Phase 3 trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore)

Introduction: In VISION, [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior androgen receptor pathway inhibitor (ARPI) and taxane therapy. PSMAfore (NCT04689828) is a phase 3 study of ¹⁷⁷Lu-PSMA-617 in taxane-naive patients with mCRPC. Here, we present data on primary, secondary and exploratory endpoints, including prostate-specific antigen (PSA) response, time to PSA progression and safety topics of interest.

Methods: Eligible adults had mCRPC, were candidates for ARPI change after one progression on prior ARPI, and had ≥ 1 prostate-specific membrane antigen (PSMA)-positive and no exclusionary PSMA-negative lesions by [⁶⁸Ga]Ga-PSMA-11 PET/CT. Candidates for poly(ADP) ribose (PARP) inhibition and patients with prior systemic radiotherapy (< 6 months ago), immunotherapy (except sipuleucel-T) or chemotherapy (except [neo]adjuvant > 12 months ago) were ineligible. Randomization was 1:1 to open-label ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks for 6 cycles) or ARPI change (abiraterone or enzalutamide). Patients randomized to ARPI change could crossover to receive ¹⁷⁷Lu-PSMA-617 following centrally reviewed radiographic progressive disease (rPD). The primary endpoint was rPFS (PCWG3-modified RECIST v1.1 criteria) and the key secondary endpoint was OS (both overall α = 0.025, one-sided). Other secondary endpoints included PSA50 response (PSA decline ≥ 50% from baseline), health-related quality of life (assessed by the Functional Assessment of Cancer Therapy – Prostate (FACT-P) questionnaire) and safety. Time to PSA progression and objective response rate (ORR) were exploratory endpoints. Primary analysis of rPFS was to occur at ~156 rPFS events and second OS interim analysis (IA) at ~125 deaths. Statistical analyses included log-rank test (time-to-event endpoints), stratified Cox proportional-hazards model (hazard ratios [HRs] and confidence intervals [CIs]) and Kaplan–Meier method (medians and CIs). Crossover-adjusted analysis was the prespecified method for OS by rank-preserving structural failure time (RPSFT).

Results: Overall, 468 patients were randomized (n = 234 per group). At primary analysis (study duration, 7.3 months; N = 467), median rPFS was 9.30 months (95% CI: 6.77–NE) for the ¹⁷⁷Lu-PSMA-617 group and 5.55 months (4.04–5.95) for ARPI change group (HR, 0.41; 95% CI: 0.29–0.56; p < 0.0001); results were similar in an exploratory analysis of rPFS at second OS IA (HR, 0.43; 95% CI: 0.33–0.54). At second IA (study duration, 15.9 months; 45.1% of target deaths), 123/146 patients (84.2%) from the ARPI change group who discontinued treatment owing to rPD crossed over; there was a positive OS trend in favor of ¹⁷⁷Lu-PSMA-617 as per RPFST but not as per unadjusted OS analysis. For ¹⁷⁷Lu-PSMA-617 versus ARPI change, median time to worsening in FACT-P total score was longer (7.46 months [95% CI: 6.08–8.51] vs 4.27 months [3.48–4.53]; HR, 0.59; 95% CI: 0.47–0.72), ORR was higher (50.7% [95% CI, 38.6–62.8] vs 14.9% [7.7–25.0]), PSA50 response was higher (57.6% [95% CI: 50.7–64.3] vs 20.4% [15.4–26.3]) and median time to PSA progression was longer (10.55 months [95% CI: 8.57–14.29] vs 4.24 months [3.48–4.44]; HR, 0.37; 95% CI: 0.29–0.48). For ¹⁷⁷Lu-PSMA-617 versus ARPI change, incidence of grade ≥ 3 adverse events (AEs) was 34% versus 44%, serious AEs 20% versus 28%, and AEs leading to discontinuation 5.7% versus 5.2%. In the ¹⁷⁷Lu-PSMA-617 group, the most common groups of any-grade treatment-emergent AEs according to safety topics of interest were dry mouth and myelosuppression (Table). Myelosuppression was the most common grade ≥ 3 safety topic of interest in both arms (Table).

Conclusions: ¹⁷⁷Lu-PSMA-617 prolonged rPFS, time to worsening in FACT-P total score and time to PSA progression, and improved ORR and PSA50 response, versus ARPI change in taxane-naive patients with PSMA-positive mCRPC, with a manageable safety profile.

Funding: Novartis

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