LBA13 Phase III trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore)

[177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolongs rPFS and OS in patients (pts) with mCRPC and prior ARPI and taxane therapy. PSMAfore (NCT04689828) examined 177Lu-PSMA-617 in taxane-naive pts. Eligible adults had mCRPC, were candidates for ARPI change after one progression on prior ARPI, and had ≥1 PSMA+ and no exclusionary PSMA– lesions by [68Ga]Ga-PSMA-11 PET/CT. Candidates for PARP inhibition and pts 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 q6w; 6 cycles) or ARPI change (abiraterone/enzalutamide). Pts randomized to ARPI could crossover to 177Lu-PSMA-617 following centrally reviewed radiographic progression (rPD). Endpoints included: rPFS (PCWG3/RECIST v1.1; primary), OS (key secondary) (both overall α=0.025, one-sided), FACT-P (secondary) and ORR/DOR (exploratory). Primary analysis was to occur at ∼156 rPFS events and second OS interim analysis (IA) at ∼125 deaths. Crossover-adjusted analysis was the prespecified method for OS by rank-preserving structural failure time (RPSFT). 468 pts were randomized. At primary analysis (median follow-up, 7.3 months; N = 467), the primary endpoint of rPFS was met (HR, 0.41; 95% CI: 0.29, 0.56; p<0.0001); this was similar at second IA (table). At second IA (45.1% of target deaths), 123/146 (84.2%) pts with rPD who discontinued ARPI crossed over; there was a positive OS trend in favour of 177Lu-PSMA-617 per RPFST but not per unadjusted OS analysis. FACT-P and ORR/DOR favoured the 177Lu-PSMA-617 arm (table). For 177Lu-PSMA-617 vs ARPI change, incidence of grade ≥3 AEs was 34% (most common: anaemia, dry mouth) vs 44%, serious AEs 20% vs 28%, and AEs leading to discontinuation 5.7% vs 5.2%.Table: LBA13Second OS IA (DCO, 21 Jun 2023; median follow-up, 15.9 months)177Lu-PSMA-617 (N=234)ARPI change (N=234)Cycles, median (range)6.0 (1–6)–rPFSaEvents, n (%)115 (49.1)168 (71.8)Median (95% CI), months12.02 (9.30, 14.42)5.59 (4.17, 5.95)HR (95% CI), p0.43 (0.33, 0.54), <0.0001TTW in FACT-P TotalbEvents, n (%)167 (71.4)187 (79.9)Median (95% CI), months7.46 (6.08, 8.51)4.27 (3.48, 4.53)HR (95% CI)0.59 (0.47, 0.72)N=105N=103ORRc, % (95% CI)41.9 (32.3, 51.9)12.6 (6.9, 20.6)N=44N=13DORc, median (95% CI), months17.1 (11.6, NE)10.1 (4.6, NE)aRadiographic progression or death bTime to worsening in FACT-P Total, clinical disease progression, or death cSoft tissue only NE, not estimable. Open table in a new tab aRadiographic progression or death bTime to worsening in FACT-P Total, clinical disease progression, or death cSoft tissue only NE, not estimable. 177Lu-PSMA-617 prolonged rPFS vs ARPI change in taxane-naive pts with PSMA+ mCRPC, with a favourable safety profile.