Persistence of aggressive biology: Outcomes of ¹⁷⁷ Lu-PSMA-617 in <i>BRCA</i> -altered mCRPC—Systematic review and meta-analysis.

Abstract

e17053 Background: BRCA1/2 alterations define an aggressive subtype of metastatic castration-resistant prostate cancer (mCRPC) associated with adverse clinical outcomes. Although ¹⁷⁷Lu-PSMA-617 improves survival in unselected mCRPC, its efficacy in BRCA-altered disease remains incompletely characterized. We conducted a systematic review and meta-analysis to evaluate outcomes of ¹⁷⁷Lu-PSMA-617 in BRCA-altered mCRPC. Methods: A comprehensive PRISMA-guided literature search was conducted on PubMed, Cochrane, and Embase to identify seven eligible studies reporting clinical outcomes of ¹⁷⁷Lu-PSMA-617 in patients with BRCA-altered mCRPC. Overall survival (OS) hazard ratios (HRs) comparing BRCA-altered vs. non-altered patients were pooled using a random-effects model with Hartung-Knapp adjustment. A complementary single-arm proportional meta-analysis was performed to estimate pooled PSA50 response rates in patients with BRCA alterations. Inter-study heterogeneity was quantified using the I² statistic. Results: Seven studies (predominantly retrospective cohort analyses; one randomized controlled trial) met inclusion criteria, contributing aggregate data on approximately 728 patients treated with ¹⁷⁷Lu-PSMA-617. Three studies provided comparative OS data (total n = 292 patients: 50 with BRCA1/2 alterations and 242 without), while two studies reported BRCA-specific PSA response rates (n = 39 BRCA-altered patients). In the comparative studies, patient characteristics included median ages ranging from 62 to 72 years and frequent prior exposure to androgen receptor pathway inhibitors (ARPI), taxanes (docetaxel and/or cabazitaxel), and, in select cohorts, prior PARP inhibitors (PARPi). BRCA-altered patients exhibited inferior OS compared with non-BRCA counterparts (pooled HR 2.01, 95% CI 0.53–7.64; I² = 11.8%). The single-arm meta-analysis yielded a pooled PSA50 response rate of 51.3% (95% CI 35.9–66.4; I² = 0%) among patients with BRCA alterations. Limited data on other endpoints, including radiographic progression-free survival (rPFS medians 4.5-17.3 months in BRCA subgroups across studies) and deeper PSA responses (PSA90 rates 9-40% in small BRCA1/2 subsets), indicated preserved biochemical and radiographic activity despite the observed survival detriment. Toxicities and discontinuation rates due to adverse events were inconsistently reported and sparsely detailed across studies. Conclusions: In this meta-analysis, BRCA-altered mCRPC treated with ¹⁷⁷Lu-PSMA-617 was associated with worse overall survival compared with non-BRCA disease, despite preserved PSA responses. These results highlight the aggressive biology of BRCA-altered mCRPC and support further biomarker-stratified studies to optimize patient selection and treatment sequencing.