CADTH Reimbursement Review

Lutetium (¹⁷⁷Lu) Vipivotide Tetraxetan (Pluvicto)

Sponsor: Advanced Accelerator Applications Canada, Inc.

Therapeutic area: Metastatic castration-resistant prostate cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Stakeholder Input

Clinical Review

Executive Summary

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

Table 1: Submitted for Review

¹⁷⁷Lu = lutetium-177; ARPI = androgen receptor pathway inhibitor; mCRPC = metastatic castration-resistant prostate cancer; NOC = Notice of Compliance; PSMA = prostate-specific membrane antigen.

Introduction

Prostate cancer is the most common cancer among men in Canada (excluding nonmelanoma skin cancers), affecting 1 in 9 men during their lifetime.¹ Prostate cancer represents approximately 20% of all new cancers diagnosed in men in Canada and 10% of cancer deaths in men.² In 2022, it was estimated that 24,600 men in Canada would be diagnosed with prostate cancer and 4,600 men would die from prostate cancer.² Patients who die from prostate have typically progressed to the metastatic castration-resistant prostate cancer (mCRPC) stage, which has a 5-year survival rate of approximately 30%.³ Castration-resistant prostate cancer (CRPC) is defined as disease progression despite castrate levels of testosterone that may present as a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of preexisting disease, and/or the appearance of new metastases.⁴

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is highly expressed in prostate cancer cells. Lutetium-177 (¹⁷⁷Lu) vipivotide tetraxetan (Pluvicto) contains the radionuclide lutetium-177, which is linked to a targeting moiety that binds to PSMA. Upon the binding of ¹⁷⁷Lu vipivotide tetraxetan to PSMA-expressing cancer cells, the beta-minus emission from lutetium-177 delivers therapeutic radiation to the targeted cell, as well as to surrounding cells, and induces DNA damage that can lead to cell death.⁵

¹⁷⁷Lu vipivotide tetraxetan injection is indicated for the treatment of adults with PSMA-positive mCRPC who have received at least 1 androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy.⁵ The sponsor has requested that ¹⁷⁷Lu vipivotide tetraxetan be reimbursed in accordance with the Health Canada–approved indication.⁶ Based on the approved indication for ¹⁷⁷Lu vipivotide tetraxetan, there are 3 relevant subpopulations for consideration in this review:

• patients previously treated with docetaxel who are considered eligible to receive cabazitaxel

• patients previously treated with docetaxel who are considered ineligible to receive cabazitaxel

• patients previously treated with both docetaxel and cabazitaxel.

¹⁷⁷Lu vipivotide tetraxetan is administered intravenously, and the recommended dose is 7.4 GBq every 6 weeks (± 1 week), for a total of 6 doses.⁵ It is available as a 1,000 MBq/mL solution for injection in single-dose vials that contain a total amount of radioactivity of 7.4 GBq (± 10%) at the time of administration.⁵

Stakeholder Perspectives

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

Patient Input

Two patient groups, the Canadian Cancer Society (CCS) and the Canadian Cancer Survivor Network (CCSN), provided input on the treatment of adults with PSMA-positive mCRPC who have been treated with an ARPI and taxane-based chemotherapy or who are not medically suitable for taxanes. Patient input was gathered from surveys and interviews with patients with mCRPC and their caregivers across Canada in August 2022. Of the 27 survey respondents, 19 were from the CCS and 8 were from the CCSN. Of the 7 patients included in the submissions who had experience with the treatment under review, 4 were from the CCS and 3 were from the CCSN.

Patients noted that mCRPC has a substantial negative impact on their quality of life (QoL) and their ability to perform the activities of daily living, including the ability to engage in sexual activity, travel and exercise, fulfill family obligations, maintain mental health, work, perform household chores, concentrate, spend time with family and friends, and fulfill practical needs (e.g., preparing meals, dressing, bathing). Patients can suffer from frequent urination, erectile dysfunction, bone and/or skeletal pain, hot flashes, weight gain, memory loss, and cognitive problems. Patient groups noted that patients are seeking new treatment options that will prolong life, maintain QoL, delay the onset of symptoms, and improve sexual function. The groups noted that existing treatment options can be associated with negative side effects and highlighted the need for effective and more tolerable treatment options.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical experts consulted by CADTH noted that there are limited effective treatments for patients with mCRPC who have progressed after treatment with an ARPI and docetaxel. Overall survival (OS) is poor for patients with disease that has been demonstrated to be refractory to multiple treatment options and for whom the symptoms of cancer progression pose a considerable burden. Other standard of care treatments, such as cabazitaxel, are associated with significant toxic effects for patients. The clinical experts noted that there is a need for therapies that improve OS and QoL for this patient population and that are better tolerated and more convenient (e.g., less need for supportive medications, less frequent administration) than current standard of care options.

The clinical experts noted that ¹⁷⁷Lu vipivotide tetraxetan could be considered for patients whose disease progressed after treatment with both an ARPI and docetaxel. The experts noted that there is uncertainty regarding the place of ¹⁷⁷Lu vipivotide tetraxetan in therapy relative to cabazitaxel for patients who are considered appropriate candidates for treatment with a second chemotherapy regimen. The clinical experts consulted by CADTH also identified the requirement for suitable PSMA-targeted PET expression, per the inclusion criteria of the pivotal VISION trial, to be a candidate for therapy. The clinical experts noted that ¹⁷⁷Lu vipivotide tetraxetan should be discontinued in patients who experience disease progression characterized by at least 2 specific adverse occurrences (i.e., sustained PSA rise, clinical progression [sustained, nonanalgesic, responsive pain; performance status decline], and radiographic progression); significant toxicity related to the treatment; or worsening of performance status (i.e., Eastern Cooperative Oncology Group Performance Status [ECOG PS] ≥ 3).

Clinician Group Input

Clinician group input (coordinated by the CCS) was received from prostate-treating clinicians in Canada with a special interest in the care of patients with metastatic prostate cancer. The clinician group noted that there are unmet needs for patients with mCRPC and a need for additional lines of therapy that can preserve QoL and provide meaningful survival benefits for patients with progressive metastatic prostate cancer. According to the clinician group, a new treatment would be most suited to patients with progressive (symptomatic, imaging, or biochemical) mCRPC, PSMA-expressing metastases identified on a diagnostic PSMA-targeted PET scan, and with adequate performance status (ECOG PS of 0 to 2) and organ function (liver and bone marrow). The clinician group also pointed out that the most meaningful clinical response to treatment for this disease would be the prevention of progression, reflected in stability or improvement in biochemical and imaging biomarkers such as serum PSA, bone scan, and CT. The clinician group emphasized that appropriate facilities, certifications, and licensed personnel for the safe delivery of unsealed radiopharmaceutical treatments would be needed for the treatment under review, as would access to diagnostic PSMA-targeted PET for proper patient selection.

Drug Program Input

The drug programs that participated in the CADTH reimbursement review process identified possible implementation issues related to the following: potential comparators for ¹⁷⁷Lu vipivotide tetraxetan; the application of PSMA testing in Canada as a diagnostic modality for identification of the target patient population and as a potential evaluator of response to therapy; the criteria used in practice to identify patients who would not be suitable for treatment with cabazitaxel; and the potential use of ¹⁷⁷Lu vipivotide tetraxetan in combination with other systemic anticancer therapies (most notably ARPIs).

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

The evidence for the review of ¹⁷⁷Lu vipivotide tetraxetan for the treatment of adults with PSMA-positive mCRPC who have received at least 1 ARPI and taxane-based chemotherapy was derived from a systematic literature review of pivotal and phase III studies, supplemented with additional information to address important gaps in the randomized controlled trial (RCT) evidence. One RCT met the eligibility criteria for the systematic review. VISION (N = 831) is a phase III, open-label, RCT conducted to evaluate the efficacy and safety of ¹⁷⁷Lu vipivotide tetraxetan administered to patients with progressive PSMA-positive mCRPC in addition to best supportive care (BSC) or best standard of care (BSoC) (the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group) relative to BSC or BSoC alone (the BSC/BSoC alone group).⁷ Patients were randomized in a 2:1 ratio to ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC or BSC/BSoC alone, with allocation stratified by lactase dehydrogenase (LDH) (≤ 260 IU/L versus > 260 IU/L), presence of liver metastases (yes versus no), ECOG PS (0 or 1 versus 2), and inclusion of a novel androgen axis drug (NAAD) in BSC/BSoC (yes versus no).

The VISION trial had considerable early withdrawal of consent and a disproportionate dropout in the BSC/BSoC alone group (patients typically cited disappointment that they would not receive ¹⁷⁷Lu vipivotide tetraxetan). This was a major limitation of the study and required the sponsor to introduce the following protocol amendments: the overall target sample size was increased; educational measures were introduced to try to bolster the retention of patients in the comparator group; and, most important from a critical appraisal perspective, the definition of a new analysis set that would be limited to patients enrolled after the protocol amendments were introduced (i.e., the progression-free survival [PFS] full analysis set [FAS]). This new analysis set was used for the primary evaluation of all end points, with the exception of OS (FAS) and the overall response rate (ORR) and disease control rate (DCR), which evaluated an even smaller subset of patients (i.e., those in the PFS-FAS who had Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST)-evaluable disease).

Efficacy Results

Table 2 summarizes results for the efficacy end points from the VISION trial. The primary and secondary end points of the VISON trial were aligned with those recommended by the Prostate Cancer Working Group 3 (PCWG3) (i.e., OS, radiographic progression-free survival [rPFS], time to first symptomatic skeletal event [SSE], health-related quality of life [HRQoL], PFS, and biochemical response [e.g., PSA]). As noted previously, only the analysis of OS was conducted using the FAS dataset.

OS: There was a statistically significant improvement in OS for patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group, compared with those in the BSC/BSoC alone group (hazard ratio [HR] = 0.62; 95% confidence interval [CI], 0.52 to 0.74; P < 0.001). Median OS was 15.3 months (95% CI, 14.2 to 16.9 months) in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and 11.3 months (95% CI, 9.8 to 13.5 months) in the BSC/BSoC alone group. Subgroup analyses based on the number of prior taxane regimens favoured ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC over BSC/BSoC alone for patients who received a single prior taxane regimen (HR = 0.59; 95% CI, 0.46 to 0.75) and those who received 2 or more prior taxane regimens (HR = 0.73; 95% CI, 0.53 to 0.99).

rPFS: There was a statistically significant improvement in rPFS for patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group, compared with those in the BSC/BSoC alone group (HR = 0.40; 99.2% CI, 0.29 to, 0.57; P < 0.001). Events of radiographic progression or death were reported for 66.0% of patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group (171 radiographic progression events and 83 deaths) and 47.4% of patients in the BSC/BSoC alone group (59 radiographic progression events and 34 deaths). Median rPFS was 8.7 months (95% CI, 7.9 to 10.8 months) in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and 3.4 months (95% CI, 2.4 to 4.0 months) in the BSC/BSoC alone group. The sponsor reported that median follow-up time for rPFS was longer in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC group (16.4 months and 3.9 months, respectively).

ORR: The ORR was statistically significantly greater in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC group (29.8% versus 1.7%), with an odds ratio (OR) of 24.99 (95% CI, 6.05 to 103.24).

DOR: Median duration of response (DOR) in patients who demonstrated a response to treatment (i.e., complete response [CR] or partial response [PR]) was 9.8 months (95% CI, 9.1 to 11.7 months) in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group. Only 2 patients in the BSC/BSoC only group demonstrated a response to treatment, and only 1 of those met the criteria for RECIST radiographic progression or death; therefore, the sponsor reported that median DOR could not be reliably estimated for the BSC/BSoC alone group.

DCR: The DCR was statistically significantly greater in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC alone group (89.0% versus 66.7%), with an OR of 5.79 (95% CI, 3.18 to 10.55; P < 0.001).

Time to first SSE: There were 256 SSEs in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group (66.5%; 60 events and 196 deaths) and 137 SSEs (69.9%; 34 events and 103 deaths) in the BSC/BSoC alone group. ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC was associated with a statistically significant reduction in the risk of SSE (or death), compared to BSC/BSoC alone (HR = 0.5; 95% CI, 0.40 to 0.62).

PFS: Progression events or death were reported for █████ of patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group (█████ radiographic progression, █████ clinical progression, █████ PSA progression, ████ death) and █████ of patients in the BSC/BSoC group (█████ radiographic progression, █████ clinical progression; █████ PSA progression; ████ death). ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC was associated with a statistically significant reduction in the risk of radiographic disease progression, clinical progression, PSA progression, or death, compared to BSC/BSoC alone (███ █████ ███ ███ ████ ██ █████ ██ █████). Median PFS was ███ ██████ (███ ███ ███ ██ ███) in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and ███ ██████ ████ ███ ███ ██ ████ in the BSC/BSoC alone group.

PSA levels: The sponsor reported a large disparity in the proportion of patients who could be evaluated for PSA doubling time between the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and BSC/BSoC alone groups (█████ and ██████ respectively). For the subset of patients who could be evaluated, mean PSA doubling time was ████ ██████ (███ ███ ████ ██ ████) in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and ████ ██████ (███ ███ ███ ██ ████) in the BSC/BSoC alone group.

BPI-SF: Worsening in pain intensity was defined as an increase from baseline of at least 30% or an increase from baseline of at least 2 points on the Brief Pain Inventory-Short Form (BPI-SF) scale at any time up to the end-of-treatment (EOT) visit, clinical disease progression, or death. Time to worsening pain was longer in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC alone group (HR = 0.52; 95% CI, 0.43 to 0.63; P < 0.001). Median time to deterioration was 5.9 months (95% CI, 4.8 to 6.9 months) in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and 2.2 months (95% CI, 1.8 to 2.8 months) in the BSC/BSoC alone group.

FACT-P: Time to worsening in Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores was defined as the time from randomization to the first occurrence of a decrease of at least 10 points in total score from baseline, clinical disease progression, or death. Total events were similar in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and BSC/BSoC alone groups (87.0% and 85.7%, respectively). Median time to worsening of the FACT-P score was shorter in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group (5.7 months; 95% CI, 4.8 to 6.6 months) than in the BSC/BSoC alone group (2.2 months; 95% CI, 1.8 to 2.8 months), with an HR of 0.54 (95% CI, 0.45 to 0.66; P < 0.001).

FACT-G: Time to worsening in Functional Assessment of Cancer Therapy-General (FACT-G) scores was defined as the time from randomization to the first occurrence of a decrease of at least 10 points in total score from baseline, clinical disease progression, or death. Median time to worsening of the FACT-G score was lower in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group (███ ███████ ███ ███ ███ ██ ███) than in the BSC/BSoC alone group (███ ███████ ███ ███ ███ ██ ███) (HR = █████ ███ ███ ████ ██ █████ ██ █████).

FAPSI-8: Time to worsening in 8-item Functional Assessment of Cancer Therapy Advanced Prostate Symptoms Index (FAPSI-8) scores was defined as the time from randomization to the first occurrence of a decrease of at least 10 points in total score from baseline, clinical disease progression, or death. Total events were nearly identical in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and BSC/BSoC alone groups (█████ ███ ██████ respectively). Median time to worsening of the FAPSI-8 score was lower in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group (███ ███████ ███ ███ ███ ██ ███) than in the BSC/BSoC alone group (███ ███████ ███ ███ ███ ██ ███) (HR = █████ ███ ███ ████ ██ █████ ██ █████).

Harms Results

Table 2 summarizes key adverse event (AE) data from the VISION trial. The sponsor reported that the following events were reported more commonly with the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC alone group (i.e., a difference of ≥ 10.0% between the groups): fatigue (43.1% versus 22.9%), dry mouth (38.8% versus 0.5%), nausea (35.3% versus 16.6%), anemia (31.8% versus 13.2%), diarrhea (18.9% versus 2.9%), vomiting (18.9% versus 6.3%), thrombocytopenia (17.2% versus 4.4%), lymphopenia (14.2% versus 3.9%), leucopenia (12.5% versus 2.0%), and urinary tract infection (11.0% versus 1.0%).⁷

A greater proportion of patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group reported at least 1 AE of grade 3 AE or higher than in the BSC/BSoC alone group (52.7% versus 38.0%). Events of grade 3 or higher that were more commonly reported in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC alone group included anemia (12.9% versus 4.9%), thrombocytopenia (7.9% versus1.0%), lymphopenia (7.8% versus 0.5%), and fatigue (5.9% versus 1.5%). Spinal cord compression was reported more commonly in the BSC/BSoC alone group than in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group (5.4% versus 1.3%).⁷ At least 1 serious adverse event (SAE) was reported for a greater proportion of patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC alone group (36.3% versus 27.8%).

Table 2: Summary of Key Results From Pivotal and Protocol-Selected Studies

¹⁷⁷Lu = lutetium-177; AE = adverse event; BPI-SF = Brief Pain Inventory-Short Form; BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; CR = complete response; DCR = disease control rate; DOR = duration of response; EDOR = expected duration of response; FAS = full analysis set; HR = hazard ratio; NE = not evaluable; OR = odds ratio; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; rPFS = radiographic progression-free survival; SAE = serious adverse event; SSE = symptomatic skeletal event.

Source: Clinical Study Report.⁷

Critical Appraisal

Internal Validity

Randomization was stratified by important prognostic factors, and baseline and demographic characteristics were generally well balanced in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and the BSC/BSoC alone groups (including receipt of prior systemic anticancer therapy). The sponsor reported that the open-label design of the VISION study was used because blinding would not be practical, owing to the specialized precautions required for administration of a radiopharmaceutical and the toxicities related to targeted radioligand therapy and because it would not be appropriate to subject patients who did not receive a radiopharmaceutical to posttreatment radiation protection protocols (e.g., maintaining physical distancing from family members). Radiographic images were evaluated using blinded independent central review, and those results were used in the primary evaluations of rPFS and ORR (local assessments were used for patient management and in sensitivity analyses).

The open-label study design contributed to the high rate of early withdrawal for those who were randomized to the BSC/BSoC alone group (i.e., patients were disappointed at not receiving ¹⁷⁷Lu vipivotide tetraxetan, leading to a lack of willingness to comply with the study protocol and/or interest in receiving therapies that were prohibited in the study protocol). The sponsor established corrective actions with a protocol amendment that included site calls to discuss the management of patients in the BSC/BSoC alone, or control, arm; investigator letters clarifying aspects of the study; and prescreening updates to improve patient education about the trial. After implementation of these measures, the sponsor noted that withdrawal of consent decreased.⁸ However, withdrawal rates in the BSC/BSoC alone group were █████ and █████ before and after the protocol amendment, respectively, compared with ████ and ████ in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group (i.e., although the rate of discontinuation from the BSC/BSoC alone group improved after the protocol amendment, it remained considerably higher than the rate observed in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group). As a result of the high dropout rate in the BSC/BSoC alone group, the sponsor also amended the protocol so that all end points, with the exception of OS, were analyzed using a newly established PFS-FAS dataset, which was composed of patients enrolled after the educational protocol amendments were introduced.⁹ The approach used is a way to handle early withdrawals; however, the analyses based on the PFS-FAS would not likely have followed the intention-to-treat (ITT) principle, which would affect many of the assumptions made about the comparisons. This approach was acceptable to the FDA and Health Canada;^8,9 however, both regulatory agencies stated that the interpretation of the magnitude of the rPFS effect was limited because of the high degree of censoring from early drop-outs in the control arm (neither the approved US label nor the Canadian product monograph include the effect size for rPFS from the VISION trial).^5,10

The high and disproportionate number of patients who withdrew from the control group could bias the study results in favour ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC, as those who remained in the study may have had poorer prognoses than those who withdrew and subsequently received treatment with regimens that were not permitted in the VISION protocol. Similarly, patients who remained in the trial may have had fewer therapeutic options (e.g., more advanced disease) and may have lacked the resources to obtain access to alternative regimens outside of the clinical trial setting (e.g., socioeconomic factors).¹¹

External Validity

The clinical experts consulted by CADTH noted that the baseline and demographic characteristics in the VISION trial are a reasonable reflection of the target patient population in Canada. The clinical experts consulted by CADTH noted that the duration of survival in the control group (i.e., 11.3 months) exceeds what would be anticipated for the target population in Canadian practice. The experts estimated that survival is typically in the range of 6 to 9 months for patients with progressive mCRPC who have demonstrated disease progression after prior treated with ARPI(s) and taxane regimen(s). It was noted that this is commonly observed in clinical trials of prostate cancer in which patients are often healthier and have fewer comorbidities than the overall patient population encountered in routine Canadian clinical practice.

All of the patients included in the VISION trial had prior exposure to at least 1 taxane regimen. At the time of screening, █████ of patients had received 2 taxane regimens and ████ had received more than 2 taxane regimens. At the time of enrolment in the VISION trial, █████ of the total study population had been treated with a single taxane and, therefore, should not have been medically suitable for another taxane regimen, per the study protocol. The clinical experts consulted by CADTH noted that this number is greater than would be anticipated in Canadian practice for the target population, in which approximately ███ ██ ███ of patients would be considered not medically suitable for cabazitaxel. An important limitation of the external validity of the VISION trial was the large proportion of patients who received cabazitaxel in the poststudy treatment setting (i.e., the VISION trial enrolment criteria stated that patients who had received a single taxane regimen would be medically unsuitable for an additional taxane regimen). The clinical experts consulted by CADTH noted that this would not be reflective of Canadian practice, in which a patient with mCRPC who is considered ineligible for a further taxane regimen is unlikely to become eligible at a later point in time, as this disease is progressive and improvements in functional status or physiologic reserve are not anticipated. Other than these issues, the clinical experts noted that subsequent therapies could be reflective of routine care for patients for whom there are no other therapies that have been shown to increase OS.

¹⁷⁷Lu vipivotide tetraxetan was administered as an add-on therapy in the VISION trial, which included concomitant administration of other systemic cancer therapies. There are no Canadian clinical practice guidelines that address the use of ¹⁷⁷Lu vipivotide tetraxetan, and the clinical experts consulted by CADTH noted that it is unclear whether the use of ¹⁷⁷Lu vipivotide tetraxetan in combination with other systemic anticancer therapies would be adopted in practice because of uncertainty regarding additional clinical benefit and harms for patients.

Several potential comparators for ¹⁷⁷Lu vipivotide tetraxetan were not permitted in the acceptable BSoC treatment regimes. These included cytotoxic chemotherapy (e.g., cabazitaxel), immunotherapies, and other systemic radioisotopes (e.g., radium-223 dichloride [Xofigo], or hemi-body radiotherapy). The rationale provided by the sponsor was that these therapies could confound the analysis of results and that systemic anticancer options in the comparator group were limited to hormone therapies, including ARPIs (e.g., abiraterone and enzalutamide). All of the patients enrolled in the trial had exposure to novel ARPIs before enrolment. This approach may have biased the treatment effects in favour of ¹⁷⁷Lu vipivotide tetraxetan, as the majority those in the BSC/BSoC alone group had already been treated with and demonstrated disease progression on the only systemic therapies that were permitted in the trial.¹¹

¹⁷⁷Lu vipivotide tetraxetan could be administered for up to 6 cycles in the VISION trial, which is consistent with recommendations in the Canadian product monograph.^5,7 The VISION trial protocol also included an additional step, in which the patient was to be evaluated after 4 cycles by the investigator for evidence of treatment response (specified as radiological response, PSA response, or clinical benefit in the opinion of the investigator), signs of residual disease on CT with contrast and/ or MRI or bone scan, and good tolerance of the treatment. Patients meeting all those criteria could receive up to 2 additional cycles at the discretion of the treating physician.^5,7 The clinical experts consulted by CADTH noted that evaluation of response to treatment in the target patient population (i.e., those with progressive mCRPC) is multifactorial and would be based on clinical response, radiographic imaging, biochemical measures, and need for medications to manage pain. It was noted that a formal assessment of response after 4 cycles (as performed in the VISION trial) is unlikely to be standardized in Canadian clinical practice and could be a challenge to implement if it was included as renewal criteria for ¹⁷⁷Lu vipivotide tetraxetan. Overall, the clinical experts consulted by CADTH noted that the distribution of doses in the VISION is likely an accurate reflection of what would occur with patients in Canada, as the treatment is generally well tolerated and relatively few AEs lead to dose reductions, interruptions, or discontinuations.

Indirect Comparisons

Description of Studies

The sponsor-submitted indirect treatment comparison (ITC) included a systematic review that used a Bayesian network meta-analysis (NMA) to evaluate the efficacy of ¹⁷⁷Lu vipivotide tetraxetan relative to other comparators(including radium-223 plus BSC, cabazitaxel plus prednisone, olaparib, mitoxantrone or placebo plus prednisone, and ARPI) for the treatment of patients with pretreated, progressive mCRPC. The NMA was based on a systematic review of the literature, and data from 8 studies were used to inform the analyses. The efficacy outcomes of interest were rPFS and OS.

Efficacy Results

The sponsor-submitted ITC reported that the results for OS favoured ¹⁷⁷Lu vipivotide tetraxetan over radium-223 plus BSC (HR = █████ ███ ████ ████ ██ ████) and over ARPI (███ █████ ███ ████ ████ ██ ████). The sponsor-submitted ITC reported that the results for rPFS favoured ¹⁷⁷Lu vipivotide tetraxetan over cabazitaxel plus prednisone (███ █████ ███ ████ ████ ██ ████), mitoxantrone or placebo plus prednisone (███ █████ ███ ████ ████ ██ ████) and over ARPI (███ █████ ███ ████ ████ ██ ████). HRs for OS and rPFS were reported as comparator versus ¹⁷⁷Lu vipivotide tetraxetan.

Critical Appraisal

The clinical heterogeneity in the analysis was related to variation in patient characteristics across the included trials. In the absence of statistical adjustment, sensitivity analyses, or subgroup analyses, the potential impact of the between-study heterogeneity cannot be evaluated. The clinical experts consulted by CADTH noted that there was heterogeneity in clinically important patient characteristics (i.e., prior receipt of chemotherapy, disease severity, and treatment indication); therefore, the ITC analysis may be subject to bias. Of particular concern was the fact that patients included in the ¹⁷⁷Lu vipivotide tetraxetan trial (i.e., VISION) had more severe disease at baseline, as indicated by a higher prior treatment count, and the fact that at least 40% of patients had received cabazitaxel before enrolment. Inconsistency in the network was not reported, likely because of the limited ability to do so, given that the network only had 1 closed loop.

Summary

The sponsor-submitted ITC had several limitations, including the lack of reporting of certain items that would better inform the certainty of the indirect evidence. Despite the heterogeneity of many patient and study characteristics, the ITC authors did not adequately conduct sensitivity or subgroup analyses to investigate the root of heterogeneity or conduct a meta-regression to adjust for effect modifiers that could influence the results. Consequentially, there is substantial uncertainty around the ITC results, and firm conclusions cannot be drawn about the efficacy of ¹⁷⁷Lu vipivotide tetraxetan relative to relevant comparators.

Other Relevant Evidence

Inclusion criteria in VISION trial specified that patients who were previously treated with docetaxel and considered eligible to receive cabazitaxel were to be excluded from the study. As this population is included in the Health Canada–approved indication, CADTH considered this to be an important gap in the evidence and, therefore, summarized the phase II TheraP trial, which enrolled patients with prior exposure to docetaxel for whom cabazitaxel was considered the appropriate treatment option.

Description of Study

TheraP was a multicentre, open-label, phase II RCT comparing the activity and safety of ¹⁷⁷Lu vipivotide tetraxetan with cabazitaxel in patients with mCRPC. The study was conducted by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. As in the VISION trial, the study enrolled patients with PSMA-positive mCRPC, but the TheraP trial used a more rigorous 2-stage screening process to determine PSMA status.

• Gallium-68 (⁶⁸Ga)-PSMA PET-CT: patients were eligible if they demonstrated a maximum standardized uptake value (SUV_max) of at least 20 at a site of disease, and an SUV_max of more than 10 at sites of measurable disease of at least10 mm.

• ¹⁸F-fluorodeoxyglucose (FDG) PET-CT: patients were ineligible if they demonstrated FDG-positive lesions with minimal PSMA expression, defined as an FDG intensity greater than ⁶⁸Ga-PSMA activity or a ⁶⁸Ga-PSMA SUV_max of less than 10 (i.e., discordant imaging).

Eligible patients were randomized in a 1:1 ratio to receive either ¹⁷⁷Lu vipivotide tetraxetan or cabazitaxel. Randomization was stratified by disease burden (> 20 sites versus ≤ 20 sites, assessed by PSMA PET-CT), previous treatment with enzalutamide or abiraterone, and study site.

Patients randomized to the ¹⁷⁷Lu vipivotide tetraxetan group received IV infusions once every 6 weeks for a maximum of 6 cycles. The starting dose was 8.5 GBq, which decreased by 0.5 GBq each subsequent cycle (i.e., not the dosage recommended in the Canadian product monograph, which is 7.4 GBq). Patients in the cabazitaxel group received IV infusions of 20 mg/m² once every 3 weeks for a maximum of 10 cycles. Patients enrolled in the TheraP trial continued to receive supportive cancer therapies (e.g., zoledronic acid, denosumab, or palliative radiotherapy). An important difference between the TheraP trial and the VISION trial is that patients were prohibited from using other systemic anticancer therapies in the TheraP trial (i.e., the study investigated use as monotherapy, which is more reflective of how ¹⁷⁷Lu vipivotide tetraxetan would be administered in Canadian clinical practice). Patients could receive any treatment after completion or discontinuation of the study drugs at the discretion of the treating clinician(s).

A total of 291 patients were screened for eligibility and 200 patients were randomized. As in the VISION trial, a greater proportion of patients in the comparator group (in this case, cabazitaxel) withdrew before receiving any doses of the study medications (16 of101 patients [15.8%] in cabazitaxel group versus 1 of 99 patients [1.0%] in the ¹⁷⁷Lu vipivotide tetraxetan group).

Efficacy Results

After 3 years of follow-up, there was no statistically significant difference in OS between ¹⁷⁷Lu vipivotide tetraxetan and cabazitaxel (HR = 0.97; 95% CI, 0.70 to 1.4; P = 0.99). ¹⁷⁷Lu vipivotide tetraxetan was statistically superior to cabazitaxel for the primary end point of PSA response (i.e., reduction of ≥ 50% from baseline) (risk difference = 29%; 95% CI, 16% to 42%); PFS (HR = 0.63; 95% CI, 0.46 to 0.86); rPFS (HR = 0.64; 95% CI, 0.46 to 0.88); ORR (relative risk = 2.12; 95% CI, 1.10 to 4.08); PSA PFS (HR = 0.60; 95% CI, 0.44 to 0.83); and pain (measured on the present pain intensity [PPI] index) PFS (HR = 0.72; 95% CI, 0.53 to 0.97).

Harms Results

Grade 1 or 2 AEs were more commonly reported in the ¹⁷⁷Lu vipivotide tetraxetan group than in the cabazitaxel group (54% versus 40%), and grade 3 or 4 AEs were more commonly reported in the cabazitaxel group than in the ¹⁷⁷Lu vipivotide tetraxetan group (53% versus 33%).

Critical Appraisal

Internal Validity

Randomization was stratified by a different set of baseline parameters than in the VISION trial (i.e., disease burden based on metastatic sites [> 20 sites versus ≤ 20], whether or not the patient had received previous treatment with enzalutamide or abiraterone, and study site). Overall, baseline and demographic characteristics were well balanced in the ¹⁷⁷Lu vipivotide tetraxetan and cabazitaxel groups in the TheraP trial. As in the VISION trial, the study drugs in the TheraP trial were administered in an open-label manner (for the reasons outlined for the VISION trial). Radiographic images in the TheraP trial were evaluated centrally, but not in a manner that was blinded to the evaluator.

As in the VISION trial, the internal validity of the TheraP trial was limited by the high and disproportionate dropout rate in the comparator group before any doses of the study medications were administered (15.8% in cabazitaxel group versus 1.0% in the ¹⁷⁷Lu vipivotide tetraxetan group). The rationale provided was similar to that for the VISION trial (i.e., patient disappointment at not having access to ¹⁷⁷Lu vipivotide tetraxetan). As in the VISION trial, the high and disproportionate number of patients who withdrew from the control group could bias the study results in favour ¹⁷⁷Lu vipivotide tetraxetan, as those who remained in the study may have had poorer prognoses in than those who withdrew (although the direction and magnitude of any potential bias is uncertain).

The phase II TheraP study was not designed or powered to evaluate differences between ¹⁷⁷Lu vipivotide tetraxetan and cabazitaxel for the primary end points that are recommended by the PCWG3 (e.g., OS). The investigators reported an OS analysis after 3 years of follow-up and noted no statistically significant differences between the 2 treatment groups; however, this analysis may be confounded by crossover and other potential differences in the subsequent therapy setting.

External Validity

Unlike in the VISION trial, ¹⁷⁷Lu vipivotide tetraxetan was administered as monotherapy in the TheraP trial (no other systemic anticancer drugs were permitted as part of the study protocol in the TheraP trial). This is likely more generalizable to the Canadian setting, as the clinical experts consulted by CADTH noted that ¹⁷⁷Lu vipivotide tetraxetan is likely to be used as monotherapy, there is a lack of evidence with which to evaluate the potential benefits of combination regimens; there is a potential for increased drug-related AEs; and there is a likelihood that reimbursement status would be limited to monotherapy.

The comparator in the TheraP trial (cabazitaxel) is highly relevant in the Canadian context for patients who have previously been treated with docetaxel and an ARPI. Unlike in the VISION trial, the TheraP study did not include the eligibility criterion that patients must be considered medically unsuitable to receive further treatment with a taxane regimen. The maximum number of cycles used in the TheraP trial (i.e., 6 cycles) was consistent with the VISION trial and the Canadian product monograph; however, the dosage strength was not consistent with recommendations in the product monograph. Patients in the TheraP trial received an initial dose of 8.5 GBq, which was decreased by 0.5 GBq each subsequent cycle; this is not reflective of the standardized dose of 7.4 GBq recommended in the product monograph.

PSMA status in the TheraP trial was determined using a 2-stage screening process, in which patients were initially screened using ⁶⁸Ga-PSMA PET-CT and then subsequently evaluated using FDG PET-CT. Patients with discordant imaging between ⁶⁸GA-PSMA PET-CT and FDG PET-CT (e.g., FDG intensity levels were greater than those observed with the ⁶⁸Ga-PSMA PET-CT) were excluded from the trial. The clinical experts consulted by CADTH noted that the more rigorous criteria applied in the TheraP trial could help identify patients who may be most likely to response to ¹⁷⁷Lu vipivotide tetraxetan; however, the need for 2 diagnostic PET-CT scans to determine PSMA status would likely pose implementation challenges in clinical practice for clinicians and the health system in Canada.

Conclusions

¹⁷⁷Lu vipivotide tetraxetan injection is indicated for the treatment of adults with PSMA-positive mCRPC who have received at least 1 ARPI and taxane-based chemotherapy. Effective treatments for patients with mCRPC who have progressed after treatment with an ARPI and docetaxel are currently limited, and all stakeholders identified important unmet medical needs, particularly for patients who are be ineligible to receive additional therapy with taxane regimens.

The CADTH review included 1 phase III RCT (VISION; N = 831) that compared the use of ¹⁷⁷Lu vipivotide tetraxetan as an add-on therapy to BSC/BSoC with BSC/BSoC alone. The VISION trial suggested that ¹⁷⁷Lu vipivotide tetraxetan was superior to BSC/BSoC alone on a series of outcomes that are considered important in the evaluation of prostate cancer therapies (i.e., OS, rPFS, time to first SSE, HRQoL, and PFS). However, there is uncertainty regarding the internal validity of the results because of several important limitations, most notably the considerable early withdrawal of consent and the disproportionate dropout rate in the BSC/BSoC alone group. The extent of the early withdrawal was substantial enough to require amendments to the VISION protocol, which included the use of a new analysis set that was limited to patients enrolled after the amendments. This new analysis set was used for the primary evaluation of all end points, with the exception of OS (as the sponsor was able to obtain mortality data for those who withdrew from the study) and ORR (which was based on a smaller subset of patients). Regulatory authorities and the clinical experts consulted by CADTH considered the results for OS to be clinically important, given that the patients enrolled in the VISION trial were heavily pretreated. The choice of BSC/BSoC as the comparator in the VISION trial and the limitations of the sponsor’s ITC preclude the drawing of any conclusions regarding the efficacy of ¹⁷⁷Lu vipivotide tetraxetan relative to other relevant comparators for OS.

The inclusion criteria in the VISION trial specified that patients who were previously treated with docetaxel and considered eligible to receive cabazitaxel were to be excluded from the study (despite this, approximately 18% of patients received cabazitaxel in the poststudy treatment setting). To address this important gap in the evidence, CADTH summarized results from the TheraP trial (N = 200), which enrolled patients with prior exposure to docetaxel for whom cabazitaxel was considered the appropriate treatment option. TheraP was a phase II study that was not designed or powered to evaluate potential differences in OS, and there was no statistically significant difference between ¹⁷⁷Lu vipivotide tetraxetan and cabazitaxel for OS. Treatment with ¹⁷⁷Lu vipivotide tetraxetan was statistically superior to cabazitaxel for the primary end point of PSA response, PFS, rPFS, ORR, PSA PFS, and pain PFS.

¹⁷⁷Lu vipivotide tetraxetan is the first drug specifically indicated for use in patients with PSMA-positive prostate cancer. The evaluation of PSMA status requires PET-CT imaging with a PSMA-targeted radioligand; at the time of CADTH’s review, this process was not routinely performed in Canadian clinical practice. The potential health system implications and imaging resource requirements may pose implementation challenges that could affect the integration and uptake of ¹⁷⁷Lu vipivotide tetraxetan in Canadian practice.

Introduction

Disease Background

Prostate cancer is the most common cancer among Canadian men (excluding nonmelanoma skin cancers), affecting 1 in 9 men during their lifetime.¹ Prostate cancer represents approximately 20% of all new cancers diagnosed in men in Canada and 10% of cancer deaths in men.² In 2022, it was estimated that 24,600 men in Canada would be diagnosed with prostate cancer and that 4,600 men would die from prostate cancer, according to the CCS.² Patients who die from prostate cancer typically progress to the mCRPC stage, and the 5-year survival rate is approximately 30%.³ The Canadian Urological Association (CUA) defines CRPC as disease progression despite castrate levels of testosterone that can present as a continuous rise in serum PSA levels, the progression of preexisting disease, and/or the appearance of new metastases.⁴

PSMA is a transmembrane glycoprotein that is highly expressed in prostate cancer cells. The CUA notes that the expression of PSMA has been observed to increase with the emergence of androgen independence in prostate cancers.⁴

Figure 1: Progression of Prostate Cancer

BCR = biochemical relapse; Int = intermediate; mCRPC = metastatic castration-resistant prostate cancer; mHSPC = metastatic hormone-sensitive prostate cancer; nmCRPC = nonmetastatic castration-resistant prostate cancer.

Source: Sponsor’s clinical summary.⁶

Standards of Therapy

Systemic Cancer Therapies

Figure 2 provides a summary of the CUA guidelines for the management of CRPC.¹² The CUA states that the optimal sequence of the available therapeutic options remains uncertain, but that changing the therapeutic mechanism of action with each line of therapy may lead to better and longer-lasting responses in patients. Cytotoxic chemotherapy with docetaxel has been the standard of care for patients with mCRPC who progress on first- or second-line androgen-deprivation therapy. The clinical experts consulted by CADTH noted that patients with mCRPC who experience disease progression after treatment with docetaxel have a poor prognosis and that there are limited effective treatment options available for these patients. For patients who are considered suitable for further chemotherapy, cabazitaxel is currently considered the standard of care and is recommended by the CUA, based on a phase III study that demonstrated that cabazitaxel had a statistically significant survival advantage over mitoxantrone for patients previously treated with docetaxel.⁴

Figure 2: CUA Guidelines for the Management of CRPC (Redacted)

CRPC = castration-resistant prostate cancer; CUA = Canadian Urological Association; mCRPC = metastatic castration-resistant prostate cancer; PSADT = prostate-specific antigen doubling time.

Figure redacted to respect copyright terms.

Source: Saad et al. (2022).¹²

CUA guidelines were updated in November 2022 to address the use of ¹⁷⁷Lu vipivotide tetraxetan.¹² The CUA notes that ¹⁷⁷Lu vipivotide tetraxetan for up to 6 cycles is recommended for patients with mCRPC and PSMA-expressing metastatic lesions who have progressed on at least 1 previous taxane chemotherapy and an ARPI (Level 1, strong recommendation). In support of the recommendation, the CUA cites the results of the TheraP trial (improvement in PSA response and fewer grade 3 or 4 AEs than cabazitaxel) and the VISION trial (improvements in all primary and secondary outcomes).

The CUA guidelines state that the following Health Canada–approved drugs have shown improvements in survival for patients with mCRPC: abiraterone acetate plus prednisone, enzalutamide, docetaxel plus prednisone or prednisolone, cabazitaxel plus prednisone or prednisolone, radium-223, olaparib, and ¹⁷⁷Lu vipivotide tetraxetan.^5,13-18 Among these treatment options, the following were considered relevant comparators for the CADTH review of ¹⁷⁷Lu vipivotide tetraxetan:

• Cabazitaxel in combination with prednisone or prednisolone, which is indicated for the treatment of patients with mCRPC previously treated with a docetaxel-containing regimen.¹⁶

• Olaparib, which is indicated as monotherapy for the treatment of adults with deleterious or suspected deleterious germline and/or somatic BRCA- or ATM-mutated mCRPC who have progressed after treatment with a new hormonal drug.¹⁴ Olaparib was previously reviewed by CADTH for use in the indicated population and received a recommendation in favour of reimbursement from the CADTH pan-Canadian Oncology Drug Review Expert Review Committee.¹⁹

• Radium-223, which is indicated for the treatment of patients with mCRPC, symptomatic bone metastases, and no known visceral metastatic disease.¹³ The clinical experts consulted by CADTH estimated that approximately 60% of patients with mCRPC who have progressed after treatment with a taxane would have bone-only metastases, and noted that the current reimbursement status of radium-223 varies across Canada.

• Another ARPI (e.g., enzalutamide if the patient was previously treated with abiraterone plus prednisone) can be administered for some patients but is considered to have limited activity.⁴

The European Society for Medical Oncology and the European Association of Urology prostate cancer guidelines were also updated to address ¹⁷⁷Lu vipivotide tetraxetan. The European Association of Urology guidelines state that ¹⁷⁷Lu vipivotide tetraxetan be offered to pretreated patients with mCRPC with 1 or more metastatic lesions and high-level expression of PSMA (exceeding the uptake in the liver) on the diagnostic radiolabelled PSMA PET-CT scan.²⁰ The European Society for Medical Oncology guidelines state that ¹⁷⁷Lu vipivotide tetraxetan should be considered (when available) for patients who have progressed on an APRI and a taxane regimen.²¹ The National Comprehensive Cancer Network treatment guidelines for mCRPC state that ¹⁷⁷Lu vipivotide tetraxetan can be a useful treatment option for patients with PSMA-positive prostate cancer who were previously treated with docetaxel and an ARPI.²²

Patients with mCRPC can receive supportive therapy with systemic corticosteroids (e.g., low-dose prednisone or dexamethasone), which can lead to improvements in palliative outcomes; palliative radiation for bone metastases; and treatment with bisphosphonates or denosumab to reduce the risk of skeletal-related events (e.g., pathological fractures, spinal cord compression, or the need for surgery or radiation therapy to bone).⁴

PSMA Testing in Canada

Figure 3 provides a summary of the CUA recommendations for the application of PSMA testing in Canadian practice. These recommendations predated the Canadian regulatory approval of PSMA-targeted pharmacotherapy and do not specifically address the use of PSMA testing to identify candidates for treatment with ¹⁷⁷Lu vipivotide tetraxetan. The CUA statement recommends that PSMA-targeted PET should not be routinely offered outside a clinical trial for patients with mCRPC (i.e., the target population of ¹⁷⁷Lu vipivotide tetraxetan).

Figure 3: CUA Recommendations for PSMA Testing (Redacted)

CRPC = castration-resistant prostate cancer; CUA = Canadian Urological Association; mCRPC = metastatic castration-resistant prostate cancer; PSADT = prostate-specific antigen doubling time; PSMA = prostate-specific membrane antigen.

Figure redacted to respect copyright terms.

Source: Shaygan et al. (2021).²⁷

There is currently 1 ⁶⁸Ga-labelled PSMA-targeted radiopharmaceutical approved for use in Canada (⁶⁸Ga-gozetotide [Illucix]).²³ Two others are currently listed as being under review by Health Canada, including 1 manufactured by the sponsor of ¹⁷⁷Lu vipivotide tetraxetan (Advanced Accelerator Applications US, Inc.).²⁴ An additional PSMA diagnostic radiopharmaceutical has been approved by the FDA (piflufolastat F 18 [Pylarify]),²⁵ but it has not been approved and is not listed as being under consideration by Health Canada at the time of this review. At least 1 additional PSMA diagnostic radiopharmaceutical is currently under development (i.e., ¹⁸F-PSMA-1007).²⁶

Drug Under Review

¹⁷⁷Lu vipivotide tetraxetan injection is indicated for the treatment of adults with PSMA-positive mCRPC who have received at least 1 ARPI and taxane-based chemotherapy.⁵ The sponsor has requested that ¹⁷⁷Lu vipivotide tetraxetan be reimbursed in accordance with the Health Canada–approved indication.⁶ Based on the approved indication for ¹⁷⁷Lu vipivotide tetraxetan, there are 3 relevant subpopulations for consideration in this review:

• patients previously treated with docetaxel who are considered eligible to receive cabazitaxel

• patients previously treated with docetaxel who are considered ineligible to receive cabazitaxel

• patients previously treated with both docetaxel and cabazitaxel.

Mechanism of Action

The product monograph states that the active moiety of ¹⁷⁷Lu vipivotide tetraxetan is the radionuclide lutetium-177, which is linked to a targeting moiety that binds to PSMA, a transmembrane protein that is highly expressed in prostate cancer. Upon the binding of ¹⁷⁷Lu vipivotide tetraxetan to PSMA-expressing cancer cells, the beta-minus emission from lutetium-177 delivers therapeutic radiation to the targeted cell, as well as to surrounding cells, and induces DNA damage, which can lead to cell death.⁵

Figure 4: Sponsor’s Proposed Place in Therapy for ¹⁷⁷Lu Vipivotide Tetraxetan

¹⁷⁷Lu = lutetium-177; ARPI = androgen receptor pathway inhibitor; mHSPC = metastatic hormone-sensitive prostate cancer; mCRPC = metastatic castration-resistant prostate cancer; PSMA = prostate-specific membrane antigen; SCO = standard of care.

Source: Sponsor’s application.⁶

Dosage and Administration

¹⁷⁷Lu vipivotide tetraxetan is administered intravenously. The recommended dose of ¹⁷⁷Lu vipivotide tetraxetan is 7.4 GBq (7,400 MBq or200 mCi) every 6 weeks (± 1 week) for a total of 6 doses.⁵ Table 3 provides recommended dose modifications for the management of adverse drug reactions. The management of severe or intolerable adverse drug reactions may require temporary dose interruption (extending the dosing interval from every 6 weeks to every 10 weeks), dose reduction, or permanent discontinuation of treatment with ¹⁷⁷Lu vipivotide tetraxetan.⁵ No dose adjustment is recommended for patients with hepatic impairment or for patients with mild (baseline creatinine clearance [CrCl] of 60 mL/min to 89 mL/min, according to the Cockcroft-Gault equation) to moderate (CrCl of 30 mL/min to 59 mL/min) renal impairment. The pharmacokinetic profile and safety of ¹⁷⁷Lu vipivotide tetraxetan has not been studied in patients with severe (CrCl of 15 mL/min to 29 mL/min) renal impairment or end-stage renal disease.⁵

¹⁷⁷Lu vipivotide tetraxetan is available as a 1,000 MBq/mL solution for injection in single-dose vials that contain a total amount of radioactivity of 7.4 GBq (7,400 MBq or 200 mCi) (± 10%) at the time of administration.⁵

Table 3: Recommended Dose Modifications for Adverse Reactions

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CrCl = creatinine clearance; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ULN = upper limit of normal.

^aThe same thresholds are also applicable to baseline values at the time of treatment initiation with ¹⁷⁷Lu vipivotide tetraxetan.

Source: Product monograph.⁵

Precautions for Post-treatment Contamination

As with other radiopharmaceuticals, the product monograph states that ¹⁷⁷Lu vipivotide tetraxetan should be used only by health professionals who are appropriately qualified in the use of radioactive prescribed substances in or on humans.⁵ Before the patient is released, the health care provider should explain the necessary radioprotection precautions that the patient should follow to minimize radiation exposure to others. After the administration of ¹⁷⁷Lu vipivotide tetraxetan, patients should be advised to limit close contact (less than 1 m) with household contacts for 2 days and with children and pregnant women for 7 days. After the administration of ¹⁷⁷Lu vipivotide tetraxetan, patients should be advised to sleep in a bedroom separate from household contacts for 3 days, from children for 7 days, or from pregnant women for 15 days.⁵

Table 4: Key Characteristics of ¹⁷⁷Lu Vipivotide Tetraxetan, Cabazitaxel, Olaparib, and Radium-223

¹⁷⁷Lu = lutetium-177; ARPI = androgen receptor pathway inhibitor; CRPC = castration-resistant prostate cancer; mCRPC = metastatic castration-resistant prostate cancer; N/A = not applicable; PARP = poly (ADP-ribose) polymerase; PSMA = prostate-specific membrane antigen.

^aHealth Canada–approved indications.

Sources: Product monographs.^5,13,14,16

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient inputs received by CADTH have been included in the stakeholder section at the end of this report.

Two patient groups, the CCS and the CCSN, provided input for the treatment of adults with PSMA-positive mCRPC who have been treated with ARPI and taxane-based chemotherapy or who are not medically suitable for taxanes. Patient input was gathered from surveys of and interview with patients with mCRPC and their caregivers in Canada in August 2022. Of the 27 survey respondents, 19 were from the CCS and 8 were from the CCSN. Of the 7 patients included in the submissions who had experience with the treatment under review, 4 were from the CCS and 3 were from the CCSN. Of these 7 patients, 2 participated in an in-depth interview.

Patients surveyed by the CCS reported that their disease had a negative effect on their QoL and their ability to perform certain routine functions, such as sexual activity, travel and exercise, family obligations, maintaining mental health, work, household chores, concentrating, spending time with family and friends, and practical needs (e.g., preparing meals, dressing, bathing). Patients surveyed by the CCSN reported frequent urination, erectile dysfunction, bone and/or skeletal pain, loss of QoL, hot flashes, weight gain, and slight memory loss related to current day-to-day experiences as a result of their disease. These patients also reported AEs related to their current treatments, such as incontinence, fatigue, diarrhea, weight gain, erectile dysfunction, urinary issues, infection, hot flashes, loss of muscle, hair loss, breast enlargement, and loss of libido. Patients surveyed by the CCS reported that changes in libido and sexual function had the most significant impact on their day-to-day lives.

Respondents to the CCSN survey reported no issues accessing therapies, but 11 of 19 respondents to the CCS survey reported experiencing 1 or more barriers to treatment. The most common barrier reported was the cost of transportation to appointments, followed by costs associated with complementary medicines recommended by their health care team (e.g., vitamins and supplements.), loss of income due to absence from work, costs associated with medical tests and procedures, and lack of familiarity with the health care system.

Patients who responded to the CCSN survey reported some outcomes they expect from a new treatment, including maintaining QoL, delaying the onset of symptoms, prolonging life, providing a cure, reducing side effects from current medications or treatments, and the return of libido, along with ease of use and easy access. When describing experiences with ¹⁷⁷Lu vipivotide tetraxetan, patients reported some side effects, including dry mouth, weakness, fatigue, low blood platelet counts, low red blood cell counts and/or anemia, nausea and/or vomiting, loss of appetite, constipation, diarrhea, abdominal pain, shortness of breath, and brain fog. All 4 patients using the treatment under review who responded to the CCS survey strongly agreed that they would recommend it to others with mCRPC, and 3 patients stated that they would choose to continue the treatment despite side effects.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in 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). A panel of 3 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating situations for which there are gaps in the evidence that could be addressed with the collection of additional data, promote the early identification of potential implementation challenges, gain insight into the clinical management of patients living with mCRPC, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). A summary of this panel discussion is presented here.

Unmet Needs

The clinical experts consulted by CADTH noted that there are limited effective treatments for patients with mCRPC who have progressed after treatment with docetaxel. OS is poor for those with disease that is refractory to multiple treatment options, and the symptoms of cancer progression pose a considerable burden for patients. Standard of care treatments, such as cytotoxic chemotherapy with cabazitaxel, are associated with significant toxicities (e.g., neuropathy and febrile neutropenia). The experts noted that many patients are often unsuitable to receive treatment with cabazitaxel because of comorbidities and/or a poor performance status. As with most advanced malignancies, there are limited treatments that can meaningfully reverse the course mCRPC for a prolonged amount of time. As in the input from the patient groups, the clinical experts noted that there is a need for therapies that improve OS and QoL and that are better tolerated and more convenient (e.g., less need for supportive medications, less frequent administration) than the current standard of care for this patient population.

Place in Therapy

The clinical experts consulted by CADTH noted that ¹⁷⁷Lu vipivotide tetraxetan could be considered a treatment option for patients whose disease has progressed after both an androgen receptor axis-targeted therapy and docetaxel. The experts noted that there is uncertainty regarding the place of ¹⁷⁷Lu vipivotide tetraxetan in therapy relative to cabazitaxel for patients who are considered appropriate candidates for a second chemotherapy regimen. They noted that the eligibility criteria for the phase III VISION trial specifically excluded such patients (although 14.9% and 18.9% of patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and BSC/BSoC alone groups, respectively, received cabazitaxel in the subsequent therapy setting), but that the phase II TheraP trial provided some evidence of comparative efficacy for ¹⁷⁷Lu vipivotide tetraxetan and cabazitaxel.

Patient Population

This treatment would be most suited for patients with the following characteristics:

• Progressive mCRPC: symptomatic, imaging, or biochemical.

• PSMA: Evidence of PSMA-expressing metastases based on a diagnostic PSMA-targeted PET scan. The criteria used in the VISION trial were considered acceptable for the identification of patients based on input from the clinical experts consulted by CADTH and input from stakeholders. It was noted that the criteria used in the phase II TheraP trial were more restrictive and could be used as alternative criteria; however, the application of those criteria would pose additional challenges for clinicians.

• Adequate performance status: ECOG PS of 0 to 2.

• Adequate organ function: liver and bone marrow.

Assessing Response to Treatment

The clinical experts noted that imaging for patients with mCRPC would typically be performed once every 12 weeks in Canadian clinical practice or earlier in response to changes in symptoms and/or clinical examination. The clinical experts consulted by CADTH noted that evaluating response to treatment in the target patient population (i.e., those with progressive mCRPC) is multifactorial and would be based on clinical response, radiographic imaging, biochemical measures, and analgesic requirements. It was noted that a formal assessment of response after 4 cycles (as conducted in the VISION trial) is unlikely to be standardized in Canadian clinical practice and could be a challenge to implement if included as renewal criteria for ¹⁷⁷Lu vipivotide tetraxetan.

Discontinuing Treatment

The clinical experts consulted by CADTH noted that ¹⁷⁷Lu vipivotide tetraxetan should be discontinued in patients who experience disease progression characterized by at least 2 specific adverse occurrences (i.e., sustained PSA rise, clinical progression [sustained, analgesic, nonresponsive pain; performance status decline], and radiographic progression); significant toxicity related to the treatment; or worsening of performance status (i.e., ECOG PS ≥ 3).

Prescribing Conditions

The product monograph states that ¹⁷⁷Lu vipivotide tetraxetan should be administered under the supervision of a health professional who is experienced in the use of radiopharmaceuticals. Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available. The clinical experts consulted by CADTH noted that these requirements, although necessary, would likely pose challenges to patient access, based on the number and/or locations of currently available facilities (e.g., regional variation, existing capacity constraints). Overall, there was consensus that ¹⁷⁷Lu vipivotide tetraxetan is ideally delivered in the setting of multidisciplinary care, with collaboration between specialists experienced in treating prostate cancer (i.e., those specializing in urologic oncology, medical oncology, nuclear medicine, radiation oncology, and diagnostic radiology).

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The full original clinician group input received by CADTH have been included in the stakeholder section at the end of this report.

Clinician group input was received from prostate-treating clinicians in Canada with a special interest in the care of those with metastatic prostate cancer. The CCS coordinated the submission.

The clinician group agreed that there have been some unmet needs for additional lines of therapy and a scarcity of treatments that induce disease modification to preserve QoL and provide meaningful survival benefits for patients with progressive metastatic prostate cancer. The clinician group indicated that radioligand therapies that target PSMA confer both disease-modifying and symptom-management benefits on this population, as suggested by the phase III VISION trial and the phase II TheraP trial. Because ¹⁷⁷Lu vipivotide tetraxetan is a PSMA-targeted radioligand therapeutic, the clinicians expect similar benefits in patients who have PSMA-expressing prostate cancer identified on diagnostic PSMA-targeted PET. The clinicians pointed out that the drug under review can be considered well tolerated, based on evidence from the randomized trials, and a good additional line of therapy compared to third-line chemotherapy or supportive care only.

The clinician group noted that the treatment would be best suited to patients with progressive (symptomatic, imaging, or biochemical) mCRPC, PSMA-expressing metastases identified on a diagnostic PSMA-targeted PET scan, and with an adequate performance status (ECOG PS of 0 to 2) and organ function (liver and bone marrow). The clinician group also pointed out that the most meaningful clinical response to treatment for this disease would be the prevention of progression, reflected in stability or improvement in biochemical and imaging biomarkers such as serum PSA, bone scan, and CT. The clinician group emphasized that appropriate facilities, certifications, and personnel licensed to deliver unsealed radiopharmaceutical treatments would be needed for the safe delivery of ¹⁷⁷Lu vipivotide tetraxetan, in addition to access to diagnostic PSMA-targeted PET for proper patient selection.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that could affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

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

¹⁷⁷Lu = lutetium-177; ⁶⁸Ga = gallium-68; ALT = alanine aminotransferase; ARPI = androgen receptor pathway inhibitor; AST = aspartate aminotransferase; BSC = best supportive care; BSoC = best standard of care; CRPC = castration-resistant prostate cancer; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FDG = ¹⁸F-fluorodeoxyglucose; mCRPC = metastatic castration-resistant prostate cancer; PSMA = prostate-specific membrane antigen.

Clinical Evidence

The clinical evidence included in the review of ¹⁷⁷Lu vipivotide tetraxetan is presented in 3 sections. The first section, the Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of ¹⁷⁷Lu vipivotide tetraxetan for the treatment of adults with PSMA-positive mCRPC who have received at least 1 ARPI and taxane-based chemotherapy.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 6. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²⁹

Table 6: Inclusion Criteria for the Systematic Review

¹⁷⁷Lu = lutetium-177; AE = adverse events; ARPI = androgen receptor pathway inhibitor; ECOG PS = Eastern Cooperative Oncology Group Performance Status; mCRPC = metastatic castration-resistant prostate cancer; NAAD = novel androgen axis drug; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; RCT = randomized controlled trial; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

^aThe clinical experts consulted by CADTH noted that a small subset of patients could be candidates for re-treatment with docetaxel.

^bRe-treatment with ARPI was not considered to be a relevant comparator by the clinical experts consulted by CADTH (as patients would have to have previously been treated with an ARPI to be considered a candidate for ¹⁷⁷Lu vipivotide tetraxetan). This has been included as a comparator in the CADTH review protocol as it was included in the sponsor’s economic evaluation and was identified as a potential comparator by the participating drug programs.

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Pluvicto (¹⁷⁷Lu vipivotide tetraxetan). The clinical trials registries searched were the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on September 7, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee (pERC) on January 11, 2023.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.³⁰ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 1 study was identified from the literature for inclusion in the systematic review (Figure 5). The included study is summarized in Table 7. A list of excluded studies is presented in Appendix 2.

Figure 5: Flow Diagram for the Inclusion and Exclusion of Studies

Table 7: Details of Included Studies

¹⁷⁷Lu = lutetium-177; ⁶⁸Ga = gallium-68; BSC = best supportive care; BSoC = best standard of care; CNS = central nervous system; FACT-G = Functional Assessment of Cancer Therapy-General; FACT-P = Functional Assessment of Cancer Therapy-Prostate; FAPSI-8 = 8-item Functional Assessment of Cancer Therapy Advanced Prostate Symptoms Index; mCRPC = metastatic castration-resistant prostate cancer; NA = not applicable; NYHA = New York Heart Association; PCWG3 = Prostate Cancer Working Group 3; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; RCT = randomized controlled trial; RLT = targeted radioligand therapy.

Note: The 5 additional reports included were the Clinical Study Report,⁷ FDA Multidiscipline Review,⁹ Health Canada Biologics Safety and Efficacy Assessment Report,⁸ Common Technical Document,⁶ and clinicaltrials.gov.³²

Source: Clinical Study Report.⁷

Description of Studies

VISION is a phase III, open-label, RCT conducted to compare the efficacy and safety of ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC with BSC/BSoC alone in patients with progressive PSMA-positive mCRPC (Figure 6). The sponsor reported that the open-label design was used because blinding would not be practical, owing to the specialized precautions required for administration of a radiopharmaceutical and the toxicities related to targeted radioligand therapy. In addition, the sponsor noted that it would not be appropriate to subject patients who did not receive a radiopharmaceutical to posttreatment radiation protection protocols (e.g., maintaining physical distancing from family members).

Patients were randomized in a 2:1 ratio to receive either ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC or BSC/BSoC alone (a rationale for the 2:1 ratio was not stated in the protocol). Randomization was stratified by LDH (≤ 260 IU/L versus > 260 IU/L), presence of liver metastases (yes versus no), ECOG PS (0 or 1 versus 2), and inclusion of NAAD in BSC/BSoC (yes versus no).

Patients were enrolled in Belgium (n = 17); Canada (n = 49); Denmark (n = 24); France (n = 70); the Netherlands (n = 38); Sweden (n = 33); the UK (n = 47); and the US (n = 553).⁷

Figure 6: Design of the VISION Study

¹⁷⁷Lu = lutetium-177; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; mCRPC = metastatic castration-resistant prostate cancer; NAAD = novel androgen axis drug; OS = overall survival; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; RECIST = Response Evaluation Criteria in Solid Tumours Version 1.1; rPFS = radiographic progression-free survival.

Source: Clinical Study Report.⁷

Populations

Inclusion and Exclusion Criteria

Eligibility criteria are summarized in Table 7. The VISION trial enrolled patients with PSMA-positive, progressive, mCRPC (i.e., serum PSA progression, soft-tissue progression, or progression of bone disease) who had received prior treatment with at least 1 NAAD and at least 1 taxane regimen. Patients who had received treatment with only 1 taxane regimen were required to be medically unsuitable to receive a second taxane regimen. The trial was limited to those with an ECOG PS of 0 to 2.⁷

PSMA-positive patients were identified using ⁶⁸Ga-PSMA-11 PET-CT scans that were evaluated centrally based on the following criteria:

1. At least 1 ⁶⁸Ga-PSMA-11-positive lesion. On PET-CT, a positive lesion was defined as having an uptake greater than normal liver parenchyma, whereas a negative lesion was defined as having an uptake less than or equal to liver uptake.

2. All lymph nodes that measured at least 2.5 cm on the short axis had to be ⁶⁸Ga-PSMA-11 positive.

3. All bone metastases with a soft-tissue component of at least 1.0 cm on the short axis had to be ⁶⁸Ga-PSMA-11-positive (patients with PSMA-negative osseous metastases without a soft-tissue component were not excluded).

4. All solid-organ metastases (e.g., lung, liver, adrenal glands.) of at least 1.0 cm on the short axis had to be ⁶⁸Ga-PSMA-11-positive.

Only patients with at least 1 PSMA-positive lesion identified on PET (i.e., criterion 1) and no negative lesions (i.e., criteria 2 to 4) were enrolled in the study, provided all other inclusion and exclusion criteria were met.⁷

Baseline and Demographic Characteristics

Table 8 provides a summary of baseline and demographic characteristics for the FAS (i.e., all randomized patients) and PFS-FAS (i.e., all randomized patients on or after March 5, 2019) in the VISION trial. Baseline characteristics were generally similar in the 2 study populations and across the treatment groups.

Data are presented separately for the FAS (all randomized patients who received at least 1 dose of the study treatment) and the PFS-FAS (all patients randomized on or after March 5, 2019). The FAS was used for the evaluation of OS and the PFS-FAS was used for the evaluation of rPFS and all secondary end points (except ORR and DCR). Details regarding these populations are reported in the Statistical Analysis section.

Table 8: Summary of Baseline Characteristics

¹⁷⁷Lu = lutetium-177; ALP = alkaline phosphatase; BSC = best supportive care; BSOC = best standard of care; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FAS = full analysis set; LDH = lactase dehydrogenase; PFS = progression-free survival; PSA = prostate-specific antigen; SD = standard deviation.

^aThe FAS was used for the evaluation of OS.

^bThe PFS-FAS was used for the evaluation of rPFS and all secondary end points (except ORR and DCR).

Source: Clinical Study Report.⁷

Prior Cancer Therapies

Table 9 provides a summary of prior surgery, radiotherapy, and systemic cancer therapy for the FAS and PFS-FAS populations in the VISION trial. Overall, exposure to all types of prior therapies was well balanced across the treatment groups in both the FAS and PFS-FAS. For prior cancer surgery, 43.2% and 39.9% of patients had received at least 1 prior therapeutic surgery for prostate cancer in the FAS and PFS-FAS populations, respectively. The majority of patients had received at least 1 prostate cancer-related radiotherapy (76.1% and 75.4% in the FAS and PFS-FAS, respectively). The most frequent site for radiotherapy was the prostate gland.⁷

The number and type of systemic therapies were well balanced between the 2 treatment groups in both the FAS and PFS-FAS populations. In the FAS, the mean number of prior systemic regimens was 5.3, and the majority of patients (79.1%) had received at least 4 different categories of treatment. All patients had received prior taxane treatment (1 regimen in 57.9% of patients and 2 regimens in 41.2%), and all patients had received prior therapy with a NAAD (1 regimen in 51.3% of patients, 2 regimens in 41.0%, and more than 2 regimens in 7.7%).⁷ As shown in Table 9, results were similar for patients in the PFS-FAS population.

Table 9: Summary of Prior Cancer Therapies

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSOC = best standard of care; FAS = full analysis set; NAAD = novel androgen axis drug; PC = prostate cancer; PFS = progression-free survival; SD = standard deviation.

^aThe FAS was used for the evaluation of OS.

^bThe PFS-FAS was used for the evaluation of rPFS and all secondary end points (except ORR and DCR).

Source: Clinical Study Report.⁷

Interventions

Intervention of Interest

Administration: ¹⁷⁷Lu vipivotide tetraxetan was administered as a slow IV injection at a dose of 7.4 GBq (± 10%) once every 6 weeks (± 1 week) for a maximum of 6 cycles. An infusion with at least 10 mL of normal saline was administered to ensure patency of the IV line before ¹⁷⁷Lu vipivotide tetraxetan administration. After ¹⁷⁷Lu vipivotide tetraxetan administration, a saline infusion of 500 mL was recommended. Cooling of the salivary glands from 30 minutes before and up to 4 hours after the ¹⁷⁷Lu vipivotide tetraxetan injection was optional to reduce the risk of salivary gland radiation injuries and depended on the centre’s standard practice. Additionally, allopurinol could be started from 7 days to 10 days after ¹⁷⁷Lu vipivotide tetraxetan therapy in patients with a high tumour burden or gout, at the investigator’s discretion.⁷

Treatment cycles: Patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group began administration with the study drug no more than 28 days after randomization. These patients received 7.4 GBq (± 10%) of ¹⁷⁷Lu vipivotide tetraxetan once every 6 weeks (± 1 week) for a maximum of 6 cycles while receiving BSC/BSoC. After the cycle 4 treatment and before the scheduled cycle 5 treatment, the investigator had to determine whether:

• the patient showed evidence of response (reported as radiological, PSA, or clinical benefit)

• the patient had signs of residual disease on CT with contrast, MRI, or bone scan

• the patient had shown good tolerance to the ¹⁷⁷Lu vipivotide tetraxetan treatment.

If the patient met all of these criteria and agreed to continue with ¹⁷⁷Lu vipivotide tetraxetan treatment, the investigator could administer 2 additional cycles. A maximum of 6 cycles of ¹⁷⁷Lu vipivotide tetraxetan was allowed. If the patient did not meet any of the criteria or did not agree to additional dosing, no further treatment with ¹⁷⁷Lu vipivotide tetraxetan would be administered during the study period.

After the final cycle of ¹⁷⁷Lu vipivotide tetraxetan, patients continued to be treated with BSC/BSoC as long as the investigator felt they were clinically benefiting (regardless of radiographic progressive disease, based on investigator's assessment, per PCWG3 criteria) or until they required a treatment regimen that was not permitted in the VISION study. For both treatment arms, the cycle duration for cycles 1 to 6 was 6 weeks, and for cycle 7 and beyond was 12 weeks. From cycle 7 onward, all patients from both treatment arms should only receive BSC/BSoC.⁷

Dose reductions and discontinuations: Only 1 dose reduction (by 20%) in administered activity was permitted. Once a dose was reduced, the ¹⁷⁷Lu vipivotide tetraxetan dose could not be re-escalated. If a patient had further toxicity that required an additional reduction in administered activity, treatment with ¹⁷⁷Lu vipivotide tetraxetan was discontinued. If a treatment delay due to an AE or toxicity management persisted for more than 4 weeks, treatment with ¹⁷⁷Lu vipivotide tetraxetan was discontinued. If treatment with ¹⁷⁷Lu vipivotide tetraxetan was discontinued due to an AE, abnormal laboratory value, or toxicity, patients continued to receive BSC/BSoC alone as long as the investigator felt they were clinically benefiting or until they required a treatment regimen not allowed in the VISION study.⁷

Comparator

The BSC/BSoC for each patient was selected by the patient’s physician before randomization, was administered per the physician’s orders before randomization, and was to continue until the patient completed the randomized treatment period and entered the long-term follow-up period. Patients were treated with BSC/BSoC as long as the investigator felt they were clinically benefiting (regardless of radiographic progressive disease, based on investigator's assessment, per PCWG3 criteria) or until they required a treatment regimen not allowed in the VISION study. Treatments for prostate cancer could include but were not limited to:

• supportive measures (e.g., pain medications, hydration, transfusions)

• ketoconazole

• androgen-reducing drugs (including any corticosteroid and 5-alpha reductases)

• abiraterone, enzalutamide, apalutamide, or any other NAAD

• radiation in any external beam or seeded form (however, systemic radioisotopes [e.g., radium-223] and hemi-body radiotherapy treatment were not permitted in the study)

• bone-targeted drugs, including zoledronic acid, denosumab, and any bisphosphonate

• combinations of any or all of the aforementioned treatments (these could be modified over time as needed).⁷

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 10. These end points are summarized here. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Overall Survival

OS was defined as the time (in months) from the date of randomization to the date of death from any cause. If the patient was not known to have died, then OS was censored. The censoring date was the date of the last study visit, or contact, before the cut-off date. The cut-off date was not used as the last contact date unless the patient was seen or contacted on that date.⁷ In response to questions from Health Canada, the sponsor provided the following explanation for how survival status was obtained for patients who were reported as lost to follow-up or off study due to withdrawal of consent.

Preemptively

• Where permitted by ethics committees (ECs) and/or institutional review boards (IRBs), informed consent included a clause that allowed survival follow-up through public registries, local physicians, or medical records in health systems or institutions.

• Study sites were instructed to explain to patients who opted to withdraw consent from the study that if they were willing to allow survival data to continue to be collected, such limited follow-up consisted only of survival status data.

Retrospectively

• Where allowed by ECs and/ or IRBs, patients who had withdrawn consent from the study were contacted and asked whether they would be willing to allow limited follow-up data collection that consisted of survival status only.

• Recurrent listings were created through data management to identify patients who were lost to follow-up or withdrew from the study.

• These patients were discussed between the sponsor and local clinical research associates, and clinical research associates discussed the patients with the respective sites.

• All informed consents forms were checked to confirm whether survival data could be searched and retrieved from public health records, whether local physicians could be contacted for survival status, and whether medical records in health systems or institutions could be used to confirm survival status. Whichever form of survival data collection was allowed was pursued.

• Where required, ECs and/or IRBs were informed and/or consulted and additional submissions were obtained, where needed, to gather survival data from the aforementioned options.

• Where permitted, searches in public health records and survival data retrieval were performed by sites for eligible patients.⁸

Radiographic PFS

rPFS was defined as the time (in months) from the date of randomization to the date of radiographic disease progression, based on the central review assessment, per PCWG3 criteria, or death from any cause. Patients who were alive without radiographic progression at the analysis data cut-off were censored for rPFS at the time of their last evaluable radiographic assessment.

The date of a radiographic progressive disease event was the date of the first CT, MRI, or bone scan identifying progressive disease or of death from any cause (whichever occurred first) for patients with no more than 1 immediately prior assessment missing.

• Progressive disease was based on overall response assessed using RECIST.

• The date of progressive disease was the date of the first appearance of new lesion(s), if applicable.

Progressive disease identified on a bone scan had to be confirmed with the following 2 rules (which allow for a flare effect at the first posttreatment scan):

• Rule 1 (progression at week 8, confirmed at week 16) — If there were at least 2 new lesions on the first posttreatment scan, they had to be confirmed with at least 2 additional lesions on the next scan (2 + 2 rule). The date of progression was the date of the first posttreatment scan.

• Rule 2 (progression at week 16 or later confirmed at next scan) — For scans performed after the first posttreatment scan, there had to be at least 2 new lesions after the first posttreatment scan (treated as a new baseline) that were persistent (confirmed) on a subsequent scan. The date of progression was the date of the scan that first documented the second lesion relative to the first posttreatment scan.

The censoring date was the date when the last evaluable radiographic assessment (CT, MRI, or bone scan) determined a lack of progression. If there were no evaluable assessments, censoring occurred at the date of randomization. Patients who had 2 or more consecutive missed tumour assessments immediately before progressive disease or death were censored at the date of the last evaluable tumour assessment before the missing tumour assessments.⁷

Progression-Free Survival

PFS was defined as the time (in months) from the date of randomization to the date of first evidence of radiographic, clinical, or PSA progression or of death from any cause, whichever occurred first.

• The date of radiographic progression was per central review assessment.

• The date of clinical progression was the earliest date of assessment in which the investigator indicated clinical progression.

• Date of PSA progression: Where a decline from baseline was documented, the date that an increase of at least 25% in PSA and an absolute increase of 2 ng/mL or more from the nadir (from all scheduled and unscheduled visits before the current visit being evaluated) was documented and confirmed by a second consecutive value obtained at least 3 weeks later. Rises in PSA within the first 12 weeks of the date of first dose of randomized treatment were ignored. Where there was no decline from baseline documented, PSA progression was defined as an increase of at least 25% increase from baseline along with an increase in absolute value of at least 2 ng/mL after 12 weeks from the first dose of the study treatment.⁷

Skeletal-Related Events

Time to first SSE was defined as the date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumour-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain, or death from any cause (whichever occurred first).⁷

Brief Pain Inventory-Short Form

The BPI-SF is a generic pain assessment tool used in research and practice for pain assessment in musculoskeletal conditions. The higher the BPI-SF score, the worse the pain. The BPI-SF measures pain intensity (on a range from 0 [no pain] to 10 [ worst pain]), as well as the way pain interferes with daily activities (on a range from 0 [no interference] to 10 [completely interferes]).⁷ Worsening pain intensity was defined as an increase from baseline of at least 30% or an increase from baseline of at least 2 points on the BPI-SF scale at any time up to the EOT visit, clinical disease progression, or death. A minimally important difference of 2 or more points or a 30% change in pain intensity items from baseline has previously been used in studies of patients with mCRPC.^33,34

Functional Assessment of Cancer Therapy-Prostate

FACT-P is a prostate cancer–specific HRQoL measure. The FACT-P total score (range, 0 to 156) consists of 5 subscales: physical well-being, social/family well-being, emotional well-being, functional well-being, and prostate cancer. Higher FACT-P scores reflect a better QoL.⁷ Improvement in FACT-P was defined as an increase from baseline in FACT-P total score of at least 10 points any time up to the EOT visit (i.e., an increase of ≥ 10 points at any single assessment would be considered an improvement event). Time to worsening of FACT-P total score was defined as the time (in months) from randomization to the first decrease from baseline greater than 10 points in FACT-P, clinical disease progression (excluding radiographic and PSA progression), or death. If no event has occurred, the censoring date is the time of the last QoL assessment.⁷ The minimally important difference for FACT-P has been estimated to be in the range of 6 to 10 points.³⁵

Functional Assessment of Cancer Therapy-General

The FACT-G total score (range, 0 to 108) consist of 4 subscales: physical well-being, social/family well-being, emotional well-being, and functional well-being.⁷ Improvement in FACT-G was defined as an increase from baseline in FACT-G total score of at least 9 points any time up to the EOT visit (i.e., an increase of ≥ 9 points at any single assessment would be considered an improvement event). Time to worsening in FACT-G score was defined as the time from randomization to the first decrease from baseline of at least 10 points in FACT-G total score, clinical disease progression, or death.

Eight-Item Functional Assessment of Cancer Therapy Advanced Prostate Symptoms Index

FAPSI-8 (range, 0 to 32) covers 8 prostate cancer–specific symptoms: 3 related to pain, 1 related to fatigue, 1 related to weight loss, 2 related to urinary difficulties, and 1 related to concerns about the condition getting worse.⁷ Improvement in FAPSI-8 score was defined as an increase from baseline in FAPSI-8 total score of at least 3 points any time up to the EOT visit (i.e., an increase of ≥ 3 points at any single assessment would be considered an improvement event). Time to worsening in FAPSI-8 score was defined as the time from randomization to the first decrease from baseline of at least 10 points in FAPSI-8 total score, clinical disease progression, or death.

Five-Level EQ-5D

HRQoL was measured using the 5-Level EQ-5D (EQ-5D-5L). The EQ-5D-5L descriptive system has 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each is rated on 5 levels of perceived problems (level 1 = no problems, level 2 = slight problems, level 3 = moderate problems, level 4 = severe problems, and level 5 = extreme problems) measured on a single day. A Canadian-specific minimum clinically important difference (MCID) of 0.037 has been reported.^36,37 An MCID of the EQ-5D-5L was not identified in patients with mCRPC. The instrument also includes a 20 cm EQ visual analogue scale (EQ-VAS) that has end points labelled 0 [worst imaginable health state] and 100 [best imaginable health state]. Respondents are asked to rate their health by drawing a line from an end point to the point on the EQ-VAS that best represents their health on that day. No MCID for the EQ-VAS in patients with mCRPC was identified.

Statistical Analysis

Power Calculation

The sample size was determined from the alternate primary end points of rPFS and OS. The term “alternate end points” is used because the study was designed so that statistical significance for either the rPFS or OS end point would be considered sufficient to have the study declared positive (i.e., it was not required that both rPFS and OS be statistically significant for the study to be declared positive).

A total of 814 patients randomized and followed on an ITT basis for a minimum of 13 months was expected to yield 508 deaths. This would provide at least 90% power to test the hypothesis that the HR for OS is 0.7306 or better with a 1-sided alpha level of at least 0.020. For rPFS, approximately 557 of 814 patients were expected to be randomized on or after March 5, 2019, with a minimum of approximately 6 months follow-up; these patients were expected to yield 364 rPFS events. This would provide 84% power to test the hypothesis that the HR of rPFS is 0.67 or better with a 1-sided alpha level of 0.004.⁷

Statistical Testing and Models

Table 10 summarizes the statistical testing and modelling approaches used for the primary, key secondary, and secondary end points in the VISION trial.

Table 10: Statistical Analysis of Efficacy End Points

BPI-SF = Brief Pain Inventory-Short Form; BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; DCR = disease control rate; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EQ-5D-5L = 5-Level EQ-5D; FACT-G = Functional Assessment of Cancer Therapy-General; FACT-P = Functional Assessment of Cancer Therapy-Prostate; FAPSI-8 = 8-item Functional Assessment of Cancer Therapy Advanced Prostate Symptoms Index; FAS = full analysis set; HR = hazard ratio; LDH = lactate dehydrogenase; NA = not applicable; NAAD = novel androgen axis drug; OR = odds ratio; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PSA = prostate-specific antigen; rPFS = radiographic progression-free survival; SSE = symptomatic skeletal event.

^aThe additional events included: events regardless of intervening missed assessments; bone progressive disease indicated by progression at week 8 and confirmed at week 16 or progression at week 16 or later without confirmation; and included all radiographic progressive disease and deaths captured in the study, including scans not centrally read that were captured on the long-term follow-up.

Source: Clinical Study Report.⁷

Statistical Testing Hierarchy

The VISION trial had 2 alternate primary efficacy end points (OS and rPFS) and used the following testing approach: a primary analysis of rPFS with an interim analysis of OS when 364 rPFS events had occurred; and a final analysis of OS when 508 deaths had occurred. The interim OS analysis was not completed by the sponsor as the targeted number of OS events for the final analysis (using the FAS population) were observed before the targeted number of rPFS events (using the PFS-FAS population).⁹

The key secondary end points were tested using a Hochberg closed-test procedure to control the overall type I error rate, whereas the key secondary efficacy end points were only statistically tested if OS was statistically significant.⁷

Table 11: Analysis of Key Secondary End Points at the Interim and Final Analyses

CI = confidence interval; NS = not statistically significant at the prespecified alpha level; OS = overall survival; rPFS = radiographic progression-free survival.

^aFinal OS will not be re-tested if the interim OS is met. The final OS results will be presented descriptively, including 95% CI and the nominal P value.

^bThe key secondary end points will not be re-tested if the final OS is met; however, the results will be presented descriptively, including 95% CI and the nominal P value.

^cThe key secondary end points will not be tested if the interim OS is not met; however, the results will be presented descriptively, including 95% CI and the nominal P value.

^dIf the key secondary end points are tested when the final OS is not met using the successful rPFS 1-sided (2-sided) alpha level of 0.004 (0.008), there will be, at most, a type I error inflation of 0.004 because the rPFS alpha level has already been allocated to the final OS test. Therefore, if the final OS is not met, the key secondary end points will only be presented descriptively, including 95% CI and the nominal P value.

^eThe key secondary end points will not be tested if the final OS is not met; however, the results will be presented descriptively, including 95% CI and the nominal P value.

Source: Clinical Study Report.⁷

Subgroup Analyses

Subgroups of interest reported in the VISION trial for rPFS and OS included the following: inclusion of NAADs as part of the assigned BSC/BSoC treatment at the start of the study (without NAAD versus with NAAD); ECOG PS at baseline (0 or 1 versus 2); and the presence of liver metastases at baseline (yes versus no). Additional subgroups reported were baseline LDH levels (≤ 260 IU/L versus > 260 IU/L); age (< 65 years versus ≥ 65 years); and race (white versus Black or African American versus Asian versus other).⁷ No formal statistical test of hypotheses was performed for the subgroups.

Analysis Populations

The analysis sets that were used to evaluate the safety and efficacy end points in the VISION trial are summarized in Table 12.

The sponsor noted that the open-label study design resulted in a high rate of early withdrawal. Patients were often disappointed at not receiving ¹⁷⁷Lu vipivotide tetraxetan, leading to a lack of willingness to comply with the study protocol and/or an interest in receiving therapies that were prohibited in the study protocol (e.g., taxanes). As part of the plan to address the early withdrawal of consent in the BSC/BSoC alone group, the sponsor amended the trial protocol so that the primary analysis of rPFS would be conducted using patients prospectively randomized on or after March 5, 2019 (i.e., the PFS-FAS population) (refer to Figure 7).⁷

Table 12: Analysis Sets

DCR = disease control rate; FAS = full analysis set; ITT = intention to treat; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumours Version 1.1; rPFS = radiographic progression-free survival.

Source: Clinical Study Report.⁷

Results

Patient Disposition

Patient disposition for the VISION trial is summarized in Figure 8 and Table 13. A total of 1179 patients were screened for eligibility. Of the 176 patients, 141 were excluded from undergoing a ⁶⁸Ga-PSMA-11 PET-CT scan because they failed to meet the eligibility criteria before imaging and 24 withdrew their consent. A total of 1,003 patients underwent a ⁶⁸Ga-PSMA-11 PET-CT scan; of the 172 patients excluded, 123 were excluded because of a negative ⁶⁸Ga-PSMA-11 PET-CT scan.⁷

A total of 831 patients were randomized to either the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group (N = 551, but for patients enrolled on or after March 5, 2019, N = 385) or the BSC/BSoC alone group (N = 280, but for patients enrolled on or after March 5, 2019, N = 196). Nearly all patients randomized to ¹⁷⁷Lu vipivotide tetraxetan (96.7%) received at least 1 dose of the study drug (the primary reason for not receiving the treatment was cited as AEs occurring between randomized at the first treatment cycle).⁷ Of the 280 patients randomized to the BSC/BSoC alone group, 71.8% received at least 1 dose of treatment.

A substantial proportion of the patients in the BSC/BSoC alone group withdrew early from the VISION trial (28.3% before receiving any part of the BSC/BSoC alone regimen). As shown in Figure 7, 56.0% of patients in the BSC/BSoC alone group who were enrolled before protocol amendment 4 withdrew before receiving a study treatment or a radiographic assessment, compared with 1.2% in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group. After the protocol amendment designed to address early withdrawal, the rate of withdrawal was reduced to 16.3% (which was still far greater than the 4.2% rate of early withdrawal in the ¹⁷⁷Lu vipivotide tetraxetan group).^8,11 Withdrawn consent was the primary reason for the high rate of early withdrawal from the BSC/BSoC alone group.

Figure 7: Protocol Amendments to Address Early Withdrawal

¹⁷⁷Lu-PSMA-617 = lutetium-177 vipivotide tetraxetan; rPFS = radiographic progression-free survival; PMSA = prostate-specific membrane antigen; SOC = standard of care.

Source: Health Canada biologics safety and efficacy assessment report⁸

█████ patients in the ¹⁷⁷Lu vipivotide tetraxetan +BSC/BSoC group discontinued the study treatment, primarily because of progressive disease (█████), AEs ███████, and lack of clinical benefit (████). As patients in both treatment groups received BSC/BSoC, the sponsor also reported discontinuations from the BSC/BSoC regimens. The primary reasons for discontinuing BSC/BSoC treatment were (¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC versus BSC/BSoC alone) progressive disease (█████ ██████ █████), lack of clinical benefit (█████ ██████ ██████), and withdrawal of consent for treatment (████ ██████ █████). The sponsor reported that the relatively higher proportion of patients who discontinued due to progressive disease in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC arm may be related to the longer period of time in which patients in this group received study-related treatment (e.g., at the data cut-off, █████ of those in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and █████ in the BSC/BSoC alone group had discontinued the study).⁷

If a patient chose to discontinue randomized treatment in the VISION study for a reason other than radiographic progression, the patient was asked to confirm whether they consented to continue to be followed for long-term safety, rPFS, and OS. If the patient did not specifically withdraw consent for long-term follow-up evaluations, the patient remained in the long term follow-up.⁷

Figure 8: Patient Disposition in the VISION Trial

¹⁷⁷Lu = lutetium-177; ⁶⁸Ga = gallium-68; BSC = best supportive care; BSoC = best standard of care; PSMA = prostate-specific membrane antigen.

* Number in square brackets indicate patients randomized on or after Mach 5, 2019

† Reasons for withdrawal of consent to treatment: none given (n = 2), travel or procedure “fatigue” (n = 1)

ǂ Reasons for withdrawal of consent to treatment: none given (n = 1), travel or procedure “fatigue” (n = 1)

§ Reasons for withdrawal of consent to treatment: receiving BSC/BSoC without 177Lu (n = 31), none given (n = 7), decided to pursue off-study treatment (n = 5), travel or procedure “fatigue” (n = 2), perceived lack of benefit (n = 1)

Source: Clinical Study Report.⁷

Table 13: Patient Disposition

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care; NA = not applicable.

Source: Clinical Study Report.⁷

Exposure to Study Treatments

Study Treatments

Table 14 provides a summary of exposure to the study treatments in the VISION trial. The median number of ¹⁷⁷Lu vipivotide tetraxetan cycles received was 5 (range, 1 to 6), and 46.5% of patients received the full 6 cycles of the study treatment.

Concomitant Medications and Cointerventions

Table 15 summarizes the protocol-permitted use of standard of care therapies.

Subsequent Treatments

Subsequent treatments (i.e., those initiated after discontinuation of the study drug) used by the patients enrolled in the VISION trial are summarized in Table 16 for nonradiation therapies and in Table 17 for radiation therapies.

Table 14: Exposure to Study Treatments

¹⁷⁷Lu = lutetium-177; AE = adverse event; BSC = best supportive care; BSoC = best standard of care; SD = standard deviation.

Source: Clinical Study Report.⁷

Table 15: Protocol-Permitted Use of Standard of Care Therapies (SAS)

¹⁷⁷Lu = lutetium-177; ARPI = androgen receptor pathway inhibitor; BSC = best supportive care; BSoC = best standard of care; SAS = safety analysis set; SoC = standard of care.

Source: Sponsor Clinical Summary.⁶

Table 16: Subsequent Exposure to Nonradiation Therapies

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care; CAR-t = chimeric antigen receptor T-cells; CI = confidence interval; HR = hazard ratio; NOS = not otherwise specified; OS = overall survival.

Some redacted cells have been deleted.

Source: Clinical Study Report.⁷

Table 17: Subsequent Exposure to Posttreatment Radiotherapy

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care.

Source: Clinical Study Report.⁷

Efficacy

Only efficacy outcomes and analyses of subgroups identified in the review protocol are reported here. Refer to Appendix 3 for detailed efficacy data.

Overall Survival

Table 18 summarizes the results for the primary analysis of OS. There was a statistically significant improvement in OS for patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group compared with those in the BSC/BSoC alone group (HR = 0.62; 95% CI, 0.52 to 0.74; P < 0.001). Deaths were reported for 62.3% of patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and for 66.8% in the BSC/BSoC alone group. Median OS was 15.3 months (95% CI, 14.2 to 16.9 months) in ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and 11.3 months (95% CI, 9.8 to 13.5 months) in the BSC/BSoC alone group. The sponsor reported that median follow-up times for OS were similar in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and BSC/BSoC alone groups (20.3 months and 19.8 months, respectively).⁷ Kaplan-Meier curves for OS are provided in Figure 9.

Table 18: Overall Survival (FAS)

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; FAS = full analysis set; HR = hazard ratio; NE = not evaluable; OS = overall survival.

^aPatients without event and still on study at data cut-off date.

^bPatients who discontinued the study for reasons other than withdrawn consent.

^cPatients who withdrew consent from the study.

^dHR for ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC vs. BSC/BSoC alone.

^eBoth the Cox proportional hazards model and log-rank test are stratified for LDH (≤ 260 IU/L vs. > 260 IU/L); the presence of liver metastases (yes vs. no); ECOG PS (0 or 1 vs. 2); and the inclusion of NAAD in BSC/BSoC at the time of randomization (yes vs. no).

^fFollow-up time = (date of event or censoring – randomization date + 1)/30.4375 (months) censoring for deaths.

Source: Clinical Study Report.⁷

Sensitivity Analyses of OS

Results of the sensitivity analysis using the PFS-FAS population were similar to those of the primary analysis (HR = 0.63; 95% CI, 0.51 to 0.79), with a median OS of 14.6 months (95% CI, 13.2 to 16.0 months) in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and 10.4 months (95% CI, 8.5 to 13.6 months) in the BSC/BSoC alone group.⁷

The FDA reported numerous sensitivity analyses for OS. In addition to those reported in Figure 10, the FDA reported that they conducted an additional OS sensitivity analysis by excluding patients who withdrew consent. The HR was 0.62 (95% CI, 0.52 to 0.75), which was also consistent with the primary analysis of OS. The FDA concluded that although the disproportionate dropout rate in the BSC/BSoC arm was a concern, ascertainment of many of the OS events from withdrawn patients, as well as multiple sensitivity analyses that considered extreme cases, and the possibility of informative censoring continued to support the statistical significance of the primary analysis. The FDA report highlighted the following sensitivity analyses.

• Extreme case: All drop-outs in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group were considered to be deaths (i.e., assumed a shortened survival time in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group) (HR = 0.66; 95% CI, 0.55 to 0.79).

• Best-case analysis: Elongated survival was assumed in the BSC/BSoC alone group by imputing data for drop-outs in the control arm based on the HR in the 20% of patients with the longest survival, either overall or in the BSC/BSoC alone arm (HR = 0.8; 95% CI, 0.67 to 0.96).

• Tipping-point analyses: The increase or decrease in the risk of death in patients who withdrew from either treatment group that would make the primary analysis of OS lose statistical significance was quantified. In tipping-point analysis 1, the hazard of survival would need to decrease by 99% in the BSC/BSoC group for OS to become nonstatistically significant, which is considered extreme and very unlikely to occur.

Figure 9: Kaplan-Meier Plot of OS (FAS)

BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; FAS = full analysis set; Lu = lutetium-177; n/N = number of events/number of patients in treatment arm; OS = overall survival; PSMA = prostate-specific membrane antigen.

Source: Clinical Study Report.⁷

Figure 10: Sensitivity Analyses of OS Reported by the FDA (FAS)

BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; FAS = full analysis set; HR = hazard ratio; OS = overall survival.

* Risk of event remains unchanged after censoring in the investigational arm.

Source: FDA Multidiscipline review.⁹

Subgroup Analyses of OS

Subgroup analyses for OS are summarized in Figure 11. Subgroup analyses based on the number of prior taxane regimens favoured ¹⁷⁷Lu vipivotide tetraxetan over BSC/BSoC alone for patients who received a single prior taxane regimen (HR = 0.59; 95% CI, 0.46 to 0.75) and for those who received 2 or more prior taxane regimens (HR = 0.73; 95% CI, 0.53 to 0.99). Because of the small number of patients, there is considerable uncertainty about the estimate of effect for the subgroup analysis of patients with a ECOG PS of 2.⁷

Figure 11: Forest Plots With Subgroup Analyses for OS (FAS)

BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; FAS = full analysis set; LDH = lactase dehydrogenase; Lu = lutetium-177; n/N = number of events/number of patients in treatment group; NAAD = novel androgen axis drug; Num. = number; OS = overall survival; PARP = poly (ADP-ribose) polymerase; PSA = prostate-specific antigen; PSADT = prostate-specific antigen doubling time; PSMA = prostate-specific membrane antigen.

Source: FDA Multidisciplinary Review⁹

Radiographic PFS

Table 19 summarizes the results of the primary analysis for rPFS. There was a statistically significant improvement in rPFS for patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group compared with those in the BSC/BSoC alone group (HR = 0.40; 99.2% CI, 0.29 to, 0.57; P < 0.001). Events of radiographic progression or death were reported for 66.0% of patients in the ¹⁷⁷Lu vipivotide tetraxetan group (171 radiographic progression events and 83 deaths) and for 47.4% in the BSC/BSoC alone group (59 radiographic progression events and 34 deaths). Median rPFS was 8.7 months (95% CI, 7.9 to 10.8 months) in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and 3.4 months (95% CI, 2.4 to 4.0 months) in the BSC/BSoC alone group. The sponsor reported that median follow-up time for rPFS was longer in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC group (16.4 months versus 3.9 months).⁷ Kaplan-Meier curves for rPFS are provided in Figure 12.

As shown in Figure 13, results in the prespecified sensitivity analyses were similar to those of the primary analysis. Subgroup analyses for rPFS are summarized in Figure 13 and generally suggested similar results for ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group compared with BSC/BSoC alone group as the primary rPFS analysis.

Table 19: rPFS Analysis (PFS-FAS)

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; FAS = full analysis set; HR = hazard ratio; NE = not evaluable; PFS = progression-free survival; rPFS = radiographic progression-free survival.

^aPatients censored without adequate postbaseline evaluations or adequate baseline assessment.

^bHR for ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC vs. BSC/BSoC alone.

^cBoth the Cox proportional hazards model and log-rank test are stratified for LDH (≤ 260 IU/L vs. > 260 IU/L); the presence of liver metastases (yes vs. no); ECOG PS (0 or 1 vs. 2); and the inclusion of NAAD in BSC/BSoC at the time of randomization (yes vs. no).

^dFollow-up time = (date of event or censoring – randomization date + 1)/30.4375 (months) censoring for death or radiographic progression.

Source: Clinical Study Report.⁷

Figure 12: Kaplan-Meier Plot of rPFS, per Independent Central Review (PFS-FAS)

BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; FAS = full analysis set; Lu = lutetium-177; n/N = number of events/number of patients in treatment arm; PSMA = prostate-specific membrane antigen; rPFS = radiographic progression-free survival.

Note: Stratified log-rank test and stratified Cox model using strata, per Interactive Response Technology, defined by LDH level, the presence of liver metastases, ECOG PS, and the inclusion of NAAD in BSC/BSoC at the time of randomization.

Source: Clinical Study Report.⁷

Figure 13: Forest Plots With Sensitivity Analyses for rPFS (PFS-FAS)

BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; FAS = full analysis set; Lu = lutetium-177; n / N = number of events/number of patients in treatment arm; PFS = progression-free survival; PSMA = prostate-specific membrane antigen; rPFS = radiographic progression-free survival.

Notes: Sensitivity analysis 1 includes events regardless of intervening missed assessments and includes all radiographic progressive disease and deaths captured in the study, including scans not centrally read; bone progressive diseases were indicated, per PCWG3 guidelines, with modified rules for confirmation after week 16.

Sensitivity analysis 2 includes deaths occurring after the start of a new anticancer therapy were censored at the start date of the new therapy.

Sensitivity analysis 3 assesses rPFS from the date of the first dose of randomized treatment.

Sensitivity analysis 4 used local investigator assessments instead of central reading.

Source: Clinical Study Report.⁷

Progression-Free Survival

Results for PFS are summarized in Table 20. ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC was associated with a statistically significant reduction in events of radiographic disease progression, clinical progression, PSA progression or death, compared to BSC/BSoC alone (HR = 0.30; 95% CI, 0.24 to 0.38; P < 0.001). Median PFS was 5.9 months (95% CI, 5.2 to 6.6 months) in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and 2.4 months (95% CI, 2.2 to 3.0 months) in the BSC/BSoC alone group.⁷ Kaplan-Meier curves are presented in Figure 14.

Table 20: Progression-Free Survival (PFS-FAS)

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; FAS = full set analysis; HR = hazard ratio; PFS = progression-free survival; PSA = prostate-specific antigen.

^aPatients censored without adequate postbaseline evaluations or adequate baseline assessment.

^bHR for ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC vs. BSC/BSoC alone.

^cThe Cox proportional hazards model is stratified for LDH (≤ 260 IU/L vs. > 260 IU/L); the presence of liver metastases (yes vs. no); ECOG PS (0 or 1 vs. 2); and the inclusion of NAAD in BSC/BSoC at the time of randomization (yes vs. no). Interactive Response Technology data for stratification are used.

^dFollow-up time = (date of event or censoring – randomization date + 1)/30.4375, censoring for death, radiographic progression, clinical progression, or PSA progression.

Source: Clinical Study Report.⁷

Figure 14: Kaplan-Meier Plot of PFS (PFS-FAS) (Redacted)

BSC/BSoC = best supportive care/best standard of care; CI = confidence interval; FAS = full analysis set; Lu-PSMA-617 = lutetium-177 vipivotide tetraxetan; n/N = number of events/number of patients in treatment arm; PFS = progression-free survival.

Confidential figure removed at the sponsor’s request.

Source: Clinical Study Report.⁷

ORR and DOR

Table 21 summarizes the results for ORR and DOR in the VISION trial. The ORR was statistically significantly greater in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC alone group (29.8% versus 1.7%), with an OR of 24.99 (95% CI, 6.05 to 103.24). The median DOR in patients who demonstrated a response to treatment (i.e., CR or PR) was 9.8 months (95% CI, 9.1 to 11.7 months) in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group. Only 2 patients in the BSC/BSoC alone group demonstrated a response to treatment, and only 1 of those met the RECIST criteria for radiographic progression or death; therefore, the sponsor reported that the median DOR could not be reliably estimated for the BSC/BSoC alone group.⁷

Disease Control Rate

Results for the DCR are summarized in Table 22. The DCR was statistically significantly greater in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC alone group (89.0% versus 66.7%), with an OR of 5.79 (95% CI, 3.18 to 10.55; P < 0.001).⁷

Table 21: ORR and DOR (Response-Evaluable Analysis Set)

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; CR = complete response; DOR = duration of response; EDOR = expected duration of response (mean DOR × ORR); ORR = overall response rate; PD = progressive disease; PR = partial response; SD = standard deviation.

^aOR of ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC vs. BSC/BSoC alone based on logistic regression model stratified for the following randomization factors: LDH (≤ 260 IU/L vs. > 260 IU/L); presence of liver metastases (yes vs. no); ECOG PS (0 or 1 vs. 2); and inclusion of NAAD in BSC/BSoC at the time of randomization (yes vs. no). P value based on Wald chi-square distribution.

^bAnalyzed using mixture distribution methodology.

^cOnly 2 patients in the BSC/BSoC alone group demonstrated a response to treatment, and only 1 of those met the RECIST for radiographic progression or death; therefore, the sponsor reported that the median DOR could not be reliably estimated for the BSC/BSoC alone group.

Source: Clinical Study Report.⁷

Figure 15: Forest Plots With Subgroup Analyses for rPFS (PFS-FAS)

BSC = best supportive care; BSoC = best standard of care; CI = confidence interval ECOG = Eastern Cooperative Oncology Group; FAS = full analysis set; LDH = lactase dehydrogenase; Lu = lutetium-177; n / N = number of events/number of patients in treatment group; NAAD = novel androgen axis drug; PARP = poly (ADP-ribose) polymerase; PFS = progression-free survival; PSA = prostate-specific antigen; PSADT = prostate-specific antigen doubling time; PSMA = prostate-specific membrane antigen; rPFS = radiographic progression-free survival.

Source: FDA Multidiscipline Review⁹

Time to First SSE

Results for time to first SSE are summarized in Table 23. There were 256 events in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group (66.5% of patients; 60 SSE events and 196 deaths) and 137 events (69.9% of patients; 34 SSE events and 103 deaths) in the BSC/BSoC alone group. ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC was associated with a statistically significant reduction in SSE (or death), compared to BSC/BSoC alone (HR = 0.5; 95% CI, 0.40 to 0.62). The median time to first SSE was 11.5 months (95% CI, 10.3 to 13.2 months) in the ¹⁷⁷Lu vipivotide tetraxetan vipivotide tetraxetan + BSC/BSoC group and 6.8 months (95% CI, 5.2 to 8.5 months) in the BSC/BSoC alone group.⁷ Kaplan-Meier curves are presented in Figure 16.

Table 22: Disease Control Rate

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; CR = complete response; PR = partial response; SD = standard deviation.

^aOR for ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC vs. BSC/BSoC alone based on a logistic regression model that stratifying for the following randomization factors: LDH (≤ 260 IU/L vs. > 260 IU/L); presence of liver metastases (yes vs. no); ECOG PS (0 or 1 vs. 2); and inclusion of NAAD in BSC/BSoC at time of randomization (yes vs. no). P value based on Wald chi-square distribution.

Source: Clinical Study Report⁷

Table 23: Analysis of Time to First SSE (PFS-FAS)

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; FAS = full analysis set; HR = hazard ratio; PFS = progression-free survival; SSE = symptomatic skeletal event.

^aHR for ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC vs. BSC/BSoC.

^bCox proportional hazards model is stratified for LDH (≤ 260 IU/L vs. > 260 IU/L); the presence of liver metastases (yes vs. no); ECOG PS (0 or 1 vs. 2); and inclusion of NAAD in BSC/BSoC at the time of randomization (yes vs. no).

^cFollow-up time = (date of event or censoring – randomization date + 1)/30.4375, censoring for death or SSE.

Source: Clinical Study Report⁷

Figure 16: Kaplan-Meier Plot of Time to First SSE (PFS-FAS) (Redacted)

BSC/BSoC = best supportive care/best standard of care; CI = confidence interval; Lu-PSMA-617 = lutetium-177 vipivotide tetraxetan; n/N = number of events/number of patients in treatment arm; PFS-FAS = progression-free survival – full analysis set; SSE = symptomatic skeletal event

Note: Stratified log-rank test and stratified Cox model stratified by LDH level, presence of liver metastases, ECOG PS, and the inclusion of NAAD in BSC/BSoC at the time of randomization.

Confidential figure removed at the sponsor’s request.

Source: Clinical Study Report.⁷

PSA Levels

Table 24 provides results for PSA doubling time, proportion of patients with PSA response (i.e., ≥ 50% decrease from baseline), proportion of patients with a decrease from baseline of at least 80%, and duration of PSA response.

• The sponsor reported a large disparity between the 2 treatment groups in the proportion of patients who could be evaluated for PSA doubling time (██████ and ██████, respectively). For the subset of patients who could be evaluated, mean PSA doubling time was ████ ██████ ████ ███ ████ ██ █████ for the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group and (████ ██████ ████ ███ ███ ██ ████) for the BSC/BSoC alone group.

• Compared with the BSC/BSoC alone group, a greater proportion of patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group had a decrease from baseline of at least 50% than in the BSC/BSoC alone group ██████ ██████ █████ ███ ██████ ███ ███ ███ ██ █████ ██ ██████ and a decrease from baseline of at least ███ █████ ██████ █████ ███ █████ ███ ███ ███ ██ █████ ██ ███████⁷

Table 24: PSA Doubling Time and PSA Response (PFS-FAS)

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care; FAS = full analysis set; PFS = progression = free survival; PSA = prostate-specific antigen.

██████ ████ ████████ ██ ███ ███████ ███████ ████████ ██ ███ ████ ██████████████ █████████ ████ ████████ ████ █████████ █████ ███ ██ █████ ███ ███████████ █████████████ █████ ██████████ ███ ███████████████ ███ ████████ ████ ███ ███████ ███ ████ ███████ ██ ███ ███████ ███ ████████ ██ ███ ███ ██ ███ █████ ███ ██████ ██████ ██ ███ ██████ ███████████ ██████ █████ ███████ ███████ ███ ██ ███ ███ ████ ██ ███ ███████████ ███ ████████ ████████ ████ ████████ ███ ██ █████ ████████████ █████████████ ███ ██████ ████ ████████ ██ ███ ████████ ███ ████████ ███ ███████ ██ ███ ██████████ ██ ████████ ███ ███ ██ ███ ████████ ██ ███ ████ ████████ █████████ ██ ████ ███████████ ██ ████████

Source: Clinical Study Report.⁷

Brief Pain Inventory-Short Form

Time to worsening on the BPI-SF pain intensity scale is reported in Table 25. Time to worsening pain was delayed in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group compared with the BSC/BSoC alone group (HR = 0.52; 95% CI, 0.43 to 0.63; P < 0.001). The median time to deterioration was 5.9 months (95% CI, 4.8 to 6.9 months) in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC arm and 2.2 months (95% CI, 1.8 to 2.8 months) in the BSC/BSoC alone group.⁷ Kaplan-Meier curves are presented in Figure 17.

Table 25: Time to Worsening on BPI-SF Pain Intensity Scale (PFS-FAS)

¹⁷⁷Lu = lutetium-177; BPI-SF = Brief Pain Inventory-Short Form; BSC = best supportive care; BSoC = best standard of care; FAS = full analysis set; PFS = progression = free survival.

██████ ██████ ████ █████████ ██████ █████ ████████ █████ ██████████ █████████ ████████ ██ █████ ██ ███████████ █████████ ██ ██████ ██████ ███████ █████████████████ ████████ █████ ████████ ███ ██ ████ ██ █████████ ██ ███████ ██ ████ ████ █████████████ ██ ███ █████ █████████ ██ ██ ████████ ██ █████████ █████████ █████ ██ ████████ ██ ████████ █████████ ██ ███ ████ ██ ███████ ███ █████ ████ ████ ██ █████████ ████████ ███████ ████████████ ██ ████████ ██████ █████ ██ ████████ ██ ███ ███ ██ ██████████ ██████████ ██████████ █████████ ██████ ███████████ ███ ██ █████ ██ ███ ███████ ███ ███ ██ ███ ████ ██████ ████ ██████ ████████ ██ █████ ██████████ ████ ██████ ████ ████ ███ ██ ██ ██ ███████ ███ ███ █████████ ██ ████ ██ ████ ███████████████████ ██ ████ ██ ████ ██ █████ ████████ ████ ██████ ████

Source: Clinical Study Report.⁷

Functional Assessment of Cancer Therapy-Prostate

Table 26 summarizes improvement, worsening, and time to worsening in FACT-P in the VISION trial. Improvement in at least 1 assessment was reported for a greater proportion of patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC alone group (45.7% versus 15.3%). The proportion of patients with FACT-P scores that worsened from baseline at any time was similar in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and BSC/BSoC alone groups (47.5% versus 44.9%).⁷

Total events for time to worsening in FACT-P scores were similar in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and BSC/BSoC alone groups (87.0% and 85.7%, respectively). Median time to worsening was shorter in those who received ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC (5.7 months; 95% CI, 4.8 to 6.6 months) than in those who received BSC/BSoC alone (2.2 months; 95% CI, 1.8 to 2.8 months), with a HR of 0.54 (95% CI, 0.45 to 0.66; P < 0.001).⁷

Figure 17: Kaplan-Meier Plot of Time to Worsening on BPI-SF Pain Intensity Scale (PFS-FAS)

BPI-SF = Brief Pain Inventory-Short Form; BSC = best supportive care; BSoC = best standard of care; CI = confidence interval; FAS = full analysis set; Lu-PSMA-617 = lutetium-177 vipivotide tetraxetan; n/N = number of events/number of patients in treatment arm; PFS = progression-free survival.

Note: Log-rank test and Cox model stratified by LDH level, presence of liver metastases, ECOG PS, and inclusion of NAAD in BSC/BSoC at the time of randomization.

Source: Clinical Study Report.⁷

Table 26: Improvement and Worsening From Baseline and Time to Worsening in FACT-P Total Score (PFS-FAS)

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care; FACT-P = Functional Assessment of Cancer Therapy-Prostate FAS = full analysis set; PFS = progression = free survival.

████████ █████ ██████████ █████████ ████████ ██ █████ ██ ███████████ █████████ ██████ █ ██████████ ██████████ ██ ██████ ███████ ██████████ ██ ███████ ██████ ██ ██████ ██ ████████ ████ ██████ ███████ █████████████████ ████████ █████ ████████ █████ ███████████ ██ ███████ ██ ██ ████████ ████████ ██ ████████ ██ ██████ █████ █████ ██ ███ ███ ████ ██ ███████ ███ ████████ █████████ ██ ███████ ██ █████████ ████████ ██ ████████ ██ ██████ █████ █████ ██ ███ ███ ████ ██ ███████ ███ ████████ ████ ██ █████████ ██ ███████ ██ ████ ████ █████████████ ██ ███ █████ █████████ ██ ████ █████ ████████ ██ ██████ █████ █████ ████████ ██ █████████ ████████ ███████ ████████████ ██ ████████ ██████ █████ ██ █^████ ██████████ ██████████ █████████ ███ ███████████ ███ ██ █████ ██ ██████████ ██ ███ ██████ ████████ ██ █████ ███████████ ████ █████ ███ █████████ ██ ████ ██ ████████ ██ ████ ██ ██████████████

Source: Clinical Study Report.⁷

Functional Assessment of Cancer Therapy-General

Table 26 summarizes improvement, worsening, and time to worsening in FACT-G in the VISION trial. Among those assessed with FACT-G, at least 1 assessment of improvement or worsening was reported for a greater proportion of patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC alone group (39.2% versus 14.8%). The proportion of patients with FACT-G scores that worsened from baseline were was in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and BSC/BSoC alone groups (43.1% versus 48.0%).⁷ Total events for time to worsening in FACT-G scores were similar in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and BSC/BSoC alone groups (85.5% and 85.2%, respectively). Median time to worsening was shorter in those who received ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC (6.6 months; 95% CI, 5.5 to 7.3 months) than in those who received BSC/BSoC alone (2.4 months; 95% CI, 2.0 to 3.1 months), with a HR of 0.53 (95% CI, 0.44 to 0.65; P < 0.001).⁷

Table 27: Improvement and Worsening From Baseline and Time to Worsening in FACT-G Total Score (PFS-FAS)

¹⁷⁷Lu = lutetium-177; BSC = best supportive care; BSoC = best standard of care; FACT-G = Functional Assessment of Cancer Therapy-General; FAS = full analysis set; PFS = progression = free survival.

████████ █████ ██████████ █████████ ████████ ██ █████ ██ ███████████ █████████ ██████ ██████████ ██████████ ██ ██████ ███████ █████████ ██ ███████ ██████ ██ ██████ ██ ████████ ████ █████████████ ██ ███████ ██ ██ ████████ ████████ ██ ████████ ██ ██████ █████ █████ ██ ██ ███ ████ ██ ███████ ███ ████████ █████████ ██ ███████ ██ █████████ ████████ ██ ████████ ██ ██████ █████ █████ ██ ██ ███ ████ ██ ███████ ███ ████████ ████ ██ █████████ ██ ███████ ██ ████ ████ █████████████ ██ ███ █████ █████████ ██ ███ █████ ████████ ██ ██████ █████ █████ ████████ ██ █████████ ████████ ███████ ████████████ ██ ████████ ██████ █████ ██ █^████ ██████████ ██████████ █████████ ██████ ███████████ ███ ██ █████ ██ ██████████ ██ ███ ██████ ████████ ██ █████ ███████████ ████ █████ ███ █████████ ██ ████ ██ ████████ ██ ████ ██ ██████████████

Source: Clinical Study Report⁷

Eight-Item Functional Assessment of Cancer Therapy Advanced Prostate Symptoms Index

Table 26 summarizes improvement, worsening, and time to worsening on FAPSI-8 in the VISION trial. Improvement in at least 1 assessment was reported for a greater proportion of patients in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC group than in the BSC/BSoC group (50.6% versus 26.0%). Worsening on FAPSI-8 was defined as a decrease from baseline of at least 3 points at any time up to the EOT visit. The proportion of patients with FAPSI-8 scores that worsened from baseline was the same in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and BSC/BSoC alone groups (42.3% for both).⁷

Total events for time to worsening were nearly identical in the ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC and BSC/BSoC alone groups (86.0% and 86.2%, respectively). Median time to worsening on FAPSI-8 was shorter in those who received ¹⁷⁷Lu vipivotide tetraxetan + BSC/BSoC (5.9; 95% CI, 4.8 to 6.9 months) than in those who received BSC/BSoC alone group (2.0 months; 95% CI, 1.7 to 2.6 months), with an HR of 0.52 (95% CI, 0.43 to 0.64; P < 0.001).⁷

Table 28: Improvement and Worsening From Baseline and Time to Worsening in FAPSI-8 Score (PFS-FAS)