Final overall survival and safety analyses of the phase 3 PSMAfore trial of [177Lu]Lu-PSMA-617 versus change of androgen receptor pathway inhibitor in taxane-naive patients with metastatic castration-resistant prostate cancer

In PSMAfore, [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC), with a favourable safety profile, versus a change in androgen receptor pathway inhibitor (ARPI). We report the final overall survival (OS) analysis and updated safety data. PSMAfore (NCT04689828) was an open-label, international, phase 3 trial. Patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who had experienced disease progression once on a previous ARPI and were candidates for ARPI change were randomized 1:1 to 177Lu-PSMA-617 or ARPI change to abiraterone or enzalutamide. Crossover from ARPI change to 177Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. Endpoints included rPFS (primary), OS (key secondary), and safety (secondary). Patients were randomized to 177Lu-PSMA-617 or ARPI change (n = 234 each): 141/234 participants (60.3%) randomized to ARPI change crossed over (75.4% of those with centrally confirmed radiographic progression). The median OS was 24.48 months (95% CI 19.55-28.94) with 177Lu-PSMA-617 versus 23.13 (19.61-25.53) with ARPI change (hazard ratio [HR] 0.91 [95% CI 0.72-1.14]; p = 0.20) based on the intention-to-treat (ITT) principle; the crossover-adjusted OS HR by inverse probability of censoring weighting modelling was 0.59 (95% CI 0.38-0.91). For 177Lu-PSMA-617 versus ARPI change, exposure-adjusted incidences of grade ≥ 3 and serious treatment-emergent adverse events were 60.8 versus 85.1 and 32.5 versus 49.9 per 100 patient-treatment years, respectively. Dry mouth occurred in 135/227 participants (59.5%; 2/227 grade ≥ 3) and anaemia in 62/227 (27.3%; 14/227 grade ≥ 3) in the 177Lu-PSMA-617 arm. OS analyses did not show a statistically significant difference between the 177Lu-PSMA-617 and ARPI arms based on the ITT principle; results were likely confounded by the high rate of crossover. The safety profile of 177Lu-PSMA-617 was favourable with no new safety signals identified.