[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: LBA13
| Second 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) | – |
| rPFS a | ||
| Events, n (%) | 115 (49.1) | 168 (71.8) |
| Median (95% CI), months | 12.02 (9.30, 14.42) | 5.59 (4.17, 5.95) |
| HR (95% CI), p | 0.43 (0.33, 0.54), <0.0001 | |
| TTW in FACT-P Total b | ||
| Events, n (%) | 167 (71.4) | 187 (79.9) |
| Median (95% CI), months | 7.46 (6.08, 8.51) | 4.27 (3.48, 4.53) |
| HR (95% CI) | 0.59 (0.47, 0.72) | |
| N=105 | N=103 | |
| ORRc, % (95% CI) | 41.9 (32.3, 51.9) | 12.6 (6.9, 20.6) |
| N=44 | N=13 | |
| DORc, median (95% CI), months | 17.1 (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.
177Lu-PSMA-617 prolonged rPFS vs ARPI change in taxane-naive pts with PSMA+ mCRPC, with a favourable safety profile.
Drs. O. Sartor, M.J. Morris and K. Fizazi have equally contributed to the study.
EudraCT 2020-003969-19. NCT04689828. Protocol release date: 13 January 2022.