A systematic review and meta-analysis on safety and efficacy of Lu-177 PSMA-617 and standardized treatment in mCRPC from randomized phase II/III trials.

e17069 Background: Lu-177 PSMA-617 delivers targeted β-radiation to prostate cancer cells, offering a distinct mechanism beyond androgen-signaling inhibition in metastatic castration-resistant prostate cancer (mCRPC). Pivotal trials have shown improved progression-free survival with favorable tolerability. As its clinical use expands, comparative evidence with established systemic therapies remains limited. This meta-analysis evaluates the pooled efficacy and safety outcomes. Methods: A systematic review and meta-analysis were performed according to PRISMA guidelines to evaluate Lu-177 PSMA-617 in mCRPC. Of 456 studies screened, seven met eligibility criteria and were included in the final analysis. Data on progression-free survival (PFS), overall survival (OS), and grade ≥3 adverse events (AEs) were extracted and pooled using a random-effects model (REML method). Hazard ratios (HRs) and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed using the I² statistic, and publication bias was evaluated using both Egger’s regression and Begg’s rank correlation. Results: A total of 2,526 patients from seven randomized trials were analyzed, including 1,365 in the Lu-177 PSMA-617 arms and 1,161 in the standard-of-care arms. Lu-177 PSMA-617 significantly improved PFS compared with control (pooled HR = 0.64; 95% CI 0.50–0.81; p < 0.001). No significant difference was observed in OS (HR = 0.91; 95% CI 0.66–1.25; p = 0.55). The pooled RR for grade ≥ 3 AEs was 0.98 (95% CI 0.83–1.14; p = 0.75). Conclusions: Across contemporary randomized trials, Lu-177 PSMA-617 consistently prolongs PFS with no significant difference in AEs. OS benefit remains unconfirmed, likely reflecting post-progression and salvage use of Lu-177 PSMA-617 in control arms in some trials, as well as disease and trial heterogeneity. The data collectively reinforce Lu-177 PSMA-617 as a well-tolerated, effective radioligand option for advanced mCRPC, warranting continued integration into earlier disease settings and combination strategy. Pooled Overall Survival comparing Lu-177 PSMA-617 and standard of care. Study HR OS for Lu-177 PSMA-617 vs standard PSMAFore 0.98 (0.75-1.28) SPLASH 1.11(0.73-1.69) VISION 0.62 (0.52-0.74) TheraP 0.97 (0.70-1.35) Enza-P 0.55 (0.36-0.84) CCT Group 1.64 (1.14-2.35) Pooled Results 0.91 (0.66-1.25)