraxetan, olaparib, and niraparib are treatment options as second-line, third-line, and later lines of therapy, with olaparib and niraparib for patients with BRCA-mutated or ATM-mutated mCRPC.

Drug Under Review

Key characteristics of talazoparib and the comparators are summarized in Table 3.

Talazoparib is indicated in combination with enzalutamide for the treatment of adult patients with HRR gene-mutated mCRPC. The recommended dose is talazoparib 0.5 mg orally once daily in combination with enzalutamide 160 mg orally once daily, until disease progression or unacceptable toxicity. The 0.1 mg and 0.25 mg capsules are available for dose reduction. Talazoparib is also approved for the treatment of breast cancer. Talazoparib has not been previously reviewed by CDA-AMC.

Talazoparib is an inhibitor of the PARP enzymes, PARP1 and PARP2. PARP enzymes are involved in cellular DNA damage response signalling pathways such as DNA repair, gene transcription, cell cycle regulation, and cell death. PARP inhibitors exert cytotoxic effects on cancer cells by 2 mechanisms, inhibition of PARP catalytic activity and by PARP trapping, whereby a PARP protein bound to a PARP inhibitor does not readily dissociate from a DNA lesion, thus preventing DNA repair, replication, and transcription and ultimately leading to apoptosis and/or cell death.

The reimbursement request is aligned with the Health Canada–approved indication.

The drug underwent the standard review pathway at Health Canada.

Table 3: Key Characteristics of Talazoparib, Enzalutamide, Abiraterone Acetate, Docetaxel, Olaparib, and Niraparib-Abiraterone Acetate

AML = acute myeloid leukemia; HRR = homologous recombination repair; mCRPC = metastatic castration-resistant prostate cancer; PARP = poly(adenosine diphosphate-ribose) polymerase.

^aGiven in combination with enzalutamide.

^bGiven in combination with prednisone.

^cGiven in combination with prednisone or prednisolone.

^dHealth Canada–approved indication.

Sources: Product monographs for talazoparib, abiraterone acetate, docetaxel, and enzalutamide.^16,18,19,22

Testing Procedure Considerations

Somatic or germline mutations occurring in the genes involved in DNA damage repair through the HRR pathway have been of interest for targeted treatments in prostate cancer.²³ Published literature suggests that alterations in HRR genes are present in approximately 25% to 30% of patients with mCRPC.^23-27 The clinical experts consulted for this review stated that, due to the occurrence of driving mutations based on prior therapy, the rate of somatic HRR mutations in this population is likely increasing over time. The presence of HRR gene mutations is associated with early onset of disease, aggressive tumours, higher recurrence rates, and worse prognosis.^23,28,29 BRCA1 and BRCA2 mutations, in particular, are associated with poor prognosis compared to other HRR mutations in the mCRPC population.²⁷

There are at least 18 genes involved in the HRR pathway that could harbour mutations associated with mCRPC.^23,30 Among them, participants in the TALAPRO-2 trial had mutations in 1 or more of the following 12 genes that are directly or indirectly involved in the HRR pathway: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.^31,32 In this trial, the most commonly mutated HRR genes in the combined intervention and placebo groups of the population with HRR deficiencies were BRCA2 (33.8%), ATM (21.6%), CDK12 (18.8%), CHEK2 (17.8%), and BRCA1 (5.8%).³² The most prevalent HRR gene mutations detected in a real-world cohort of individuals with mCRPC using both somatic and germline testing methods were in BRCA2 (13.4%), CDK12 (7.7%), and ATM (6.2%).³⁰ Mutations in the other genes in the HRR pathway are less common and the prevalence varies across the published literature.^27,28,33,34 The clinical experts noted that, in the rare occurrence where a patient is identified with an HRR gene mutation other than 1 of the 12 genes included in the TALAPRO-2 study, treatment with talazoparib would still be considered.

Germline, or hereditary, mutations are identified using NGS from a saliva or blood sample.³ In Canada, patients can typically access this test by referral to specialized hereditary cancer clinic services.³ In some jurisdictions, such as British Columbia, germline testing can be accessed through “mainstreaming,” where the medical oncologist can directly order the test.³⁵ The patient would then be referred to a hereditary cancer clinic with a geneticist and genetic counselling services only if a pathogenic, likely pathogenic, or variant of uncertain significance was found.^3,35-37 Somatic mutations are also identified through NGS, usually using fresh or archival tumour biopsy tissue or circulating tumour DNA from a blood sample.³ NGS testing on tumour tissue can identify mutations of both germline and somatic origins, although it is unable to differentiate between them.^3,36,37

The 2023 Canadian Urological Association guideline recommends testing patients with metastatic prostate cancer for hereditary mutations in ATM, BRCA1, BRCA2, CHEK2, MLH1, and PALB2.³⁶ Similarly, the Canadian Urological Association recommends that patients with mCRPC should receive tumour genomic profiling to inform the selection of therapy. At minimum, this should include mutations in ATM, BRCA1, and BRCA2; however, panels should align with germline panels as much as possible, and ideally also include CHEK2, MLH1, PALB2, and CDK12.³⁶ To make the most efficient use of available resources and timelines when determining eligibility for a targeted treatment in patients with metastatic prostate cancer, the Canadian Urological Association suggests starting with somatic mutation testing of archived primary or metastatic tumour tissue and following with germline testing only if variants associated with hereditary cancer risk are identified.³⁶ If no mutations are identified using a tumour NGS panel, germline testing may still be indicated if the panel did not include the recommended genes for hereditary mutation testing.³⁶ According to the clinical experts consulted for this review, practice in Canada does not always reflect the Canadian Urological Association recommendations. There is considerable variability between and within jurisdictions in the timing of testing, who orders the test, the type of test offered, and the genes covered.

We considered the potential impacts of HRR gene mutation testing to ascertain eligibility for talazoparib for the treatment of adult patients with mCRPC, including to health systems, patients (including families and caregivers), and costs. There are existing concerns related to testing within health systems, impacting patients, and costs. However, if talazoparib were to be funded, minimal additional impact is anticipated. A small proportion of patients who have mutations in genes other than BRCA1, BRCA2, or ATM may not be identified for eligibility for talazoparib depending on what testing panels are available in their jurisdiction. Key considerations and relevant information available from materials submitted by the sponsor, input from the clinical experts consulted by the review team, and sources from the literature were validated by the review team when possible and are summarized in Table 4.

Table 4: Considerations for HRR Gene Mutation Testing for Establishing Treatment Eligibility With Talazoparib in mCRPC

CDA-AMC = Canada's Drug Agency; CI = confidence interval; ctDNA = circulating tumour DNA; CUA = Canadian Urological Association; HRR = homologous recombination repair; mCRPC = metastatic castration-resistant prostate cancer; NGS = next-generation sequencing.

^aCDA-AMC have not evaluated or critically appraised this evidence to determine its validity or reliability.

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

CDA-AMC received 2 patient group inputs from PROCURE and CCS. PROCURE is a charitable organization which promotes and contributes to the financing of research and educates, supports, and informs patients affected by prostate cancer. PROCURE gathered information from more than 3,500 patients with localized, locally advanced, metastatic, recurrent, hormone sensitive, or CRPC, with or without metastases through phone calls, and conducting 2 online surveys — the Canadian survey in 2022 with 263 patients who responded and the Quebec survey in 2018 (the total number of patients who responded was not reported). CCS supports patients living with cancer in Canada through research, transformative advocacy, and compassionate support. CCS conducted a survey to gather perspectives on disease experience from 21 patients with mCRPC and 3 caregivers of patients with mCRPC from April to May 2023.

According to PROCURE’s input, in addition to distress and treatment decisions, rising PSA levels after treatment, recurrence, hormone therapy and its side effects, as well as metastases are among the main concerns of patients. Additionally, 50% of the patients who responded to the survey in Canada reported that the main challenges posed by treatment included managing side effects, living with uncertainty, and maintaining a positive attitude. PROCURE also noted that patients who responded to the survey in Quebec hope that future treatments for prostate cancer slow down the progression of cancer (94%), extend life expectancy (94%), improve the quality of life (98%), help manage or diminish side effects (93%), and decrease PSA levels (91%).

Based on the CCS input, mCRPC mostly impacted the sexual activity of patients, followed by their ability to work, maintain positive mental health, concentrate, travel, exercise, or conduct household chores. CCS added that some of the barriers the patients faced when receiving treatment included transportation costs to appointments, long wait times to receive tests or treatments, and lack of familiarity with the health care system. According to the CCS input, the majority of patients who responded to the survey (67%) reported receiving 3 or more lines of treatment and 8% indicated they had received 1 line of treatment, while 13% reported having received 2 lines of treatment. CCS noted that the most common current treatments included hormone therapies, external beam radiation, surgical procedures, chemotherapy, and corticosteroids. Notably, no patients who responded to the survey reported using targeted therapy. Some of the side effects of current treatments reported by CCS included fatigue, hot flashes, dizziness, peripheral neuropathy, pain, nausea, vomiting, changes in libido, sexual function or fertility, and problems in the mouth, tongue, and throat. CCS stated that many patients are highly motivated to extend survival, despite potential side effects.

PROCURE noted that prostate cancer treatments have physical and psychological impacts. Physical impacts included side effects (incontinence, erectile dysfunction, and bowel issues), effects associated with hormone therapies (hot flashes, loss of libido, weight gain, cardiovascular risks, osteoporosis, and so forth), and pain related to metastases; psychological impacts included anxiety, depression, loss of self confidence, fatigue, and fear of cancer returning which causes stress and uncertainty, and affecting sleep, appetite, and concentration. PROCURE emphasized the importance of emotional support in addition to medical care and added that access to health care professionals (sexologists, psychologists, physiotherapists, kinesiologists) is often limited due to cost, lack of available services, or long wait times, leaving many patients without adequate support.

Regarding patients’ partners, family members, and caregivers, PROCURE explained that caregiving is a demanding role and comes with stress, anxiety, and depression. Intimate relationships are affected due to loss of libido, fatigue, and changes in masculine characteristics often lead males to avoid intimacy with their partners, resulting in significant consequences. PROCURE added that if a father carries a genetic mutation and has prostate cancer, both sons and daughters are at an increased risk of developing certain cancers, such as prostate, breast, and ovarian cancer, if they inherit the altered gene, thus ███████ ██████████ ███ ███████ ███████ █████████ ███ █████████ ██ ██████ ███ █████ ███ █████ ██ ███ ███████ ██████ Children may experience anxiety due to the family history and concerns about their own risk of developing cancer. CCS also noted the negative impact of disease on caregivers and children such as transportation costs, caregiving costs, loss of income due to absence from work, and lack of familiarity with the health care system.

Based on the PROCURE input, while current treatments are often effective, they eventually face resistance over time, limiting their long-term benefits. PROCURE added that standard treatments for metastatic cancer, such as hormone therapy and chemotherapy, are systemic and nontargeted, exposing the entire body to often severe side effects. Therapeutic options targeting genetic mutations in prostate cancer remain limited to the BRCA gene and are only available when this mutation is confirmed through tumour biopsy or genetic testing. This restriction reduces treatment alternatives for many patients, highlighting the need for new therapeutic approaches. PROCURE highlighted that patients face both emotional and practical concerns regarding treatment efficacy, cancer progression, long-term health impact, and overall life expectancy.

Both patient groups clarified that patients' expectations with regards to new treatments included cancer control with fewer side effects, longer-lasting effects, delayed onset or elimination of metastases, decreased or maintained PSA levels over a long period, convenient treatment regimens, prolonged life, and improved quality of life. Patients also expected treatments to be affordable, have better accessibility, better follow-up for long-term issues, and to be heard and taken seriously.

In terms of experience with the drug under review, the patient groups explained that they did not have access to patients who have experience with the drug under review. PROCURE clarified that there are 2 distinct indications for this treatment, depending on its use in North America versus Europe. The European indication, which is broader, allows the use of this combination in patients with mCRPC, with or without a genetic mutation, when chemotherapy is not clinically indicated. In contrast, in the US and Canada, the approach remains more conservative, restricting the use of this treatment to patients with HRR gene alterations. CCS highlighted the importance of companion diagnostic genetic testing.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC 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, and 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 because mCRPC is a terminal phase of prostate cancer, the unmet needs of patients would be new treatments that would prolong survival and improve quality of life, while exposing patients to minimal toxicity. Both clinical experts highlighted that the balance between treatment efficacy and quality of life would be important.

Place in Therapy

Clinical experts noted that it remains unclear whether talazoparib plus enzalutamide would lead to a shift in the current treatment paradigm. This uncertainty stems from the increased use of ARPIs in patients with metastatic CSPC and nonmetastatic CRPC. They noted that many medical oncologists would favour a change to chemotherapy in patients progressing on an ARPI in the metastatic CSPC and nonmetastatic CRPC settings. They noted that if a treatment was used in metastatic CSPC, it is not likely the patient will receive it again for first-line mCRPC (with the occasional exception of docetaxel if given at least 1 year prior). The clinical experts noted that talazoparib plus enzalutamide may have a limited role as a first-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; however, it may have a role in subsequent lines of therapy.

Patient Population

The clinical experts indicated that patients best suited for talazoparib plus enzalutamide would be those who match the eligibility criteria of the TALAPRO-2 trial, which included first-line treatment for HRR gene-mutated mCRPC, with no prior ARPI in the metastatic CSPC setting (with the exception of abiraterone acetate) and no contraindications to talazoparib or enzalutamide. They did not indicate any issues or challenges related to diagnosis or misdiagnosis of mCRPC and noted that there are no predictive biomarkers to guide treatment.

Assessing the Response Treatment

The clinical experts indicated that in clinical practice, a combination of radiographic, biochemical (e.g., PSA), and clinical parameters (i.e., decrease in disease-related symptoms) is used to determine whether a patient with mCRPC is responding or progressing while receiving treatment. They noted that the frequency of evaluation can be variable from patient to patient, but at the very least, assessments should be performed at 3-month intervals.

Discontinuing Treatment

The clinical experts indicated that treatment with talazoparib plus enzalutamide should be discontinued if patients experience disease progression (as defined radiologically or clinically), treatment is intolerable, or if it is the patient’s preference.

Prescribing Considerations

The clinical experts noted that PARP inhibitors such as talazoparib have the potential to be toxic; therefore, patients receiving talazoparib plus enzalutamide should be under the care of a medical oncologist who can manage toxicity associated with therapy, in the community.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

CDA-AMC received 1 input from the OH (CCO) Genitourinary Cancer Drug Advisory Committee for this submission. The OH (CCO) Drug Advisory Committees provide timely, evidence-based clinical and health system guidance on drug-related issues in support of the OH (CCO) mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. The OH (CCO) Genitourinary Cancer Drug Advisory Committee gathered information from 5 clinicians.

According to the clinician group input, the treatment goal is prolonging life and improving quality of life. The current treatments for mCRPC include abiraterone acetate, enzalutamide, docetaxel, and radium-223 (in patients who are ineligible to receive docetaxel), all given concurrently with ADT. Cabazitaxel is another option after docetaxel use in the mCRPC setting. Similarly, olaparib monotherapy might be a treatment option after treatment with an ARPI for mCRPC in males with BRCA2, BRCA1, or ATM aberrations. Olaparib plus abiraterone acetate is also available (while niraparib-abiraterone acetate is under funding consideration) for those who have not been treated with ARPI in the metastatic CSPC setting or nonmetastatic CRPC setting.

The clinician group explained that there are no cures currently available for metastatic prostate cancer and there is a need for treatments that prolong life.

Based on input from a clinical expert consulted by CDA-AMC, the place in therapy of talazoparib in combination with enzalutamide is for the treatment of patients with mCRPC who are treatment naive. The group noted that treatment with chemotherapy or ARPI in the metastatic CSPC setting should not preclude eligibility for treatment with talazoparib plus enzalutamide, as per the TALAPRO-2 trial. The group noted that PSA and serial radiographic imaging would be used to monitor response to therapy and that significant side effects and progression of disease on imaging are among the factors for considering discontinuation of the treatment. The clinician group noted that medical oncologists, radiation oncologists, and urologists specialized in prostate cancer care are among the specialists or prescribers that would be required for prescribing the treatment. The OH (CCO) Genitourinary Cancer Drug Advisory Committee added that access to this (and other) combinations in this setting would also require ongoing efforts to ensure equitable, timely access to genomic testing of relevant alterations for all eligible males with prostate cancer living in Canada.

Drug Program Input

The drug programs provide input on each drug being reviewed through the 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 CDA-AMC for this review are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

AAP = abiraterone acetate plus prednisone; CDA-AMC = Canada's Drug Agency; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HRR = homologous recombination repair; mCRPC = metastatic castration-resistant prostate cancer; PARP = poly(adenosine diphosphate-ribose) polymerase; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; PFS = progression-free survival.

Clinical Evidence

The objective of this Clinical Review report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of talazoparib 0.5 mg plus enzalutamide 160 mg, taken orally once daily in the treatment of adult patients with HRR gene-mutated mCRPC. The focus will be placed on comparing talazoparib plus enzalutamide to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of talazoparib plus enzalutamide is presented in 4 sections with our 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. Our assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section typically includes sponsor-submitted long-term extension studies; however, none were submitted by the sponsor. The third section includes indirect evidence from the sponsor. The fourth section typically includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence; however, none were submitted by the sponsor.

Included Studies

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

• 1 pivotal trial identified in the systematic review

• 1 indirect treatment comparison.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the review team.

Description of Studies

Characteristics of the included studies are summarized in Table 6.

Table 6: Details of Studies Included in the Systematic Review

ADT = androgen deprivation therapy; AE = adverse event; AR = androgen receptor; BICR = blinded independent central review; BPI-SF = Brief Pain Inventory–Short Form; CRPC = castration-resistant prostate cancer; CSPC = castration-sensitive prostate cancer; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-PR25 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer; GnRH = gonadotropin-releasing hormone; HRR = homologous recombination repair; mCRPC = metastatic castration-resistant prostate cancer; mCSPC = metastatic castration-sensitive prostate cancer; OS = overall survival; PARP = poly(adenosine diphosphate-ribose) polymerase; PCWG3 = Prostate Cancer Clinical Trials Working Group 3; PFS = progression-free survival; PK = pharmacokinetics; PSA = prostate-specific antigen; QoL = quality of life; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; rPFS = radiographic progression-free survival.

Note: PFS2 was defined as the time from the date of randomization to the date of investigator documented disease progression on the first subsequent antineoplastic therapy for prostate cancer, or death from any cause, whichever occurs first.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

TALAPRO-2¹ is a phase III, randomized, double-blind, placebo-controlled, multicentre trial that aimed to assess the efficacy and safety of talazoparib 0.5 mg plus enzalutamide 160 mg, taken orally once daily, or matched placebo plus enzalutamide in adult patients with mCRPC (Figure 1). The trial enrolled adult patients with asymptomatic or mildly symptomatic mCRPC who had not started systemic cancer treatment after the diagnosis of CRPC (metastatic or nonmetastatic), with the exception of ADT and first-generation antiandrogen drugs. The trial included 2 prespecified populations. Enrolment began in cohort 1, which included patients with and without HRR gene alterations. Once enrolment was complete in cohort 1, enrolment continued but was restricted to patients with HRR gene alterations. Cohort 2 (population with HRR deficiencies) consisted of all patients with HRR deficiencies enrolled in the trial and is the focus of this review as it aligns with the Health Canada–approved indication and the sponsor’s reimbursement request.

Patients who were enrolled in cohort 2 were randomly assigned 1:1 using a centralized interactive web response system (N = 399, at 287 sites across 26 countries) to talazoparib plus enzalutamide (n = 200) or placebo plus enzalutamide (n = 199). In total, 10 patients from Canada were included. Randomization was stratified by previous treatment with NHT (abiraterone acetate, abiraterone, or orteronel) or taxane-based chemotherapy (docetaxel) for CSPC (yes or no), and HRR gene alteration status (deficient versus nondeficient or unknown). The patients and investigators were blinded to talazoparib or placebo, while enzalutamide was open label.

The trial included a screening period up to 42 days, a treatment period until discontinuation criteria were met, which included radiographic progression by BICR, an adverse event (AE) leading to permanent discontinuation, patient decision to discontinue treatment, or death. All patients were followed during a posttreatment phase after discontinuation criteria were met, which included the 28 days after the last dose of study treatment. Patients were subsequently followed during a long-term follow-up phase with imaging and PSA measurements.

The outcomes relevant to this review included the primary outcome of rPFS, and secondary outcomes of OS, patient-reported pain symptoms measured via BPI-SF, HRQoL measured via EORTC QLQ-PR25 functional and symptom scales, and safety. The rPFS data are based on the primary analysis data cut-off date of October 3, 2022, and supported by the data cut-off date of September 3, 2024. All other outcomes are based on the data cut-off date of September 3, 2024.

Populations

Inclusion and Exclusion Criteria

Patients who were eligible were asymptomatic or mildly symptomatic adult patients with mCRPC who had not started systemic cancer treatment after the diagnosis of CRPC (metastatic or nonmetastatic), with the exception of ADT and first-generation antiandrogen drugs. Patients were allowed to have previously received abiraterone acetate or docetaxel for CSPC but were ineligible to participate if they had received any prior treatment with second-generation androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide), a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer. Patients were required to have had an ECOG PS score of 0 or 1, and progressive disease at study entry, which was based on at least 1 of the following criteria during ADT: PSA progression, soft tissue disease progression defined by RECIST 1.1, or bone disease progression defined by the Prostate Cancer Clinical Trials Working Group 3.

Interventions

Patients received talazoparib 0.5 mg as two 0.25 mg capsules plus enzalutamide 160 mg as four 40 mg capsules, taken orally once daily, or matched placebo plus enzalutamide. Placebo capsules were identical in appearance to talazoparib capsules. Participants with moderate renal impairment would receive talazoparib 0.35 mg once a day plus enzalutamide 160 mg once a day to account for the lower talazoparib clearance in this subpopulation. Patients were to continue treatment until BICR-determined radiographic progression, no longer clinically benefiting in the opinion of the investigator, unacceptable toxicity, withdrawal of consent, or death. After radiographic progression, treatment could be continued if the investigator determined benefit was still being derived.

The following concomitant treatments were permitted during the trial: bisphosphonates or denosumab, ADT with a gonadotropin-releasing hormone agonist or antagonist, hematopoietic growth factors, red blood cell transfusions, erythropoietin and erythropoiesis-stimulating drugs, thrombopoietin analogues and/or platelet transfusions, COVID-19 vaccines, and analgesics. The following treatments were prohibited during the trial: prednisone, cytotoxic chemotherapy, hormonal therapy (e.g., bicalutamide, nilutamide, flutamide, estrogens, 5-alpha reductase inhibitors), NHT with the exception of enzalutamide (e.g., abiraterone acetate, apalutamide, darolutamide), biologic therapy, radionuclide therapy, or other PARP inhibitors.

Outcomes

A list of efficacy end points assessed in this Clinical Review report is provided in Table 7, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review according to the clinical experts consulted for this review and input from patient and clinician groups and public drug plans. Using the same considerations, we selected end points that were considered to be most relevant to inform 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.

Table 7: Outcomes Summarized From the Studies Included in the Systematic Review

BICR = blinded independent central review; BPI-SF = Brief Pain Inventory–Short Form; EORTC QLQ-PR25 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer; OS = overall survival; rPFS = radiographic progression-free survival.

^aStatistical testing for these outcomes were adjusted for multiple comparisons (e.g., hierarchal testing).

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Radiographic Progression-Free Survival

The primary outcome of rPFS assessed by BICR was defined as the time from the date of the randomization to first objective evidence of radiographic progression as assessed in soft tissue per RECIST 1.1 or in bone (upon subsequent confirmation) per Prostate Cancer Clinical Trials Working Group 3, or death due to any cause, whichever occurred first. Tumour assessments were done with CT or MRI of chest, abdomen, and pelvis, and whole-body bone scan every 8 weeks through to week 25 and every 12 weeks thereafter. Soft tissue responses were confirmed by a follow-up radiographic assessment at least 4 weeks later with no evidence of confirmed bone disease progression on repeated bone scans at least 6 weeks apart per Prostate Cancer Clinical Trials Working Group 3.

Overall Survival

The secondary outcome of OS was defined as the time from randomization to the date of death due to any cause. Patients last known to be alive were censored at the date of last contact.

Time to Deterioration of Pain

The secondary outcome of time to deterioration in patient-reported pain symptoms was measured using question 3 from the BPI-SF: “Please rate your pain by marking the box beside the number that best describes your pain at its worst in the last 24 hours.” A summary of its measurement properties is in Table 8. The BPI-SF is a 9-item instrument that uses a self-reported scale assessing level of pain, its effect on activities of daily living, and analgesic medication use. Question 3 uses a scale of 0 (no pain) to 10 (pain as bad as you can imagine), with lower scores indicating less pain. The MID for the BPI-SF and for question 3 is considered greater or equal to 2 points in patients with various cancers, including metastatic prostate cancer.^65,66 Time to this event was defined as the time from randomization to onset of pain progression, where pain progression was defined as a 2-point or more increase from baseline for 2 consecutive visit periods at least 4 weeks apart without a decrease in WHO analgesic usage score. Patients without observed pain progression at the time of analysis were censored at the date of last BPI-SF assessment. Pain and analgesic assessments were completed via pain and analgesic logs, respectively, for 7 consecutive days before study visits, and pain score averages during the period of reporting were calculated. Assessments were performed at baseline, every 4 weeks through week 53, every 8 weeks after week 53, and then every 12 weeks until the end of the study.

Health-Related Quality of Life

The secondary outcome of HRQoL was measured by change in baseline in patient-reported disease-specific functioning and symptom scales using EORTC QLQ-PR25 (Table 8). The EORTC QLQ-PR25 is a prostate cancer-specific module of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire that assesses the functioning and symptoms of patients with prostate cancer. Patients self-rate their current state of pain as it relates to urination, ease and frequency of urination, bowel, and other symptoms and signs during the past week. Patients also answer 5 questions about weight loss or gain and sexual interest and 4 questions about sexual activity during the past 4 weeks and choose 1 of 4 possible responses that record level of intensity (not at all, a little, quite a bit, very much) within each dimension. Scores are linearly transformed onto a scale of 0 to 100, with higher scores indicating worse symptoms or better functioning. A MID of 5 points has been used for the EORTC QLQ-PR25 in patients from Taiwan with various stages of prostate cancer and treatments.⁶⁷ Assessments were performed at baseline, every 4 weeks through week 53, every 8 weeks after week 53, and then every 12 weeks until end of study.

Safety Outcomes

The assessment of safety was based on the incidence of TEAEs, serious TEAEs, notable TEAEs, TEAEs leading to discontinuation, TEAEs leading to dose modification, and deaths. AEs were reported at each study visit and coded to preferred term and system organ class using the Medical Dictionary for Regulatory Activities and classified by severity using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Safety assessments were done at screening and every 2 weeks up to week 17, every 4 weeks up to week 53, every 8 weeks thereafter while on study drug, then 28 days after discontinuation of all study treatments or before initiation of a new antineoplastic or investigational therapy, whichever occurred first.

Table 8: Summary of Outcome Measures and Their Measurement Properties

BPI-SF = Brief Pain Inventory–Short Form; CRPC = castration-resistant prostate cancer; EORTC = European Organisation for Research and Treatment of Cancer; EORTC QLQ-PR25 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer; ICC = intraclass correlation coefficient; mCRPC = metastatic castration-resistant prostate cancer; MID = minimal important difference; vs. = versus.

Statistical Analysis

A summary of the statistical analysis of efficacy outcomes is provided in Table 9.

Sample Size and Power Calculation

Sample size and power calculations were based on a stratified log-rank test. The following assumptions were used to determine the sample size for the primary outcome of rPFS:

• 1:1 randomization of patients to talazoparib plus enzalutamide versus placebo plus enzalutamide

• 15% discontinuation rate at 12 months for rPFS and 6% dropout at 20 months for OS

• median rPFS assumed to be 16 months for placebo plus enzalutamide and the median rPFS for talazoparib plus enzalutamide assumed to be 23 months, with an HR of 0.696

• median OS assumed to be 35 months for placebo plus enzalutamide and the median OS for talazoparib plus enzalutamide assumed to be 46.7 months, with an HR of 0.75 under the exponential model assumption

• approximately 15% of the all-comers population were assumed to harbour HRR deficiencies

• nonuniform patient accrual over 16.3 months in the all-comers population followed by an additional 13.5 months to enrol additional patients with HRR-deficient mCRPC.

For the primary comparison of rPFS in the population with HRR deficiencies (i.e., combining patients with HRR deficiencies from cohort 1 and cohort 2), 224 rPFS events based on BICR assessment would provide 85% power to detect an HR of 0.64 using a 1-sided stratified log-rank test at a significance level of 0.0125, and 2 interim analyses using a Lan DeMets alpha spending and a Lan DeMets beta spending function to determine the nonbinding boundaries and preserve the overall error rate. It was estimated that 380 patients with HRR deficiencies would be needed to observe the 224 events.

The study will be underpowered for OS in the population with HRR deficiencies. The final analysis for OS in the population with DNA damage response deficiency will occur at the time of the final analysis of OS in the all-comers population. It was estimated that 173 OS events in the population with HRR deficiencies will have occurred at this time, providing 36% power to detect an HR of 0.75 using a 1-sided log-rank test at a significance level of 0.0125.

Statistical Testing

rPFS was analyzed using a 1-sided log-rank test, stratified by randomization stratification factors, and the Kaplan-Meier method. To maintain overall type I error at or below a 1-sided alpha of 0.025, alphas were split equally (1-sided alpha = 0.0125) between cohorts 1 and 2. The HR and associated 95% CI were estimated using a Cox proportional hazards model, with a 2-sided 95% CI and corresponding P value estimated based on the Brookmeyer-Crowley method. The distribution of time-to-event rPFS, including median rPFS and event-free rates at selected time points, was estimated using the Kaplan-Meier method for each treatment group.

For OS, a hierarchical stepwise gatekeeping testing procedure was used to preserve the overall type I error only if the difference in rPFS was significant, using a 1-sided alpha of 0.0125. Time to deterioration of pain was estimated by the Kaplan-Meier method, and 2-sided 95% CIs were based on the Brookmeyer-Crowley method. Analysis for EORTC QLQ-PR25 consisted of mean change from baseline and overall change from baseline using a longitudinal mixed effects model. The pain and HRQoL outcomes were not controlled for multiplicity. Safety data were analyzed descriptively.

Subgroup Analysis

For the prespecified subgroups of interest, the stratified HR of rPFS were performed by BRCA alteration status and prior treatment with NHT or taxane therapy. These analyses were not adjusted for multiplicity.

Censoring and Data Imputation Methods

For rPFS, the following criteria and hierarchy were applied to censoring: no adequate baseline assessment, start of new antineoplastic therapy, event after missing assessments, withdrawal of consent, lost to follow-up, no adequate postbaseline tumour assessment, and ongoing without an event. For OS, the following criteria and hierarchy were applied to censoring: withdrawal of consent, lost to follow-up, and ongoing without an event. For all outcomes, missing data were not imputed.

Sensitivity Analyses

Sensitivity analyses are summarized in Table 9.

Table 9: Statistical Analysis of Efficacy End Points — TALAPRO-2 Trial

BICR = blinded independent central review; BPI-SF = Brief Pain Inventory–Short Form; CSPC = castration-sensitive prostate cancer; EORTC QLQ-PR25 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer; HRR = homologous recombination repair; NHT = novel hormonal therapy; NR = not reported; OS = overall survival; rPFS = radiographic progression-free survival; vs. = versus.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Analysis Populations

The efficacy outcomes were analyzed based on the intention-to-treat population (ITT), regardless of whether treatment was administered. For the pain and HRQoL outcomes, only patients with baseline and at least 1 postbaseline assessment were analyzed. The safety outcomes were analyzed using the safety population, defined as patients who received at least 1 dose of any study medication.

Results

Patient Disposition

A summary of patient disposition is in Figure 1.

In total, 2,896 patients were screened, and 200 were randomized to the talazoparib plus enzalutamide and 199 to placebo plus enzalutamide groups; 169 patients were included from cohort 1 and 230 patients from cohort 2. Two patients in the talazoparib plus enzalutamide group were not treated with either study drug and 1 patient was treated with only enzalutamide. At the data cut-off date of September 3, 2024, 74.7% (n = 148) of patients in the talazoparib plus enzalutamide group discontinued treatment with talazoparib, and 89.9% (n = 179) of patients in the placebo plus enzalutamide group discontinued placebo. The most common reason for discontinuation in both groups was disease progression (talazoparib plus enzalutamide = 28.3%; placebo plus enzalutamide = 41.7%), followed by global deterioration of health status (talazoparib plus enzalutamide, n = 35; placebo plus enzalutamide, n = 44), and AEs (talazoparib plus enzalutamide, n = 25; placebo plus enzalutamide, n = 15). Discontinuations from enzalutamide were reported for 75.8% (n = 150) of patients in the talazoparib plus enzalutamide group and 89.9% (n = 179) of patients in the placebo plus enzalutamide group, with disease progression as the most frequently reported reason for discontinuation in both groups (28.8% and 41.2%, respectively).

Figure 1: Summary of Patient Disposition — Population With HRR Deficiencies, TALAPRO-2 Trial

CSR = Clinical Study Report; DDR = DNA damage response (described as HRR in this figure); HRR = homologous recombination repair.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

A summary of baseline patient characteristics of the ITT population is in Table 10. 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. Overall, key baseline characteristics were generally balanced between treatment groups, except the talazoparib plus enzalutamide group had a ██████ ████ ████████ █████ ███ █████ ██████ █████ ███ █ ██████ ██████████ ██ ████████ ███ ███ ████████ ██████ █████████ ██████ ██████ ██████. The trial population was predominately white (68%), with a median age of 70 years. Most patients had an ECOG PS score of 0 (approximately 62%), indicating good overall performance; normal or mild renal impairment (approximately 90%); bone and soft tissue disease-site metastasis (approximately 84%); a Gleason score greater than or equal to 8 (approximately 74%); and had █████ ███████ ████ ███████ ██ ██████ ██████████████ ████ ███ ████████████████ ██████████████ ██████████████ █████ In both groups, the most commonly detected HRR gene alteration was BRCA2 (33.8%), followed by ATM (21.6%), CDK12 (18.8%), and CHEK2 (17.8%).

Table 10: Summary of Baseline Characteristics — Population With HRR Deficiencies, TALAPRO-2 Trial

ECOG PS = Eastern Cooperative Oncology Group Performance Status; HRR = homologous recombination repair; PSA = prostate-specific antigen; SD = standard deviation.

Note: Racial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

The median treatment durations for talazoparib and placebo were 88.3 weeks in the talazoparib plus enzalutamide group (relative dose intensity = 78.3%) and 60.0 weeks in the placebo plus enzalutamide group (relative dose intensity = 100.00%). The median treatment durations for enzalutamide were 90.5 weeks (relative dose intensity = 99.83%) in the talazoparib plus enzalutamide group and 60 weeks (relative dose intensity = 100.00%) in the placebo plus enzalutamide group. The average daily dose administered for talazoparib was ████ ██ and ████ ██ for placebo. The average daily dose administered for enzalutamide in the talazoparib plus enzalutamide group was █████ ██ and █████ ██ in the placebo plus enzalutamide.

There were more dose interruptions and reductions due to AEs in the talazoparib plus enzalutamide group than in the placebo plus enzalutamide group. Dose interruptions of talazoparib due to AEs were reported in █████ ███████ ██ █████████ ███ █████ ███ ███ of patients taking placebo. In both groups, the most common AEs leading to dose interruptions were anemia, neutrophil count decreased, and platelet count (percent not reported). Dose reductions of talazoparib due to AEs were reported in 54.5% (n = 108) of patients taking talazoparib and 5.0% (n = 10) of patients taking placebo. In both groups, the most common AE leading to dose reductions was anemia (percent not reported).

████ ████████ █████ █ ██ ██████ received at least 1 concomitant medication during the trial ███ ████ ████ ███ ██████████ ███████ ██████. In both groups, the most common classes of concomitant medications were ██████████ ██████████████ ████ and ████████████████ ██████ ██ ██████. Most concomitant medications were used consistently between the 2 treatment groups, except ███████████ ████████████ were more commonly used in the talazoparib plus enzalutamide group than placebo plus enzalutamide ██████ ███ ███████

Subsequent Anticancer Therapy

Fewer patients (36.9%) in the talazoparib plus enzalutamide group received subsequent anticancer therapy than in the placebo plus enzalutamide group (56.8%), with the most common subsequent anticancer therapy being taxane-based therapy (26.3% versus 39.2%, respectively).

Efficacy

Only those efficacy outcomes and analyses of subgroups identified as important to this review are reported. The main findings for the efficacy outcomes for the TALAPRO-2 trial are from the data cut-off dates of October 3, 2022, and September 3, 2024. The boundary for statistical significance for the primary outcome of rPFS was met at the data cut-off date of October 3, 2022; therefore, rPFS data were reported descriptively at the September 3, 2024, data cut-off date (i.e., not controlled for type I error). All other outcomes are based on the data cut-off date of September 3, 2024.

rPFS by BICR

Table 11 provides a summary of results for rPFS by BICR. In total, 170 events had occurred in both groups by the data cut-off date of October 3, 2022. The median duration of follow-up for rPFS was 17.5 months (range not reported) for the talazoparib plus enzalutamide group and 16.8 months (range not reported) for the placebo plus enzalutamide group. The median rPFS was not reached (95% CI, 21.9 months to not reached) in the talazoparib plus enzalutamide group and 13.8 months (95% CI, 11.0 months to 16.7 months) for the placebo plus enzalutamide group (log-rank test P < 0.0001), with a between-group HR of 0.45 (95% CI, 0.33 to 0.61) in favour of talazoparib plus enzalutamide. The Kaplan-Meier–estimated probability of rPFS at 12 months was █████ ████ ███ ████ ██ █████ ██████ █████ ████ ███ ████ ██ █████ in the talazoparib plus enzalutamide and placebo plus enzalutamide groups, respectively, with a between-group difference of █████ ████ ███ ████ ██ ██████ The results of sensitivity analyses were consistent with the primary analysis. At the second data cut-off date of September 3, 2024, rPFS descriptive results were consistent with the first data cut-off date (Table 10). The median rPFS was 30.7 months (95% CI, 24.3 months to 38.5 months) in the talazoparib plus enzalutamide group and 12.3 months (95% CI, 11.0 months to 16.5 months) in the placebo plus enzalutamide group. The Kaplan-Meier–estimated probability of rPFS at 48 months was █████ ████ ███ ████ ██ █████ ██████ █████ ████ ███ ███ ██ █████ in the talazoparib plus enzalutamide and placebo plus enzalutamide groups, respectively, with a between-group difference of █████ ████ ███ ████ ██ ██████

rPFS Subgroup Analyses

The rPFS results were consistent across the subgroup analyses of interest by BRCA alteration status (with or without) and prior treatment with NHT or taxane therapy in favour of talazoparib plus enzalutamide. Based on the data cut-off date of September 3, 2024, the stratified HR for patients with BRCA alterations was 0.26 (95% CI, 0.16 to 0.42), and without BRCA alterations was 0.65 (95% CI, 0.47 to 0.91). For patients with prior NHT or taxane exposure, the rPFS HR was ████ ████ ███ ████ ██ █████, and for patients with no prior NHT or taxane exposure, the HR was ████ ████ ███ ████ ██ ██████

Table 11: rPFS by BICR — ITT Population With HRR Deficiencies, TALAPRO-2 Trial

BICR = blinded independent central review; CI = confidence interval; HRR = homologous recombination repair; ITT = intention to treat; NE = not estimable; rPFS = radiographic progression-free survival.

^aBased on Kaplan-Meier estimates.

^bP values were tested within a hierarchical testing strategy to control for multiple comparisons.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Figure 2: Kaplan-Meier Plot of rPFS by BICR — ITT Population With HRR Deficiencies, TALAPRO-2 Trial

BICR = blinded independent central review; CI = confidence interval; HR = hazard ratio; HRR = homologous recombination repair; ITT = intention to treat; NE = not estimable; PFS = progression-free survival; rPFS = radiographic progression-free survival.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Overall Survival

Table 12 provides a summary of results for OS. In total, 219 events had occurred in both groups by the data cut-off date of September 3, 2024. The median follow-up for OS was 44.2 months (range not reported) for the talazoparib plus enzalutamide group and ████ ██████ (range not reported) for the placebo plus enzalutamide group (Figure 3). The median OS was 45.1 months (95% CI, 35.4 months to not reached) for the talazoparib plus enzalutamide group and 31.1 months (95% CI, 27.3 months to 35.4 months) in the placebo plus enzalutamide group (log-rank test P < 0.0001), with a between-group HR of 0.62 (95% CI, 0.48 to 0.81) in favour of talazoparib plus enzalutamide. The results of sensitivity analyses were consistent with the primary analysis. The Kaplan-Meier–estimated probability of OS at 12 months was █████ ████ ███ ████ ██ █████ ██████ █████ ████ ███ ████ ██ ████ ██ ███ ████████████████████████ ███ ████████████████████ ███████ █████████████ ███████ █████ ███████████ ████ ████ ███ ████ ██ ██████ The Kaplan-Meier–estimated probability of OS at 48 months was █████ ████ ███ ████ ██ █████ ██████ █████ ████ ███ ████ ██ █████ █████████████ ███████████ █████ ████ ███ ████ ██ ██████ ██ ███ ████████████████████████ ███ ████████████████████ ███████ █████████████

Table 12: Overall Survival — ITT Population With HRR Deficiencies, TALAPRO-2 Trial

CI = confidence interval; HRR = homologous recombination repair; ITT = intention to treat; NE = not estimable.

^aBased on Kaplan-Meier estimates.

^bP values were tested within a hierarchical testing strategy to control for multiple comparisons.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Figure 3: Kaplan-Meier Plot of OS by BICR — ITT Population With HRR Deficiencies, TALAPRO-2 Trial

BICR = blinded independent central review; CI = confidence interval; HR = hazard ratio; HRR = homologous recombination repair; ITT = intention to treat; NE = not estimable; OS = overall survival.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Time to Deterioration of Pain by BPI-SF

At the data cut-off date of September 3, 2024, 58 events had occurred in both groups, and the median time to deterioration of pain was not reached in either group (Figure 4). The stratified between-group HR was 0.55 (95% CI, 0.33 to 0.94) in favour of talazoparib plus enzalutamide. ███ ████████████ ███████████ ██ █████ ████ ██ ████ ███████████ ██ ██ ██████ ███ █████ ████ ██ ███ █████████ ██████ █████ ████ ██ ███ █████████ █████████████ ███████████ ████ ████ ███ ████ ██ ███████ ███ ██ ██ ██████ ███ █████ ████ ██ ███ █████████ ██████ █████ ████ ██ ███ █████████ █████████████ ███████████ █████ ████ ███ ███ ██ ██████ ██ ███ ████████████████████████ ███ ████████████████████ ███████ █████████████

Figure 4: Kaplan-Meier Plot of Time to Deterioration in Pain Symptoms by BPI-SF — ITT Subset Population With HRR Deficiencies, TALAPRO-2 Trial

BPI-SF = Brief Pain Inventory–Short Form; CI = confidence interval; HR = hazard ratio; HRR = homologous recombination repair; ITT = intention to treat; NE = not estimable.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

HRQoL by EORTC QLQ-PR25

The EORTC QLQ-PR25 functional and symptom scale scores at the data cut-off date of September 3, 2024, are provided in Figure 5 and Figure 6, respectively. Of the ITT population, ██ ███ ██ ███ patients in the talazoparib plus enzalutamide group and ██ ███ ██ ███ patients in the placebo plus enzalutamide group contributed to the analyses at week 109, except for the incontinence aid symptoms score, which was informed ██ ██ ███ ██ patients, respectively. No comparison was made for the sexual functioning score due to limited data. The sexual activity score and the symptom scale scores were generally maintained and similar in both treatment groups up to week 109. Improvements in urinary and bowel symptoms favoured the talazoparib plus enzalutamide group, with urinary symptoms reaching the MID threshold of greater or equal to 5 points, suggesting a clinically important improvement. All other scale scores did not reach the clinically important MID threshold.

Figure 5: [Redacted]

Note: Figure 5 contained confidential information and was removed at the request of the sponsor.

Figure 6: Forest Plot of Estimated Treatment Difference in EORTC QLQ-PR25 Symptom Scales — ITT Population With HRR Deficiencies, TALAPRO-2 Trial

CI = confidence interval; ENZA = enzalutamide; EORTC QLQ-PR25 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer; HRR = homologous recombination repair; ITT = intention to treat; TALA = talazoparib.

Note: Results are based on the data cut-off date of September 3, 2024.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Harms

Harms data reported in this section are from the data cut-off date of September 3, 2024, and summarized in Table 13.

Treatment-Emergent Adverse Events

Almost all patients in both treatment groups reported at least 1 TEAE (99.5% with talazoparib plus enzalutamide and 97.5% with placebo plus enzalutamide). The most frequently reported TEAEs in the talazoparib plus enzalutamide group were anemia (66.7% versus 18.6% with placebo plus enzalutamide), fatigue (34.8% versus 28.1% with placebo plus enzalutamide), and decreased neutrophil count (34.8% versus 7.0% with placebo plus enzalutamide); a higher proportion of patients in the talazoparib plus enzalutamide group reported these TEAEs than the placebo plus enzalutamide group. The most frequently reported TEAEs in the placebo plus enzalutamide group were fatigue (28.1% versus 34.8% with talazoparib plus enzalutamide), arthralgia (24.6% versus 16.7% with talazoparib plus enzalutamide), and back pain (23.1% versus 24.2% with talazoparib plus enzalutamide). A higher proportion of patients in the talazoparib plus enzalutamide group experienced at least 1 grade 3 or grade 4 TEAE ███████ versus the placebo plus enzalutamide group ████████

Serious TEAEs

The incidence of serious TEAES were higher in the talazoparib plus enzalutamide group ███████ versus the placebo plus enzalutamide group ███████ In both groups, ██████ █████ ████████ ███ ███████ █████ █████████ █████ ██ █████ were the most frequently reported serious TEAEs.

Withdrawals Due to TEAES

A higher proportion of TEAEs that led to study treatment discontinuation were reported in the talazoparib plus enzalutamide group (████) versus the placebo plus enzalutamide group (████), with anemia being the most common reason (████ ███ ████). Enzalutamide-only treatment discontinuation was reported for ████ of patients in the talazoparib plus enzalutamide group versus ████ in the placebo plus enzalutamide group.

Mortality

A lower proportion of deaths were reported in the talazoparib plus enzalutamide group (46.5%) versus placebo plus enzalutamide (63.3%), with ███████ ███████████ being the primary reason for death in both groups ██████ ██████ ███████

Notable Harms

The incidence of notable harms in both treatment groups was comparable and infrequent. Second primary malignancies (other than hematologic) occurred in ████ ███ ████ of patients, and embolic and thrombotic events occurred in 5.6% and 1.0% of patients in the talazoparib plus enzalutamide and placebo plus enzalutamide groups, respectively. There was 1 case of pneumonitis in each group.

Table 13: Summary of Harms Results — Safety Population With HRR Deficiencies, TALAPRO-2 Trial

AE = adverse event; HRR = homologous recombination repair; SAE = serious adverse event; TEAE = treatment-emergent adverse event; WBC = white blood cell.

^aOnly included events which occurred in > 2 patients.

Sources: TALAPRO-2 HRR-deficient Clinical Study Report.¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

TALAPRO-2 was a randomized, double-blind, phase III trial. The patients and investigators were blinded to talazoparib or placebo but enzalutamide was open label. This design was appropriate because different dosing and oral tablets across the 2 treatment groups may have made blinding to enzalutamide impractical. Randomization procedures, including stratification by prior NHT or taxane therapy for CSPC and HRR gene alteration status (deficient versus nondeficient or unknown) were appropriate and conducted by interactive response technology. The talazoparib plus enzalutamide group had a ██████ ████ ████████ █████ ███ █████ ██████ █████ ███ █ ██████ ██████████ ██ ████████ ███ ███ ████████ ██████ █████████ ██████ ██████ ██████. These imbalances were likely due to chance, as ███ █████ ████████ ███████████████ ██ ████████ ████████ ████████ ███████ ██████ and based on clinical expert feedback, unlikely to have confounded the effect between treatment and outcomes.

Sample size and power calculations were based on the primary outcome of rPFS, and the trial was powered to detect significant differences for rPFS, but it was underpowered for the secondary outcome of OS. The interim analyses were preplanned with adequately justified stopping boundaries and the prespecified analyses of rPFS and OS were appropriately controlled for multiple comparisons. All other analyses were descriptive (i.e., not controlled for type I error), including the pain and HRQoL outcomes, which were deemed clinically important outcomes for the disease. The sample size for the prespecified subgroup analyses of interest for rPFS was small; the trial may not have been powered to detect subgroup differences.

Although patients and investigators were blinded to treatment assignment (enzalutamide was open label), there was a potential for unblinding due to the imbalances in TEAEs, particularly anemia across treatment groups (i.e., higher in the talazoparib plus enzalutamide group). Knowledge of treatment assignment could increase the risk of bias in the measurement of subjective outcomes, including HRQoL and subjective harms, although the extent and direction of bias cannot be predicted. To minimize the risk of bias in the measurement of rPFS, the trial performed tumour assessments using RECIST 1.1 criteria and radiographic scans were assessed by BICR. In addition, the findings of the sensitivity analyses for rPFS were consistent with the primary analysis.

Patients were permitted to receive posttreatment anticancer medications after study treatment had been discontinued (36.9% in the talazoparib plus enzalutamide group versus 56.8% in the placebo plus enzalutamide group), which may influence the assessment of OS. Because no sensitivity analyses were performed to test treatment policy strategy for OS (e.g., exclude the effect of subsequent therapies), the estimated effect would be a combination of treatment with talazoparib plus enzalutamide versus placebo plus enzalutamide, plus subsequent treatments. Therefore, survival results might be partially attributable to treatments administered after disease progression rather than the study treatment itself, although without the necessary analysis the direction and magnitude of bias is unclear. However, this is a relevant comparison, as it is reflective of how the intervention and comparator and subsequent therapies would be used in practice in Canada.

Based on the Clinical Study Report and statistical analysis plan, the proportional hazards assumption was not assessed or discussed. Despite the absence of these results, visual inspection of the Kaplan-Meier curves for rPFS and OS appears to indicate a clear separation (at approximately 3 months and 8 months, respectively), after which there appeared to be sustained proportionality throughout study treatment.

HRQoL was assessed by the BPI-SF and EORTC QLQ-PR25 questionnaires, which have been validated in patients with metastatic prostate cancer with evidence of reliability, responsiveness, and MID. The result of these outcomes was subject to potential bias due to more than 50% of missing data in each group, with a higher proportion of missing data in the placebo plus enzalutamide group, which could have biased the results in favour of talazoparib plus enzalutamide. For the EORTC QLQ-PR25, no models other than the mixed model for repeated measures were tested that applied alternative imputation methods or sensitivity analyses to assess the impact of missing data. The results were also subject to bias potentially due to differential incidence of notable harms such as anemia, although the direction and extent of bias are unclear.

External Validity

In general, the population requested for the reimbursement aligns with the approved Health Canada–approved indication, and the dosing and administration of talazoparib plus enzalutamide were consistent with the approved product monograph. However, the trial provided talazoparib plus enzalutamide as first-line treatment only (i.e., patients had not received prior systemic therapy for mCRPC) while the approved Health Canada indication is line agnostic. Therefore, there is no direct comparative evidence for the use of talazoparib plus enzalutamide in the second-line, third-line, and later-line settings. The clinical experts consulted by CDA-AMC noted that many medical oncologists currently favour prescribing chemotherapy for the first-line treatment of mCRPC in patients who have previously progressed on an ARPI in the metastatic CSPC and nonmetastatic CRPC settings. Therefore, the experts indicated that most clinicians would likely prescribe talazoparib plus enzalutamide as a second-line and beyond treatment due to the decreasing number of patients who are ARPI naive in the first-line mCRPC setting.

According to the clinical experts consulted by CDA-AMC, the eligibility criteria and baseline characteristics of the TALAPRO-2 trial are generalizable to adult patients with mCRPC in the setting in Canada, except that the trial did not include patients with an ECOG PS of greater than 1. The clinical experts indicated that patients with good ECOG PS or a score of 0 to 2 should be eligible for talazoparib plus enzalutamide, if they are able to tolerate the therapy. The clinical experts noted that although enzalutamide was an appropriate comparator when the TALAPRO-2 trial was designed and executed, the current treatment paradigm has shifted since then toward the use of chemotherapy as the most common first-line treatment for patients with mCRPC. The evidence submitted to CDA-AMC did not include head-to-head comparisons between talazoparib plus enzalutamide and chemotherapy, which represents a gap in the available direct evidence given the potential shared place in therapy when used as first-line treatments for mCRPC.

Dose adjustments were allowed in the trial and the methods were outlined in the protocol. The clinical experts noted that dose adjustments or modifications are anticipated in a clinical practice setting to manage AEs while maintaining drug benefit.

The trial included outcomes that were important to patients. The patient group indicated that stopping disease progression, prolonging life, improving symptoms and HRQoL, and reducing treatment side effects are important to them.

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 expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^74,75

• 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 rPFS and OS were set according to the presence or absence of an important effect based on thresholds informed by the clinical experts consulted for this review. A threshold could not be determined for time to deterioration of pain by BPI-SF; therefore, the target of certainty appraisal was any effect. The reference points for the certainty of the evidence assessment for EORTC QLQ-PR25 functional and symptom scale scores were set according to the presence or absence of an important effect based on a threshold informed by the literature.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for talazoparib plus enzalutamide versus placebo plus enzalutamide.

Long-Term Extension Studies

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

Indirect Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the review team.

Objectives for the Summary of Indirect Evidence

The aim of this section is to summarize and critically appraise 1 sponsor-submitted MAIC⁷⁶ to inform the pharmacoeconomic model and fill gaps in the comparative evidence for other treatments of interest for adults with HRR gene-mutated mCRPC.

Description of Indirect Comparison

The study selection criteria and methods for the MAIC are summarized in Table 14. The protocol for the systematic literature review was a priori registered with PROSPERO (registration number CRD42021283512).

Table 14: Study Selection Criteria for Indirect Treatment Comparisons Submitted by the Sponsor

CDA-AMC = Canada’s Drug Agency; CRPC = castration-resistant prostate cancer; ITC = indirect treatment comparison; mCRPC = metastatic castration-resistant prostate cancer; NICE = National Institute for Health and Care Excellence; ORR = objective response rate; OS = overall survival; PSA = prostate-specific antigen; rPFS = radiographic progression-free survival.

Sources: Matching-adjusted indirect comparison technical report.⁷⁶ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

MAIC Design

Objectives

The objective of the MAIC was to assess the treatment effects of talazoparib plus enzalutamide versus relevant comparators of interest, which included enzalutamide monotherapy, AAP, niraparib-abiraterone plus prednisone, and olaparib plus AAP in adults with HRR-gene-mutated mCRPC.

███ ████ ███ █████████ ██ ████ ██ █ ██████ ███████ ███ ████████ █ █████ █████ ██ ███████████. The comparators previously listed were considered relevant to public payers in Canada by the sponsor and the comparisons are summarized in this section.

Study Selection Methods

A systematic literature review was initially conducted on September 9, 2021, and updated on October 3, 2022, and August 8, 2024. The review included RCTs assessing first-line treatments in adults with asymptomatic or mildly symptomatic mCRPC and reported on relevant outcomes (Table 13). Identified trials were assessed for eligibility against predefined inclusion and exclusion criteria and further narrowed to only include trials that reported relevant outcomes for patients with HRR gene-mutated alterations. Two reviewers independently screened relevant citations for inclusion, and discrepancies were resolved through consensus or by a third reviewer. Data extraction and quality assessment of included studies were performed by 1 reviewer and validated by a second reviewer, and discrepancies were resolved by a third reviewer. Risk of bias assessment of included studies was performed using the National Institute for Health and Care Excellence: Single Technology Appraisal Evidence Submission checklist for assessment of risk of bias in RCTs.

Search Results and Feasibility Assessment

The literature review identified 49 unique RCTs, of which 42 had published results that met the inclusion criteria for first-line treatments in adults with mCRPC. Three trials (TALAPRO-2, PROpel, and MAGNITUDE) reported data on patients receiving relevant first-line treatment for mCRPC who had HRR gene-mutated alterations and data on survival outcomes, and were included in the feasibility assessment. One trial (BRCAAway) that compared olaparib plus abiraterone acetate to olaparib alone and abiraterone acetate alone among patients with HRR gene-mutated mCRPC was excluded because it did not report on rPFS or OS. The TALAPRO-2 study compared talazoparib plus enzalutamide versus enzalutamide, the PROpel study compared olaparib plus AAP versus AAP, and the MAGNITUDE study compared niraparib-abiraterone plus prednisone versus AAP.

A feasibility assessment was undertaken to determine the extent of heterogeneity across the included 3 trials, and if indirect treatment comparisons would be appropriate. The following potential sources of heterogeneity were explored: study design, patient eligibility criteria, baseline patient characteristics, outcome characteristics, and efficacy or safety results. ███ ███████ ██ ███ ██████████ ██████████ ████ █████████████ ██████ ███ ███████ ███ ███ ███████ ████████ ████ ██ ████████████ ███████ ██ ███████ ████ ███████ ███ █████████ ███ ████ ██ ██████ ███ █████████ ██████ ███ ████ ███ ██ ██ ███ ███ ████████████ ███████████ There was no common treatment comparator between the TALAPRO-2, PROpel, and MAGNITUDE studies; therefore, unanchored MAICs were chosen using individual patient data from the TALAPRO-2 study and summary-level data from the comparator trials. The authors noted that a network meta-analysis was considered but determined unfeasible due to the lack of a common comparator between the TALAPRO-2, PROpel, and MAGNITUDE trials.

MAIC Analysis Methods

Unanchored MAICs were performed by matching and adjusting patients from the TALAPRO-2 trial to match the marginal distribution (e.g., mean and variance) of covariates in patients who received the comparator treatment. Key factors for adjustment were identified and ranked in order of importance based on published analyses⁷⁷ on prognostic strength in mCRPC and refined based on clinical input from a practising clinician experienced in treating mCRPC consulted by the sponsor. Presence of BRCA1, BRCA2, or PALB2 HRR gene alterations was also considered for adjustment based on external clinical input as an exploratory analysis. The final list of 12 factors, ranked from 1 (most important) to 12 (least important) is in Table 15.

After completing the matching phase of the MAIC, patients remaining from the TALAPRO-2 study were weighted using logistic regression and method of moments. Trial stratification factors at randomization by HRR alternation status and prior NHT or taxane-based therapy in the CSPC setting, which were reported in all 3 trials, were adjusted where necessary. Following the population adjustment of the TALAPRO-2 study’s population with HRR deficiencies to the comparator trials, rPFS and OS estimates of the comparative efficacy of talazoparib plus enzalutamide versus comparator treatments were derived by digitizing published Kaplan-Meier curves and applying the Guyot method. A dataset combining weighted individual patient data and pseudoindividual patient data were then used to fit a weighted Cox proportional hazards model with a binary treatment indicator. The estimated regression coefficient for the treatment indicator was used to represent the log HR for talazoparib plus enzalutamide versus the comparator treatment, and the corresponding variance was estimated using a robust sandwich estimator. Effect estimates were exponentiated and reported as HRs with 95% CIs for the population with HRR gene mutations. The effective sample size was calculated to reflect the sample size of the weighted population, and population differences between the TALAPRO-2 study and the comparator trials were assessed using standardized mean differences; a standardized mean difference between 0 and 0.1 was considered a small difference, a standardized mean difference of greater than 0.1 and less than or equal to 0.2 was a moderate difference, and a standardized mean difference of greater than 0.2 was a substantial difference. Scenario analyses were conducted to investigate the impact on the treatment effect estimates, effective sample size, and standardized mean difference when adjusting for additional covariates in the analyses. These analyses were conducted sequentially, adjusting incrementally for the remaining factors in order of importance, until the final model contained all available factors.

Table 15: Factors for Adjustment in the MAICs

ADT = androgen deprivation therapy; BPI-SF = Brief Pain Index–Short Form; ECOG PS = Eastern Cooperative Oncology Group Performance Status; MAIC = matching-adjusted indirect comparison; mCRPC = metastatic castration-resistant prostate cancer; NR = not reported in the trial; PSA = prostate-specific antigen; vs. = versus.

Sources: MAIC technical report.⁷⁶ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results of Indirect Treatment Comparison

Summary of Included Studies

Trial characteristics such as phase, study design, blinding, setting, and number of patients randomized, and outcome reporting for rPFS and OS were generally similar between the TALAPRO-2, PROpel, and MAGNITUDE trials. In the assessment of patient eligibility criteria, the included trials generally recruited adult patients with confirmed adenocarcinoma of the prostate, who had asymptomatic or mildly symptomatic disease, were surgically or medically castrated, had metastatic disease, and did not receive prior cytotoxic chemotherapy. Substantial heterogeneity was noted for the MAGNITUDE study, which had broader eligibility criteria than the TALAPRO-2 study by permitting the prior use of AAP in the mCRPC state. Although only 4 months or less of AAP was allowed, approximately 25% of the patients were not truly naive, whereas all patients were treatment naive in the mCRPC state in the TALAPRO-2 trial. Therefore, matching was not possible for this criterion. The PROpel trial was broader than the TALAPRO-2 study for the pain criteria measured by BPI-SF. The PROpel study had no eligibility restrictions based on BPI-SF, whereas the TALAPRO-2 study required patients to have a score of less than or equal to 3 on question 3 of the BPI-SF (worst pain in the last 24 hours). In the PROpel study, 25.8% of patients in the olaparib plus AAP group were considered symptomatic (defined as those with a BPI-SF score ≥ 4 and/or opiate use). Therefore, matching was not possible on this criterion.

The authors noted that it was not possible to account for all differences between the trial populations. Analyses between the TALAPRO-2 study and comparator trials were limited by reporting of baseline characteristics of interest in the comparator trials. Additionally, the ability to account for intertrial differences was further limited by those characteristics for which eligibility criteria were broader in the aggregate comparator trials than in the TALAPRO-2 study. Both comparator trials included patients with the HRR gene mutations BRCA1 and BRCA2.

Results

The unadjusted and adjusted baseline characteristics for the population with HRR deficiencies for the TALAPRO-2 study versus the PROpel study and the TALAPRO-2 study versus the MAGNITUDE study are summarized in Figure 7 and Figure 8, respectively. The primary analysis for the PROpel and MAGNITUDE studies adjusted MAICs for 5 factors and 8 factors, respectively. ███ ████ ██████ ███ ██████████ ███████████ ███████ █████████ ███ ███ ██████████ ██████ ██████ ████ ██ ████ ████ ████ ██████████ █ █████ ██████████. For the TALAPRO-2 trial, the rPFS and OS data are based on the data cut-off date of September 3, 2024. A summary of the primary rPFS and OS results in the population with HRR deficiencies is in Table 16.

Figure 7: [Redacted]

Note: Figure 7 contained confidential information and was removed at the request of the sponsor.

Figure 8: [Redacted]

Note: Figure 8 contained confidential information and was removed at the request of the sponsor.

Radiographic Progression-Free Survival

Talazoparib Plus Enzalutamide Versus Olaparib Plus AAP (PROpel Trial)

In the primary analysis, the result ████████ ████████████████████████ ██████ ████████ ████ ████ ███ ███████ ████ ██████████ ███████ ███ ███████ ████████ ███ ███ ████████ ████████ ██████ ████████ █████ ██████ ███ ████ ███ ██████ ███████████████ ███ ███████████ ████████ █████████ ███ ████ ████ ████████████

Talazoparib Plus Enzalutamide Versus Niraparib-Abiraterone Plus Prednisone (MAGNITUDE Trial)

In the primary analysis, the result ████████ ████████████████████████ ██████ █████████ ████ ████ ███ ███████ ████ ██████████ ███████ ███ ███████ ████████ ███ ███ ████████ ████████ ██████ ████████ █████ ██████ ███ ████ ███ ██████ ███████████████ ███ ███████████ ████████ █████████ ███ ████ ████ ████████████

Talazoparib Plus Enzalutamide Versus AAP

In the primary analysis for each comparison between the TALAPRO-2 study versus the PROpel and MAGNITUDE studies, the results ████████ ████████████████████████ ██████ ████ ███ ███████ ████ ██████████ ███████ ███ ███████ ████████ ███ ███ ████████ ████████ ██████ ████████ █████ ██████ ███ ████ ███ ██████ ███████████████ ███ ███████████ ████████ █████████ ███ ████ ████ ████████████

Overall Survival

Talazoparib Plus Enzalutamide Versus Olaparib Plus AAP

In the primary analysis, the point estimate for the between-group HR ████████ ████████████████████████ ██████ ████████ ████ ███ ███ ███ ███ ██ ████████ ███ ███████████ ██ ██ ██████████ ██ ████ ███ ██████████ ███ ████████ ██████ ███████ ███ ██████ ███ ███████ ████ ██████████ ███████ ███ ███████ ████████ ███ ███ ████████ ████████ ██████ ████████ █████ ██████ ███ ████ ███ ██████ ███████████████ ███ ███████████ ████████ █████████ ███ ████ ████ ████████████

Talazoparib Plus Enzalutamide Versus Niraparib-Abiraterone Plus Prednisone

In the primary analysis (adjusted for 8 factors), the result ████████ ████████████████████████ ██████ █████████ ████ ████ ███ ███████ ████ ██████████ ███████ ███ ███████ ████████ ███ ███ ████████ ████████ ██████ ████████ █████ ██████ ███ ████ ███ ██████ ███████████████ ███ ███████████ ████████ █████████ ███ ████ ████ ████████████

Talazoparib Plus Enzalutamide Versus AAP

In the primary analysis for each comparison between the TALAPRO-2 study versus the PROpel and MAGNITUDE studies, the ███████ ████████ ████████████████████████ ██████ ████ ███ ███████ ████ ██████████ ███████ ███ ███████ ████████ ███ ███ ████████ ████████ ██████ ████████ █████ ██████ ███ ████ ███ ██████ ███████████████ ███ ███████████ ████████ █████████ ███ ████ ████ ███████████.

Table 16: Summary of MAIC Results for rPFS and OS — Population With HRR Gene Mutations

AAP = abiraterone acetate plus prednisone; BICR = blinded independent central review; CI = confidence interval; HR = hazard ratio; HRR = homologous recombination repair; MAIC = matching-adjusted indirect comparison; OS = overall survival; rPFS = radiographic progression-free survival; vs. = versus.

Note: An HR below 1.0 indicates an improved outcome for talazoparib plus enzalutamide relative to olaparib plus AAP, niraparib-abiraterone plus prednisone, or AAP.

Sources: MAIC technical report.⁷⁶ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal of MAIC

The methods used to conduct the systematic literature review for the MAIC were a priori registered, and used appropriate criteria to search databases, select studies, extract data, and assess risk of bias of the included studies. The MAIC did not include comparisons between talazoparib plus enzalutamide and chemotherapy, which represents a gap in the available indirect evidence given the shared place in therapy for mCRPC. The MAIC included relevant outcomes identified by the CDA-AMC team (rPFS and OS); however, clinically relevant and patient-relevant outcomes such as pain, HRQoL, and harms were not included in the comparisons. Due to a lack of a common comparator group between trials, unanchored MAICs were conducted, and attempts were made to adjust for important prognostic factors and treatment effect modifiers (i.e., clinical factors).

To account for between-study differences in patient baseline characteristics, several potentially relevant clinical factors were matched in the weighting process for each comparison between the TALAPRO-2 study and comparator trials. The methods used to identify and rank the clinical factors were considered appropriate. The process involved identifying and ranking clinical factors in order of importance based on published analyses for mCRPC and refined based on clinical input from a practising clinician experienced in treating patients with mCRPC consulted by the sponsor. For both the PROpel and MAGNITUDE trials, adjustments were limited by how, and if, these variables were reported in both trials. The TALAPRO-2 study stratified by prior NHT or taxane therapy per interactive web response system as a single variable whereas the PROpel and MAGNITUDE studies reported these variables separately. The PROpel study used the interactive web response system value, whereas the MAGNITUDE study did not specify interactive web response system or electronic data capture. Because interactive web response system values were combined in the TALAPRO-2 study but electronic data capture values were presented separately, electronic data capture values were used to align with reporting of comparator trials. Further, the TALAPRO-2 study stratified by prior therapy in the CSPC stage. The PROpel study reported the proportion of patients who received NHT and taxane-based therapy but did not specify the disease stage. The MAGNITUDE study reported the proportion of patients who received NHT and taxane-based therapy in the metastatic CSPC or nonmetastatic CRPC stage into a single variable. There were important differences in eligibility criteria between the MAGNITUDE and TALAPRO-2 studies. The MAGNITUDE study allowed the use of AAP in the mCRPC setting for 4 months or less whereas all patients were treatment naive in the mCRPC setting within the TALAPRO-2 trial. Because only summary-level data were available for the MAGNITUDE study, patients who were not truly treatment naive could not be removed when performing analyses. It is possible that these patients had different disease characteristics compared to the rest of the trial population. Overall, the magnitude and direction of potential bias due to imbalances for the rPFS and OS estimates cannot be predicted. The proportional hazards assumption was also not assessed or discussed. Because the unanchored nature of the MAIC requires a stronger assumption (than an anchored MAIC) that all effect modifiers and prognostic factors have been included in the analysis, which was not possible, definitive conclusions based on these results are not recommended. Further, the sponsor’s highest-ranked (most important) factor for adjustment in the MAIC, time to mCRPC from continuous ADT, could not be adjusted for in the analysis.

Additionally, following the weighting process after adjusting for 8 clinical factors, the effective sample size of the talazoparib cohort for the primary analysis declined by more than 50% of the original sample size for the comparison with niraparib-abiraterone plus prednisone. A significant reduction in sample size can contribute to imprecision, increasing uncertainty of the results. A notable reduction in effective sample size also suggests that results may be heavily influenced by a subset of the sample in the trials that may not be representative of the full sample. Given that the population of these analyses were weighted to the TALARPO-2 study, the results may be driven by a subset of patients in the talazoparib group, limiting generalizability to the full population presented by the TALAPRO-2 study. Due to the limitations in the MAICs, the effects of talazoparib plus enzalutamide on PFS and OS compared with comparators in the MAICs are uncertain.

Studies Addressing Gaps in the Systematic Review Evidence

No additional studies were submitted by the sponsor.

Discussion

Summary of Available Evidence

One pivotal phase III, randomized, double-blind trial and 1 indirect treatment comparison submitted by the sponsor were summarized in this report.

The TALAPRO-2 trial (cohort 2, N = 399) met the inclusion criteria for the systematic review conducted by the sponsor. An objective of the trial was to assess the efficacy and safety of talazoparib 0.5 mg plus enzalutamide 160 mg, taken orally once daily, or matched placebo plus enzalutamide in adult patients with HRR-deficient mCRPC. The trial enrolled adults with asymptomatic or mildly symptomatic mCRPC who had not started systemic cancer treatment after the diagnosis of CRPC (metastatic or nonmetastatic), with the exception of ADT and first-generation antiandrogen drugs. Patients were allowed to have previously received abiraterone acetate or docetaxel for CSPC but were ineligible to participate if they had received any prior treatment with second-generation androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide), a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer. Patients were required to have had an ECOG PS score of 0 or 1, and progressive disease at study entry. The approved Health Canada indication and reimbursement request aligned with the trial’s population with HRR deficiencies. The outcomes relevant to this review included the primary outcome of rPFS, the key secondary outcome of OS and HRQoL outcomes of time to deterioration of pain symptoms measured via BPI-SF and EORTC QLQ-PR25 functional and symptom scales, and safety. The rPFS data are based on the primary analysis data cut-off date of October 3, 2022, and supportive data from the data cut-off date of September 3, 2024. All other outcomes were based on the data cut-off date of September 3, 2024. Overall, key baseline characteristics were generally balanced between treatment groups. The trial population was predominately white (68%), with a median age of 70 years. Most patients had an ECOG PS score of 0 (approximately 62%), indicating good overall performance; normal or mild renal impairment (approximately 90%); bone and soft tissue disease-site metastasis (approximately 84%); a Gleason score greater than or equal to 8 (approximately 74%); and had prior therapy with surgery or biopsy (█████████████ ████ and first-generation antiandrogens (█████████████ ███). In both groups, the most commonly detected HRR gene alteration was BRCA2 (33.8%), followed by ATM (21.6%), CDK12 (18.8%), and CHEK2 (17.8%). ███ ████████████████████████ █████ ███ █ ██████ ████ ████████ █████ ███ █████ ██████ █████ ███ █ ██████ ██████████ ██ ████████ ███ ███ ████████ ██████ █████████ ██████ ██████ ██████. These imbalances were likely due to chance, as ███ █████ ████████ ███████████████ ██ ████████ ████████ ████████ ███████ ██████.

To inform the pharmacoeconomic model and fill gaps in the comparative evidence for other treatments of interest for adults with HRR gene-mutated mCRPC, a MAIC was conducted by the sponsor. The objective of the MAIC was to assess the treatment effects of talazoparib plus enzalutamide versus relevant comparators, which included enzalutamide monotherapy, AAP, niraparib-abiraterone plus prednisone, and olaparib plus AAP in adults with HRR gene-mutated mCRPC. Outcomes of interest included rPFS and OS. Key clinical factors for adjustment were identified and ranked in order of importance based on published analyses on prognostic strength in mCRPC and refined based on clinical input received by the sponsor from a practising clinician experienced in treating mCRPC. Individual patient data from the TALAPRO-2 trial population with HRR deficiencies were adjusted to match the marginal distribution (e.g., mean, variance) of clinical factors of patients for each comparison between the PROpel (olaparib plus AAP versus AAP) and MAGNITUDE (niraparib-abiraterone plus prednisone versus AAP) trials. Because there was no common treatment comparator between the TALAPRO-2 trial and the comparator trials, unanchored MAICs were conducted. Point estimates for rPFS and OS were reported as HRs with 95% CIs.

Interpretation of Results

The evidence from the pivotal trial, the TALAPRO-2 study, addressed treatment outcomes noted to be important by both patients and clinicians. The patient group input indicated that stopping disease progression, prolonging life, improving symptoms and HRQoL, and reducing treatment side effects are important to them. Similarly, the clinical experts consulted by the review team indicated that because mCRPC is a terminal phase of prostate cancer, the unmet needs of patients would be new treatments that would prolong survival and improve quality of life, while exposing patients to minimal toxicity. Both clinical experts highlighted that the balance between treatment efficacy and quality of life would be important.

Efficacy

The TALAPRO-2 trial supported a clinically meaningful improvement of talazoparib plus enzalutamide over placebo plus enzalutamide for rPFS and OS in adults with HRR gene-mutated mCRPC. At the data cut-off date of October 3, 2022, the trial met its primary outcome of rPFS, with a median duration of follow-up of 17.5 months for the talazoparib plus enzalutamide group and 16.8 months for the placebo plus enzalutamide group. The median rPFS was not reached (95% CI, 21.9 months to not reached) in the talazoparib plus enzalutamide group and was 13.8 months (95% CI, 11.0 months to 16.7 months) for the placebo plus enzalutamide group. At the data cut-off date of September 3, 2024, the median rPFS was 30.7 months (95% CI, 24.3 months to 38.5 months) in the talazoparib plus enzalutamide group and 12.3 months (95% CI, 11.0 months to 16.5 months) in the placebo plus enzalutamide group. The between-group difference in probability of rPFS at 12 months (data cut-off date of October 3, 2022) and 48 months (data cut-off date of September 3, 2024) was █████ ████ ███ ████ ██ █████ ███ █████ ████ ███ ████ ██ ██████ ████████████. For the GRADE assessment, the clinical experts consulted by CDA-AMC suggested a clinically important threshold of 20% and 5% for between-group absolute risk difference at 12 months and 48 months, respectively. Based on these thresholds, there was moderate certainty of evidence for a clinically important increase in the probability of rPFS at 12 months and 48 months, respectively. The rPFS findings were generally consistent across the subgroup analyses by BRCA alteration status (with or without) and prior treatment with NHT or taxane therapy in favour of talazoparib plus enzalutamide. The HR for the BRCA alterations subgroup was larger than the subgroup without BRCA alteration, in favour of talazoparib plus enzalutamide. The sample size for the prespecified subgroup analyses of interest was small and was not powered to detect subgroup differences. At the data cut-off date of September 3, 2024, the median duration of follow-up for OS was 44.2 months in the talazoparib plus enzalutamide group and ████ ██████ for the placebo plus enzalutamide group. The median OS was 45.1 months (95% CI, 35.4 months to not reached) for the talazoparib plus enzalutamide group and 31.1 months (95% CI, 27.3 months to 35.4 months) for the placebo plus enzalutamide group. The between-group difference in probability of OS at 12 months and 48 months was ████ ████ ███ ████ ██ ████ ███ █████ ████ ███ ████ ██ ██████ ████████████. For the OS GRADE assessment, the clinical experts suggested a clinically important threshold of 10% and 5% for between-group absolute risk difference at 12 months and 48 months, respectively. Based on these thresholds, there was high certainty of evidence for little to no clinically important difference in the probability of OS at 12 months, and clinically important increase in the probability of OS at 48 months. Because patients were permitted to receive posttreatment anticancer therapy after study treatment had been discontinued (36.9% in the talazoparib plus enzalutamide group versus 56.8% in the placebo plus enzalutamide group), the potential treatment benefit on OS would have been subject to a degree of uncertainty.

At the data cut-off date of September 3, 2024, the median time to deterioration of pain symptoms was not reached in either group. For the GRADE assessment, clinically important thresholds at 12 months and 48 months could not be determined; therefore, the target of certainty was any effect. There was low certainty of evidence for a higher probability of being free of pain progression at 12 months and 48 months, respectively, in favour of talazoparib plus enzalutamide. The low certainty of evidence at 12 months was attributed to very serious imprecision due to the 95% CI for the between-group difference including both the possibility of benefit and harm, and at 48 months was attributed to risk of bias due to missing outcome data. For the EORTC QLQ-PR25 functional and symptom scale scores at week 109, there was low certainty of evidence in little to no clinically important difference in functional or symptom scores, based on an MID estimate of 5 points, or the evidence was very uncertain about the effect compared to placebo plus enzalutamide. The low certainty of evidence was attributed to risk of bias due to missing outcome data. The very low certainty of evidence was attributed to serious imprecision due to the 95% CI for the between-group difference including the possibility of important harm, little to no difference or important benefit, and risk of bias due to missing outcome data. No data were available for the sexual functioning score.

The CDA-AMC reviewers and the clinical experts noted some potential gaps and implementation challenges in applying the evidence from the trial. The CDA-AMC reviewers noted that because the trial and sponsor-submitted MAIC evaluated talazoparib plus enzalutamide as first-line treatment only (i.e., patients had not received prior systemic therapy for mCRPC) and the approved Health Canada indication is line agnostic, there is no direct or indirect comparative evidence for the use of talazoparib plus enzalutamide in later-line settings.

The clinical experts noted that enzalutamide was an appropriate comparator when the TALAPRO-2 trial was designed and executed; however, the current treatment paradigm has shifted since then toward the use of chemotherapy as the most common first-line treatment for patients with HRR-deficient mCRPC. The evidence submitted to CDA-AMC did not include head-to-head comparisons between talazoparib plus enzalutamide and chemotherapy, which represents a gap in the available direct evidence given the potential shared place in therapy for mCRPC when used as first-line treatments. As such, the clinical experts indicated that most clinicians would likely prescribe talazoparib plus enzalutamide as a second-line and beyond treatment due to the decreasing number of patients who are ARPI naive in the first-line mCRPC setting.

Based on the sponsor-submitted unanchored MAICs, the rPFS HR point estimates and 95% CIs ████████ ████████████████████████ ██████ ████████ ████ ████ █████████ ████ ████ ███ ███ ██████ ███ ███ ███ ███████ ████████ ████████████████████████ ██████ █████████ ████ ███ ███ ███ ██████ ███ ██ █████ ████████ ████████ ████████████████████████ ██████ ████████ ████ ███ ███ ███ ███ ██ ████████ ███ ███████████ ██ ██ ██████████ ██ ████ ███ ██████████ ███ ████████ ██████ ███████ ███ ██████ ███ ████████████ ███████ ██████████ ███ ███ ████████ ██ █████████. The rPFS and OS primary analyses for the MAICs in the PROpel and MAGNITUDE studies adjusted for 5 and 8 treatment effect modifiers and prognostic factors, respectively. However, not all factors could be matched or adjusted, including the factor rated of highest importance; therefore, imbalances remained. There were also differences in trial eligibility criteria that could not be controlled for by matching. Because the unanchored nature of the MAIC requires a stronger assumption (than an anchored MAIC) that all effect modifiers and prognostic factors have been included in the analysis, which was not possible, the effects of talazoparib plus enzalutamide on rPFS and OS compared with the comparator drugs in the MAICs are uncertain and conclusions based on these results are not recommended.

Harms

At the data cut-off date of September 3, 2024, almost all patients in both treatment groups reported at least 1 TEAE. The most frequently reported TEAEs in the talazoparib plus enzalutamide group were anemia, fatigue, and decreased neutrophil count, and occurred more frequently than in the placebo plus enzalutamide group. A higher proportion of patients in the talazoparib plus enzalutamide group also experienced at least 1 grade 3 or grade 4 TEAE. The incidence of serious TEAEs was higher in the talazoparib plus enzalutamide group, with ██████ ███ ███████ █████ ██████████ being the most frequently reported. A higher proportion of TEAEs that led to study treatment discontinuation was reported in the talazoparib plus enzalutamide group, with anemia being the most common reason. The incidence of death was lower in the talazoparib plus enzalutamide group, with ███████ ███████████ being the primary reason for death in both groups. The incidence of notable harms, which included embolic and thrombotic events and pneumonitis, was comparable and infrequent in both treatment groups. The clinical experts indicated that the incidence of these TEAEs is expected with talazoparib plus enzalutamide, and that with appropriate care, the TEAEs would be manageable for many patients. The patient group input for this review highlighted a need for alternative tolerable treatments. However, it is uncertain whether talazoparib plus enzalutamide is a more tolerable treatment compared to placebo plus enzalutamide because a higher incidence of TEAEs, particularly anemia, and serious TEAEs were reported with this treatment regimen.

The sponsor-submitted MAIC did not include harms; therefore, no conclusions could be drawn on the relative safety of talazoparib plus enzalutamide versus other relevant comparators.

Conclusion

Evidence from 1 phase III, randomized, double-blind trial (TALAPRO-2) reported on outcomes that were important to both patients and clinicians. The trial showed moderate certainty of evidence that treatment with talazoparib plus enzalutamide results in a clinically important increase in rPFS at 12 months and 48 months, respectively, compared to placebo plus enzalutamide in adults with HRR-deficient mCRPC in the first-line setting. The trial showed high certainty of evidence of a clinically important increase in OS at 48 months in favour of talazoparib plus enzalutamide. There was low certainty of evidence for a higher probability of being free of pain progression at 12 months and 48 months, respectively, in favour of talazoparib plus enzalutamide. Up to 109 weeks, no definitive conclusions can be drawn on other HRQoL outcomes due to concerns of imprecision and missing outcome data. There were no new safety signals identified, and the safety of talazoparib plus enzalutamide was consistent with the known safety profiles of the individual drugs, although the trial showed a higher proportion of TEAEs and serious TEAEs when compared with placebo plus enzalutamide. Due to limitations of the indirect treatment comparison, mostly attributed to the heterogeneity across studies and lack of safety assessment, no conclusions can be drawn on the relative efficacy and safety of talazoparib plus enzalutamide compared to relevant comparators, which included olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP alone. The evidence submitted to CDA-AMC did not include direct or indirect comparisons between talazoparib plus enzalutamide and chemotherapy, which represents a gap in the available evidence given the potential shared place in therapy for HRR-deficient mCRPC when used as first-line treatments. The TALAPRO-2 trial and submitted indirect treatment comparison evaluated talazoparib plus enzalutamide as a first-line treatment only; therefore, the efficacy and safety of talazoparib plus enzalutamide as a second-line or later-line treatment for HRR-deficient mCRPC represents a gap in the evidence.

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Pharmacoeconomic Review

Abbreviations

Economic Review

The objective of the economic review undertaken by Canada’s Drug Agency (CDA-AMC) is to review and critically appraise the pharmacoeconomic evidence submitted by the sponsor on the cost-effectiveness and budget impact of talazoparib plus enzalutamide compared to abiraterone acetate plus prednisone (AAP), enzalutamide, niraparib-abiraterone plus prednisone, and olaparib plus AAP for treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).

Table 1: Submitted for Review

HRR = homologous recombination repair; mCRPC = metastatic castration-resistant prostate cancer; NOC = Notice of Compliance.

Note: While 0.1 mg, 0.25 mg, 0.35 mg, 0.5 mg, and 1 mg capsules are listed in the product monograph, the sponsor noted that 0.35 mg, 0.5 mg, and 1 mg capsules are not currently available in Canada.

Summary

• Talazoparib is available as 0.1 mg and 0.25 mg capsules.¹ At the submitted price of $99.35 per capsule, the 28-day cost of talazoparib is expected to be $5,564 per patient, based on the Health Canada–recommended dosage.^1,2 When used in combination with enzalutamide, the 28-day cost is expected to be $8,833 per patient.

• Clinical efficacy in the economic analysis for talazoparib plus enzalutamide compared to enzalutamide was derived from the TALAPRO-2 trial. Evidence submitted by the sponsor indicates that talazoparib plus enzalutamide is likely to improve radiographic progression-free survival (rPFS) and overall survival (OS) compared with enzalutamide among patients with HRR gene-mutated mCRPC. Clinical efficacy for all other comparators was informed by a sponsor-submitted matching-adjusted indirect comparison (MAIC). As not all effect modifiers and prognostic factors could be matched or adjusted for, the results of the MAIC are uncertain and conclusions could not be drawn on the relative efficacy of talazoparib plus enzalutamide with comparators included in the MAIC (olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP).

• The results of the CDA-AMC base case suggest the following.

  • Talazoparib plus enzalutamide will be associated with higher costs to the health care system than enzalutamide (incremental costs = $183,217), primarily driven by increased costs associated with drug acquisition.

  • Talazoparib plus enzalutamide may be associated with a gain of 0.87 life-years compared to enzalutamide. When the impact on health-related quality of life is also considered, talazoparib plus enzalutamide may result in a gain of 0.76 quality-adjusted life-years (QALYs) compared to enzalutamide.

  • The incremental cost-effectiveness ratio (ICER) of talazoparib plus enzalutamide compared to enzalutamide was $242,571 per QALY gained in the CDA-AMC base case. Approximately 49% of the incremental benefit of talazoparib plus enzalutamide versus enzalutamide was gained in the extrapolated period (median OS follow-up = 44.2 months; maximum follow-up not reported). CDA-AMC was unable to adequately explore uncertainty due to limitations with the available evidence (the absence of data to support sustained treatment effect and use beyond first-line treatment), and issues with the model structure.

• Due to significant uncertainty associated with the sponsor’s submitted MAIC, comparative effectiveness between talazoparib plus enzalutamide and olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP is too uncertain to determine. Therefore, there is no robust evidence to support a price premium of talazoparib plus enzalutamide in relation to other poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors plus androgen receptor pathway inhibitor (ARPI) combinations (i.e., olaparib plus AAP and niraparib-abiraterone plus prednisone).

• Clinical expert input sought for this review noted that chemotherapy (e.g., docetaxel) and radium-223 may also be considered relevant comparators for talazoparib plus enzalutamide in the indicated population. Neither of these treatments were included in the analysis.

• CDA-AMC estimates that the budget impact of reimbursing talazoparib plus enzalutamide for the indicated population will be approximately $21.8 million over the first 3 years of reimbursement compared to the amount currently spent on enzalutamide, AAP, olaparib plus AAP, and niraparib-abiraterone plus prednisone, with an estimated expenditure of $23.4 million on talazoparib over this period (talazoparib plus enzalutamide = $37.2 million). The actual budget impact of reimbursing talazoparib plus enzalutamide will depend on the distribution of market shares for patients with HRR gene-mutated mCRPC, the proportion of patients with HRR BRCA mutations, and the uptake of talazoparib plus enzalutamide.

Summary of the Submitted Economic Evaluation

The sponsor submitted a cost-utility analysis to estimate the cost-effectiveness of talazoparib plus enzalutamide from the perspective of a public drug plan payer in Canada over a lifetime horizon (20 years).³ The modelled population comprised adult patients with HRR gene-mutated mCRPC, which is aligned with the Health Canada–approved indication and was based on a subset of the participants in the TALAPRO-2 trial. The sponsor’s base-case analysis included costs related to drug acquisition, adverse events, disease management, subsequent therapies, and end of life.

In the sponsor’s base case, talazoparib plus enzalutamide was associated with incremental costs of $155,649 and 0.93 incremental QALYs relative to enzalutamide. This resulted in an ICER of $168,095 per QALY gained. Of the incremental benefit compared to enzalutamide (0.93 incremental QALYs), approximately 57% of the benefit was predicted to be accrued after the treatment duration of the TALAPRO-2 trial (median OS follow-up = 44 months). Additional information about the sponsor’s submission is summarized in Appendix 3.

CDA-AMC identified several key issues with the sponsor’s analysis (refer to Table 2; full details are provided in Appendix 4). A revised base case was therefore developed.

Table 2: Key Issues With the Sponsor’s Economic Submission

AAP = abiraterone acetate plus prednisone; ABI = abiraterone acetate; ARPI = androgen receptor pathway inhibitor; CDA-AMC = Canada’s Drug Agency; ENZA = enzalutamide; HRR = homologous recombination repair; HRR = homologous recombination repair; MAIC = matching-adjusted indirect comparison; mCRPC = metastatic castration-resistant prostate cancer; NIRA = niraparib; OLA = olaparib; RDI = relative dose intensity; rPFS = radiographic progression-free survival; TALA = talazoparib; TTD = time to treatment discontinuation; vs. = versus.

Note: Full details of the issues identified by CDA-AMC are provided in Appendix 3.

CDA-AMC Assessment of Cost-Effectiveness

The CDA-AMC base case was derived by making changes to model parameter values and assumptions (refer to Table 8), in consultation with clinical experts. Due to the limitations identified with the MAIC that preclude conclusions regarding the relative effects of talazoparib plus enzalutamide compared with olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP, the results in this section will be presented for talazoparib plus enzalutamide versus enzalutamide only. Detailed information about the comparison of talazoparib plus enzalutamide versus enzalutamide only is provided in Appendix 4.

Impact on Health Care Costs

Talazoparib plus enzalutamide is expected to be associated with additional health care costs compared to enzalutamide (incremental costs = $183,217). This increase in health care spending results from drug acquisition costs associated with talazoparib plus enzalutamide in the first-line setting (refer to Figure 1). All other costs to the health system are expected to be largely similar between talazoparib plus enzalutamide versus enzalutamide.

Figure 1: Impact of Talazoparib Plus Enzalutamide Versus Enzalutamide on Health Care Costs

AAP = abiraterone acetate plus prednisone; ENZA = enzalutamide; TALA = talazoparib; vs. = versus.

Notes: Drug-related costs include drug acquisition costs, administration, premedication, drug monitoring, and adverse event management.

Results for olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP are not presented in this figure. Refer to Appendix 4 for full results.

Impact on Health

Relative to enzalutamide, talazoparib plus enzalutamide is expected to increase the amount of time a patient remains progression free by approximately 0.87 years (refer to Figure 2). Considering the impact of treatment on both quality and length of life, talazoparib plus enzalutamide is expected to result in 0.76 additional QALYs per patient compared to enzalutamide.

Figure 2: Impact of Talazoparib Plus Enzalutamide Versus Enzalutamide on Patient Health

AAP = abiraterone acetate plus prednisone; ENZA = enzalutamide; QALY = quality-adjusted life-year; TALA = talazoparib vs. = versus.

Note: Results for olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP are not presented in this figure. Refer to Appendix 4 for full results.

Overall Results

The results of the CDA-AMC base case suggest an ICER of $242,571 per QALY gained for talazoparib plus enzalutamide compared to enzalutamide (refer to Table 3). Additional details on the CDA-AMC base case are available in Appendix 4.

Table 3: Summary of CDA-AMC Economic Evaluation Results

CDA-AMC = Canada's Drug Agency; ENZA = enzalutamide; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; TALA = talazoparib; vs. = versus.

Note: Publicly available list prices were used for all comparators.

Uncertainty and Sensitivity

• Due to uncertainty in the comparative clinical evidence, including the lack of long-term evidence and lack of data to inform treatment effectiveness waning over time, the predicted costs and QALYs in the CDA-AMC base case are uncertain.

  • Uncertainty was able to be explored for the scenario analyses outlined in Table 2. Assumptions on sustaining treatment effect indefinitely had the largest impact on the cost-effectiveness conclusions (refer to Table 12, Appendix 4).

• HRR gene mutations need to be confirmed before talazoparib plus enzalutamide treatment is initiated. The clinical experts described the availability of HRR mutation testing as very heterogeneous within and between jurisdictions, including variability in the genes included in each panel. If talazoparib is reimbursed, jurisdictions may need to add more genes to existing panels. Based on clinical expert feedback, it is unclear how or if this would impact health care resources.

• CDA-AMC noted that the proposed Health Canada indication for talazoparib plus enzalutamide allows for use in any line of treatment. Therefore, there is no direct comparative evidence for the use of talazoparib plus enzalutamide in the second-line, third-line, and later-line settings. The cost-effectiveness of talazoparib plus enzalutamide in later lines of treatment remains unknown.

Summary of the Budget Impact

The sponsor submitted a budget impact analysis (BIA) to estimate the 3-year (2026 to 2028) budget impact of reimbursing talazoparib plus enzalutamide for use in adult patients with HRR gene-mutated mCRPC. The sponsor assumed that the payers would be CDA-AMC–participating public drug plans and derived the size of the eligible population using an epidemiologic approach based on incident (new) patients only. The price of talazoparib was aligned with the price included in the sponsor’s economic evaluation, while the prices of comparators were based on the publicly available list prices. Additional information pertaining to the sponsor’s submission is provided in Appendix 5.

CDA-AMC identified a number of issues with the sponsor’s estimated budget impact and made changes to model parameters and assumptions in consultation with clinical experts to derive the CDA-AMC base case (Appendix 5). CDA-AMC estimated that 790 individual patients would be eligible for treatment with talazoparib plus enzalutamide over a 3-year period, of whom 204 are expected to receive talazoparib plus enzalutamide. The estimated incremental budget impact of reimbursing talazoparib plus enzalutamide is expected to be approximately $21.8 million over the first 3 years, with an expected expenditure of $23.4 million on talazoparib (the 3-year expenditure on talazoparib plus enzalutamide regimen is estimated to be $37.2 million). The actual budget impact of reimbursing talazoparib plus enzalutamide will depend on the number of people eligible for treatment, the proportion of patients with BRCA mutations, and the uptake of talazoparib plus enzalutamide.

Conclusion

Based on the CDA-AMC base case, talazoparib plus enzalutamide would be considered cost-effective at the submitted price if the public health care system was willing to pay at least $242,571 for each additional QALY gained. If the public health care system is not willing to pay that amount, a price reduction should be considered (refer to Figure 3; full details of the impact of price reductions on cost-effectiveness are presented in Table 11). The estimated cost-effectiveness is uncertain due to different comparators within subgroups of the indication, limitations with the clinical evidence, exclusion of a relevant comparator, and issues with the model structure. Based on available information on indirect comparative effectiveness, there is no robust evidence to support a price premium of talazoparib plus enzalutamide in relation to olaparib plus AAP and niraparib-abiraterone plus prednisone.

The budget impact of reimbursing talazoparib plus enzalutamide to the public drug plans in the first 3 years is estimated to be approximately $21.8 million. The 3-year expenditure on talazoparib alone (i.e., not accounting for current expenditure on the rest of the regimen or comparators) is estimated to be $23.4 million (the 3-year expenditure on the talazoparib plus enzalutamide regimen is estimated to be $37.2 million). The estimated budget impact is uncertain due to uncertainty in the distribution of market shares for patients with HRR gene-mutated mCRPC, in the proportion of patients with BRCA mutations, and in the uptake of talazoparib plus enzalutamide.

Figure 3: Summary of the CDA-AMC Economic Analysis and Price Reduction

AAP = abiraterone acetate plus prednisone; CDA-AMC = Canada’s Drug Agency; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year.

Note: “Expenditure” includes only the drug cost of talazoparib. The price reductions in this table are applied only to talazoparib. Results for olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP are not presented in this figure.

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32.Chi KN, Rathkopf D, Smith MR, et al. Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2023;41(18):3339-3351. doi: 10.1200/JCO.22.01649 PubMed

Appendix 1: Cost Comparison Table

Please 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 CDA-AMC–participating public 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 4: Cost Comparison for Treatments for Metastatic Castration-Resistant Prostate Cancer

Note: All prices are from the Ontario Drug Benefit Formulary (accessed May 2025),⁴ unless otherwise indicated, and do not include dispensing fees. Recommended dosages are based on product monographs, unless otherwise indicated.

^aSponsor’s submitted price and recommended dosage.³

^bPrices from Ontario Exceptional Access Program (accessed May 2025).⁵

Table 5: Cost Comparison for Additional Treatments for Metastatic Castration-Resistant Prostate Cancer

Note: All prices are from the IQVIA Delta PA database (accessed May 2025), unless otherwise indicated, and do not include dispensing fees. Recommended dosages are based on product monographs, unless otherwise indicated.

^aBased on an assumed body surface area of 1.98 m².

^bPrice sourced from Woon et al. (2018).⁶

Appendix 2: Input Relevant to the Economic Review

Please note that this appendix has not been copy-edited.

This section is a summary of the input received from the patient groups, clinician groups, and drug plans that participated in the CDA-AMC review process.

Patient input was received from Canadian Cancer Society and PROCURE. Both groups conducted surveys with patients living in Canada (PROCURE surveyed 263 patients living in Canada with prostate cancer in 2018 and 2022, and the Canadian Cancer Society surveyed 21 individuals with mCRPC and 3 caregivers). Patient input indicates that treatment goals include slowing down the progression of cancer and extending OS without introducing additional severe side effects than standard therapies. Moreover, patient input noted that talazoparib plus enzalutamide allows patients to refrain from taking corticosteroids as part of their treatment regimen, which can be beneficial in reducing the side effects associated with long-term steroid use (e.g., weight gain, osteoporosis, and increased risk of infections) and reducing the number of pills required per day. Regarding HRR testing, patient input noted that while most provinces have access to publicly funded genetic testing programs, the availability and scope of these tests can vary significantly, which can be a barrier to timely access to treatment. Regarding current treatment options, most patients who responded to the survey reported receiving 3 or more lines of treatment, with the most commonly being hormone therapies (i.e., luteinizing hormone-releasing hormone agonists, antagonists, and antiandrogen drugs). Patient input also noted many severe adverse events associated with current treatment options (e.g., nausea, vomiting, change in sexual function, fertility) with significant impact on patient’s quality of life. No survey respondents had experience with the drug under review.

Clinician group input was received from Ontario Health (Cancer Care Ontario) Genitourinary Cancer Drug. The current pathway of care for patients with mCRPC includes abiraterone, enzalutamide, docetaxel, radium-223 (in docetaxel ineligible patients) all given concurrently with androgen deprivation therapy. In addition, clinical input indicates that cabazitaxel is another option after docetaxel intensification, as well as olaparib-abiraterone and niraparib-abiraterone for those who have not intensified with ARPIs. Clinical input noted that treatment goals include prolonging life and maximizing quality of life, as there currently remains no cure for these patients. Finally, clinician input indicates that talazoparib plus enzalutamide will be best suited for patients with mCRPC who are treatment naive.

Input from CDA-AMC–participating drug plans noted that there is a statement in the product monograph that the talazoparib should maintained in the original bottle to protect the capsules from the light. However, it is unclear whether the capsules need to be maintained in the original packaging when dispensed to the patients, and if so, consideration regarding drug wastage, depending on how the drug is packaged, needs to be taken into account. Drug plan input indicates that not all jurisdictions have access to testing for all HRR pathway genes. Finally, plans questioned whether patients currently receiving monotherapy with enzalutamide (or abiraterone) be able to switch to talazoparib plus enzalutamide.

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

• Treatment goals of OS, as well as adverse events, were modelled.

CDA-AMC was unable to address the following concerns:

• Comparative effectiveness between talazoparib plus enzalutamide and other relevant comparators such as docetaxel, cabazitaxel, and radium-223.

Appendix 3: Summary of the Sponsor’s Submission

Please note that this appendix has not been copy-edited.

Summary of the Sponsor’s Economic Evaluation

For the pharmaceutical reviews program, clinical and economic information is submitted to CDA-AMC by the sponsor. The CDA-AMC health economics team reviews the submitted economic information and appraises the information in collaboration with clinical experts and the clinical review team to evaluate key assumptions, influential parameters, and the overall rigour of the economic submission. Based on what the team learns through this process, adjustments may be made to the sponsor’s model to produce the CDA-AMC base case. The CDA-AMC base case represents the team’s current understanding of the clinical condition, clinical evidence currently available, and best interpretation of the economic evidence based on the information provided.

For the review of talazoparib plus enzalutamide, the sponsor provided a cost-utility analysis and a BIA. The sponsor’s economic submission is summarized in Table 6.

Table 6: Key Components of the Sponsor’s Economic Evaluation

AAP = abiraterone acetate plus prednisone; ABI = abiraterone acetate; AE = adverse event; BSA = body surface area; CRPC = castration-resistant prostate cancer; ENZA = enzalutamide; ICER = incremental cost-effectiveness ratio; HRR = homologous recombination repair; MAIC = matching-adjusted indirect comparisons; NIRA = niraparib; OLA = olaparib; OS = overall survival; NICE = National Institute for Health and Care Excellence; PD = progressed disease; PSM = partitional survival model; QALY = quality-adjusted life-year; rPFS = radiographic progression-free survival; TALA = talazoparib; TTD = time to treatment discontinuation.

^aSponsor assumed relative dose intensity of 81.05% for talazoparib and 100% for enzalutamide.³

^bThe sponsor’s rationale for this methodologic choice was that it allows the use of real-world evidence to adjust ENZA’s survival curves, although this approach was not part of the sponsor’s base case. Additionally, the long-term OS evidence for ENZA was not used to inform the MAIC.

^cResults of scenario analyses that had a meaningful impact on the estimated ICER compared to the sponsor’s base case. Additional scenarios were submitted that had no meaningful impact on the estimated ICER included time horizon of 10 years, discount rates of 0% and 3%, health states utilities for PD from TALAPRO-2, alternate parametric functions for OS, and inclusion of genetic testing.

Table 7: Summary of the Sponsor’s Economic Evaluation Results

AAP = abiraterone acetate plus prednisone; ABI = abiraterone acetate; ENZA = enzalutamide; ICER = incremental cost-effectiveness ratio; NIRA = niraparib; OLA = olaparib; QALY = quality-adjusted life-year; TALA = talazoparib; vs. = versus.

Appendix 4: Additional Details of CDA-AMC Reanalyses

Please note that this appendix has not been copy-edited.

Clinical Data in the Economic Model

The key clinical efficacy data used to inform the economic model (i.e., rPFS, OS, and time to treatment discontinuation [TTD]) were derived from the TALAPRO-2 trial (data cut: September 2024) for talazoparib plus enzalutamide and enzalutamide. The sponsor submitted a model that used an alternative definition for rPFS definition that incorporates the progression or death event into the rPFS end point for patients previously censored, instead of the primary rPFS definition from the TALAPRO-2 trial. The rationale for using an alternate rPFS definition is that the primary rPFS definition led patients to be censored before experiencing radiographic progression or death – due to either missing assessments or the timing of events – which can lead to an inflation of rPFS and cause the rPFS Kaplan-Meier curve to cross the OS Kaplan-Meier curve.³ The sponsor did not apply the same censoring adjustment to the OS curve. The relative efficacy between enzalutamide and talazoparib plus enzalutamide appeared to be similar when comparing both rPFS definitions, with the key difference being a reduction in proportion in rPFS in both treatment arms. Based on the TALAPRO-2 trial, the CDA-AMC Clinical Review found that talazoparib plus enzalutamide may improve rPFS and OS when compared to enzalutamide monotherapy, with the potential treatment benefit on OS subjected to a degree of uncertainty due to differences in the proportion of patients permitted to receive posttreatment anticancer therapy after study treatment had been discontinued.

Estimates of relative efficacy for the other comparators in economic evaluation were obtained from the sponsor’s MAIC. The outcome of interest from the MAIC, as it relates to the economic evaluation, was rPFS and OS. The CDA-AMC Clinical Review noted that although rPFS and OS were adjusted some effect modifiers and prognostic factors in the MAIC, not all factors could be matched or adjusted, therefore imbalances remained. Overall, the magnitude and direction of potential bias due to imbalances for the rPFS and OS estimates cannot be predicted and definitive conclusions based on these results are not recommended. Furthermore, the MAIC used to inform the economic model matched patients from the enzalutamide monotherapy arm from the TALAPRO-2 trial to olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP, instead of patients from the talazoparib plus enzalutamide arm, the drug under review. The hazard ratio derived from this analysis was then applied to the enzalutamide monotherapy rPFS and OS curves. Thus, in the analysis talazoparib plus enzalutamide was not compared to olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP. Finally, the proportional hazards assumption was also not assessed or discussed.

Key Issues of the Submitted Economic Evaluation

CDA-AMC identified the following key issues with the sponsor’s analysis:

• The submitted model does not align with the indicated population. The proposed indication for talazoparib plus enzalutamide is for all adult patients with HRR gene-mutated mCRPC, irrespective of the line of treatment. The TALAPRO-2 trial was restricted to patients receiving their first-line treatment in the mCRPC setting (i.e., patients had not received prior systemic therapy for mCRPC) while the approved Health Canada indication allows for use in any line of treatment. Therefore, there is no direct comparative evidence for the use of talazoparib plus enzalutamide in the second-line, third-line, and later-line settings. The clinical expert input indicated that talazoparib plus enzalutamide would likely be used as second-line and beyond treatment in clinical practice in Canada. The cost-effectiveness of talazoparib plus enzalutamide as later lines of treatment remains unknown.

  • CDA-AMC was unable to address this limitation associated with the model structure and the lack of clinical data in later lines of therapy.

• Comparative effectiveness estimates derived from the MAIC are highly uncertain. Given there is no head-to-head comparison between talazoparib plus enzalutamide and olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP, the sponsor submitted an unanchored MAIC as source of comparative effectiveness to inform rPFS and OS in the economic model. CDA-AMC noted that olaparib plus AAP and niraparib-abiraterone plus prednisone are both indicated to be used in first-line treatment of patients with deleterious or suspected deleterious germline and/or somatic BRCA-mutated mCRPC, which represent only part of the population eligible for talazoparib plus enzalutamide based on Health Canada indication (i.e., any HRR gene mutations, line agnostic). Based on TALAPRO-2 trial distribution of mutations, BRCA mutations are expected to be between 30% to 40% of all HRR mutations in this population. Therefore, olaparib plus AAP and niraparib-abiraterone plus prednisone would not be relevant comparators for between 60% to 70% of patients receiving first-line therapy. Olaparib and niraparib are available as second-line or later-line treatments in patients with BRCA and/or ATM mutations (based on the TALAPRO-2 trial, BRCA and ATM mutations account for up to 60% of all HRR mutations), so if talazoparib plus enzalutamide is used in subsequent lines of therapy there are various potential comparators. Moreover, as stated in the Clinical Data in the Economic Model section, the MAIC has several limitations that preclude any conclusions regarding the comparative effectiveness between talazoparib plus enzalutamide and olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP in this population.

  Additionally, in the MAIC, the sponsor matched patients from the enzalutamide monotherapy arm from the TALAPRO-2 trial to patients from the PROpel study (olaparib plus AAP) and MAGNITUDE study (niraparib-abiraterone plus prednisone and AAP), instead of patients from the talazoparib plus enzalutamide arm, the drug under review. The hazard ratio derived from the MAIC were then applied to enzalutamide monotherapy arm to derive progression-free survival and OS curves for olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP in the economic model. Therefore, there is no analysis comparing talazoparib plus enzalutamide with olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP, and the use of the MAIC estimates that uses enzalutamide as the reference treatment to inform the efficacy of talazoparib plus enzalutamide relative to the other comparators is methodologically inappropriate. Any conclusions regarding comparative effectiveness remain highly uncertain given the modelling choice made by the sponsor (i.e., all comparators were modelled against enzalutamide monotherapy). In addition to these concerns, the CDA-AMC Clinical Review identified limitations with the MAICs, such that the effects of talazoparib plus enzalutamide on rPFS and OS compared with olaparib plus AAP, niraparib-abiraterone plus prednisone, and AAP are uncertain and definitive conclusions based on these results are not recommended. Therefore, based on available information, there is no robust evidence to support a price premium of talazoparib plus enzalutamide in relation to olaparib plus AAP and niraparib-abiraterone plus prednisone. The clinical expert input sought by CDA-AMC for this review noted that AAP is in the same class of treatments (ARPIs) as enzalutamide, and these treatments are generally considered to have similar effects.

  • This issue could not be addressed due to issues related to the MAIC.

• The long-term treatment effect of talazoparib is uncertain. In the base-case analysis submitted by the sponsor, the clinical evidence was based on the TALAPRO-2 trial (median OS follow-up of 44.2 months) which were extrapolated for the sponsor’s lifetime time horizon. Talazoparib plus enzalutamide’s treatment effects on rPFS and OS were maintained for the entire time horizon, which includes approximately 15 years of extrapolated data. For instance, CDA-AMC noted that 0.4% and 2.2% of patients who received enzalutamide and talazoparib plus enzalutamide, respectively, were projected to be progression free after 10 years in the sponsor’s base case. These proportions were considered significantly overestimated according to clinical expert input sought by CDA-AMC during this review. Based on clinical expert input, the proportion of patients who were progression free would likely approach zero after 3 years. Moreover, clinical expert input sought by CDA-AMC for this review indicated that the benefit accrued while receiving talazoparib treatment is not expected to be sustained indefinitely, with no known mechanism of action to support the sustained effect of talazoparib over time, especially after disease progression. In circumstances where either treatment will be delivered for a time horizon longer than the trial duration, or that treatment is assumed to have a continued effect on event rates postdelivery, assumptions relating to the continuation of long-term treatment effect must be considered carefully.^15,16

  In addition to issues related to the plausibility of sustained treatment effect, CDA-AMC highlights that the use of different definitions of rPFS in the TALAPRO-2 trial and the economic model introduce additional uncertainty in the analysis. CDA-AMC maintained the use of alternative rPFS definition as the relative efficacy between enzalutamide and talazoparib plus enzalutamide remained similar and programming issues prevented CDA-AMC to use the original rPFS definition.

  Finally, CDA-AMC noticed that the sponsor assumed the end of follow-up for OS was 67 months. The submitted Kaplan-Meier graph for OS showed no patients at risk of an event after 64 months and the sponsor did not provide the maximum follow-up for OS upon request.

  • CDA-AMC revised the waning of treatment effect assumption to start waning gradually for 12 months after the trial. It is important to clarify that the CDA-AMC revised assumption does not imply a complete absence of benefits from talazoparib plus enzalutamide versus enzalutamide monotherapy. Instead, it still shows some level of sustained separation between the rPFS and OS curves. However, the relative advantages of talazoparib plus enzalutamide versus enzalutamide gradually decline. CDA-AMC conducted 2 scenario analyses to explore the impact of the waning treatment effect of talazoparib plus enzalutamide: treatment effect is lost immediately after the TALAPRO-2 trial and treatment effect is sustained indefinitely. In addition, CDA-AMC changed the maximum follow-up of OS to 64 months.

• TTD is uncertain. In the sponsor’s base case, time on treatment for patients receiving talazoparib plus enzalutamide was informed by parametric distributions fitted to patient-level data on TTD of talazoparib plus enzalutamide and enzalutamide from the TALAPRO-2 trial. Based on the TALAPRO-2 trial, patients continued treatment until at least 1 of the following events occurred: radiographic progression and the patient is no longer clinically benefiting in the opinion of the investigator, an adverse event leading to permanent discontinuation, patient decision to discontinue study treatment, or death.¹⁷ The sponsor selected the gamma distribution for the base-case analysis, stating that it provided a more clinically plausible extrapolation. CDA-AMC notes that the TTD estimated in the sponsor’s base case resulted in 24% and 7% of patients still receiving talazoparib plus enzalutamide treatment at year 3 and 5 posttreatment initiation. In contrast, the sponsor’s extrapolation of rPFS estimated that 38% and 17% of patients treated with talazoparib plus enzalutamide would be progression free at 3-years and 5-years posttreatment initiation. That is, within this period between 10% and 14% of patients receiving talazoparib plus enzalutamide would continue to experience rPFS benefit after treatment with talazoparib plus enzalutamide is discontinued. In addition, based on the sponsor’s choice of extrapolation, the proportion of patients expected to remain on treatment with talazoparib plus enzalutamide only reaches 0% at approximately 16 years, and the proportion of patients would be progression free only reaches 0% at 19 years, showing a gap of 3 years where patients would remain progression free without receiving any treatment. The gap between rPFS and TTD results in patients accruing benefits while not incurring any treatment costs. Clinical expert input indicated that TTD should be better aligned with time to radiological progression among patients treated with talazoparib plus enzalutamide, as patients were not expected to remain progression free while not on treatment. Additionally, only a small percentage of patients are expected to remain without receiving any treatment. Clinical expert input indicated that the long-term extrapolation proposed by the sponsor lacked face validity considering the discrepancy generated between TTD and rPFS extrapolations. Furthermore, clinical expert input remarked that if it is assumed that rPFS is durable over time, then it should also be reasonable to assume that time on treatment is maintained for a comparable period of time. Because the sponsor estimated that 0.01% of patients receiving talazoparib plus enzalutamide remain radiologically progression free at the end of the model’s 20-year lifetime horizon, a TTD of 0.1% at the same time point was deemed more clinically plausible than patients remaining 3 years in progression free without any treatment. In comparison with enzalutamide monotherapy, the gap between TTD and rPFS of patients receiving talazoparib plus enzalutamide is much wider, underestimating the treatment costs for talazoparib plus enzalutamide, and resulting in bias that favour talazoparib plus enzalutamide.

  • CDA-AMC conducted a scenario analysis where TTD was set to be equal to rPFS for all treatments, which based on clinical expert input is more reflective of what is observed in clinical practice.

• Use of relative dose intensity (RDI) underestimated drug acquisition costs. In the sponsor’s base-case analysis, the mean RDI observed in the TALAPRO-2 trial and literature were used to derive the drug acquisition cost for all therapies (i.e., expected versus observed doses; talazoparib plus enzalutamide = 81%, enzalutamide = 100%, olaparib = 98.2%, niraparib = 99.4%). The inclusion of RDI may underestimate the total cost of talazoparib in real-world clinical practice as the dose received by patients may be different from the planned dose for several reasons (i.e., missed, delayed, or de-escalated doses). CDA-AMC notes that, when considering wastage, each reason determining a reduction in RDI may have a different impact on drug costs. Likewise, it is unclear how treatment discontinuation influences RDI. Furthermore, for oral therapies, pharmacies in Canada are likely to fill and dispense prescriptions in full. Without evidence to suggest that patients will delay filling prescriptions, it is not certain that unused tablets will result in lower drug costs. Additionally, the sponsor did not provide justification as to why compliance in the real-world setting would be expected to be different across treatments included in the model.

  • In the CDA-AMC base case, RDI was assumed to be 100% for all treatments.

• Exclusion of potentially relevant comparators. The sponsor did not include chemotherapy (e.g., docetaxel) or radium-223 as relevant comparators from the economic analysis. Clinical expert input sought by CDA-AMC for this review noted that there have been changes in the treatment landscape for prostate cancer patients since the TALAPRO-2 trial was conducted). Clinical expert input obtained by CDA-AMC indicated that in many treatment settings in Canada, patients with HRR gene-mutated metastatic castration-sensitive prostate cancer are receiving treatment intensification with ARPIs (including AAP and enzalutamide) earlier in the disease management (i.e., during the castration-sensitive phase). As a result, it is expected that patients who progress to mCRPC may have already received ARPI treatment and were unlikely to be treated with them again. Clinical expert input sought by CDA-AMC for this review noted that docetaxel is indicated in combination with prednisone or prednisolone for the treatment of patients with androgen-independent (hormone-refractory) mCRPC, and radium-223 is indicated for patients with mCRPC with symptomatic bone metastases and no known visceral metastatic disease; both treatments were considered relevant comparator for the current review of talazoparib plus enzalutamide. No direct or indirect evidence was provided to inform the comparative effectiveness of these treatments in the shared place in therapy for HRR gene-mutated mCRPC. Therefore, the cost-effectiveness of talazoparib plus enzalutamide in relation to docetaxel and radium-223 is unknown.

  • CDA-AMC was unable to address this limitation given lack of clinical comparatives effectiveness data between talazoparib plus enzalutamide and docetaxel or radium-223.

• The model structure does not reflect clinical practice. The model submitted by the sponsor only accounted for 1 line of subsequent treatment after first-line therapy and assumed that patients would remain in palliative care after the failure of second-line treatment. For patients receiving talazoparib plus enzalutamide as first-line treatment, this assumption resulted in patients spending 30% of their time in the progressed disease state receiving subsequent treatment, and the remaining time (70%) in palliative treatment. Feedback from clinical experts consulted by CDA-AMC indicated that patients with HRR gene-mutated mCRPC are generally treated with an average of 3 lines of therapy in clinical practice. Patients are expected to spend most of their time on subsequent lines of treatment, instead of palliative care.

  Additionally, CDA-AMC noted a coding error in the subsequent treatment costs for olaparib plus AAP and niraparib-abiraterone plus prednisone resulting in those treatments having zero subsequent treatment costs.

  • CDA-AMC was unable to address issues related to the model structure. CDA-AMC fixed the coding error to reflect the actual weighted average cost of second-line treatment for olaparib plus AAP and niraparib-abiraterone plus prednisone.

CDA-AMC Reanalysis of the Economic Evaluation

The CDA-AMC base case was derived by making changes in model parameter values and assumptions, in consultation with clinical experts (refer to Table 8). The impact of these changes, individually and collectively, is presented in Table 9. Due to high uncertainty with the MAIC results, Table 9 and Table 11 will be presented for talazoparib plus enzalutamide versus enzalutamide only, while Table 10 will include all comparators.

Table 8: Revisions to the Submitted Economic Evaluation

AAP = abiraterone acetate plus prednisone; ABI = abiraterone acetate; CDA-AMC = Canada’s Drug Agency; NIRA = niraparib; OLA = olaparib; OS = overall survival; RDI = relative drug intensity; rPFS = radiographic progression-free survival.

Note: CDA-AMC was unable to resolve the issues with uncertain cost-effectiveness of TALA + ENZA in later lines of therapy, lack of clinical plausibility of rPFS estimates, uncertainty in comparative effectiveness between TALA + ENZA and OLA + AAP, NIRA-ABI, and AAP, and exclusion of docetaxel as comparator.

Table 9: Summary of the Stepped Analysis

CDA-AMC = Canada’s Drug Agency; ENZA = enzalutamide; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; TALA = talazoparib.

Note: The CDA-AMC reanalysis is based on the publicly available prices of the comparator treatments.

Table 10: Disaggregated Results of the CDA-AMC Base Case

AAP = abiraterone acetate plus prednisone; ABI = abiraterone; AE = adverse event; ABI = abiraterone acetate; CDA-AMC = Canada’s Drug Agency; ENZA = enzalutamide; LY = life-year; NIRA = niraparib; OLA = olaparib; QALY = quality-adjusted life-year; TALA = talazoparib.

Note: The model results for OLA + AAP, NIRA-ABI, and AAP are uncertain, as the evidence informing these treatments is associated with substantial uncertainty.

Price Reduction Analysis

CDA-AMC conducted price reduction analyses using the sponsor’s base case and the CDA-AMC base case (refer to Table 11).

Table 11: Results of the Price Reduction Analysis for Talazoparib

CDA-AMC = Canada’s Drug Agency; ENZA = enzalutamide; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; TALA = talazoparib; vs. = versus.

^aSponsor’s submitted price for talazoparib.³

Assessment of Uncertainty

CDA-AMC used the CDA-AMC base case to conduct scenario analyses to address uncertainty within the economic evaluation. The results are provided in Table 12.

1. Talazoparib plus enzalutamide treatment effect was assumed to be sustained indefinitely throughout the entire time horizon (10 years).

2. Talazoparib plus enzalutamide treatment effect was assumed to wane immediately after the trial (42 months for rPFS and 64 months for OS).

3. TTD was assumed to be equal to progression-free survival for talazoparib plus enzalutamide and comparators.

Table 12: Results of CDA-AMC Scenario Analyses

CDA-AMC = Canada’s Drug Agency; ENZA = enzalutamide; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; TALA = talazoparib; TTD = time to treatment discontinuation.

^aDeterministic analyses.

Issues for Consideration

• Talazoparib plus enzalutamide is indicated for the treatment of adult patients with HRR gene mutations. HRR gene mutations need to be confirmed before talazoparib plus enzalutamide treatment is initiated. The clinical experts described the availability of HRR mutation testing as very heterogeneous within and between jurisdictions. While next generation sequencing panels for mCRPC are generally available across Canada, there is variability in the genes included in each panel. There are also concerns regarding large backlogs in the hereditary cancer clinics for germline genomic testing based on clinical expert input sought by CDA-AMC for this review. If talazoparib is reimbursed, jurisdictions may need to add more genes to existing panels. It is unclear how or if this would impact human and other health care resources. To provide consistent service across the country, upscaling existing testing infrastructure, workflows, and technologies may be needed. In addition, there may be a need for formal education strategies directed toward health care workers, such as primary care physicians, medical oncologists, and geneticists, to increase awareness and knowledge regarding precision medicine options and genomic testing in patients with mCRPC. However, according to clinical expert input, the structure needed for genomic testing already exists, and no to minimal additional impact is anticipated if talazoparib is reimbursed. The sponsor submitted a scenario analysis that suggested incorporation of genetic testing considerations (current cost of next generation sequencing and number of patients needed to test to identify 1 individual with HRR mutation) would have a minimal impact on the ICER was considered. The impact of the potential need for upscaling testing capacity or expanding testing panels were not considered in the cost-effectiveness analysis.

• CDA-AMC noted that olaparib plus AAP and niraparib-abiraterone plus prednisone are both indicated to be used in first-line treatment of patients with deleterious or suspected deleterious germline and/or somatic BRCA-mutated mCRPC, which represent only between 30% and 40% of all HRR mutations in this population based on the TALAPRO-2 trial. Available evidence suggests patients with HRR BRCA mutations may have worse treatment outcomes in comparison with patients with non-BRCA HRR gene mutations.¹⁸

• The sponsor indicated that the smallest dispensable unit is per capsule, which indicates that the original package does not need to be maintained. The product monograph for talazoparib states that it should be maintained in the original bottle to protect the capsules from light. If individual capsules are not dispensed, the total costs and wastage associated with talazoparib are underestimated in the analysis, and the cost-effectiveness is underestimated.

• The flat pricing of talazoparib ($99.35 for 0.25 mg, and 0.1 mg presentation forms) may be an issue for consideration if there are supply chain issues to deliver the standard dose presentation in Canada. This can lead to a significant cost increase when the same treatment dose needs to be dispensed using lower-dose tablets. For example, a shortage in the 0.25 mg tablet could lead to the need to dispense 5 tablets of 0.1 mg instead of 2 tablets of 0.25 mg, increasing the drug costs by 2 and a half times.

Appendix 5: Budget Impact Analysis

Please note that this appendix has not been copy-edited.

Summary of the Submitted BIA

The sponsor submitted a BIA that estimated the expected incremental budgetary impact of reimbursing talazoparib for the treatment of adult patients with HRR gene-mutated mCRPC.

The BIA was conducted from the perspective of public drug plan payers over a 3-year time horizon (2026 to 2028), with 2025 as the base year. The sponsor’s estimate reflects the aggregated results from the jurisdictional provincial budgets (excluding Quebec) as well as the Non-Insured Health Benefits Program. The sponsor estimated the eligible population using an epidemiological approach incorporating incident (i.e., new) patients only. It was assumed that the uptake of talazoparib would displace all the other comparators by the same proportion (10%), compared to a scenario without reimbursement of talazoparib. The sponsor’s base case included drug acquisition costs. The market uptake for talazoparib was estimated using the sponsor’s internal market research and interviews with clinicians in Canada. The key inputs to the BIA are documented in Table 13. The sponsor assumed no patients died or switched therapies within the BIA.

The sponsor estimated the 3-year incremental budget impact associated with reimbursing talazoparib for the treatment of adult patients with HRR gene-mutated mCRPC would be $20,002,109 (year 1 = $1,971,265; year 2 = $6,231,893; year 3 = $11,798,951).

Table 13: Key Model Parameters