RT Journal Article SR Electronic T1 Phase 3 trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore) JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 241064 OP 241064 VO 65 IS supplement 2 A1 Herrmann, Ken A1 Sartor, Oliver A1 Castellano, Daniel A1 de Bono, Johann A1 Shore, Neal A1 Chi, Kim A1 Crosby, Mike A1 Piulats, Josep A1 Flechon, Aude A1 Wei, Xiao A1 Mahammedi, Hakim A1 Roubaud, Guilhem A1 Študentová, Hana A1 Ghebremariam, Samson A1 Kpamegan, Euloge A1 Kreisl, Teri A1 Delgoshaie, Neda A1 Lehnhoff, Katja A1 Morris, Michael A1 Fizazi, Karim YR 2024 UL http://jnm.snmjournals.org/content/65/supplement_2/241064.abstract AB 241064 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