5099 Background: The international, randomized, phase III ENZAMET trial (n=1125) showed improved overall survival (OS) with ADT plus ENZA vs ADT plus NSAA for mHSPC. Observational studies showed that the mHSPC genetic landscape is comparable to castration resistant prostate cancer (CRPC). Prognostic and predictive impact of inherited pathogenic variants (PVs), including those affecting BRCA1 , BRCA2 and other DNA damage and repair (DDR) genes, on androgen receptor pathway inhibitor (ARPI)-treated mHSPC is under investigation. Methods: Whole exome sequencing of germline DNA prospectively obtained from ENZAMET pts. Variant annotation and effect prediction identified PVs (altered “+” vs wild-type “-”). Prognostic effect of PVs was assessed within arms. Endpoints: clinical progression-free survival (PFS) and OS by Kaplan-Meier method. Hazard ratios (HRs) were estimated using Cox models. Multivariable analyses (MVA) adjusted for Gleason score (GS), volume (vol), metachronous vs synchronous and docetaxel (D) use. Results: All 847 available samples were successfully sequenced. 123 PVs were identified in 117 (13.8%) pts, of which 46 (5.43%) pts harbored a PV in ≥1 DDR gene. The rate of pathogenic germline BRCA1 / BRCA2 (BRCA) PVs was 2.13% (39.1% of DDR PVs). Proportions of arm, D use, vol and visceral disease were similar between DDR+ vs DDR- and BRCA+ vs BRCA-. Synchronous mHSPC in DDR+ vs DDR- and BRCA+ vs BRCA- was 41.3% vs 63.0% and 44.4% vs 62.2%, respectively. PFS and OS estimates were similar between BRCA+ and BRCA- groups in the overall cohort (5-yr OS: 55.6% vs 61%; 3-yr PFS: 50% vs 53.5%, respectively) and in the ENZA arm, but differed in the NSAA arm (Table). BRCA+ treated with ADT+NSAA (67% D use) had shortest PFS (median PFS: 11.3m vs 24.9m BRCA-, HR 1.85, 95% CI: 0.95-3.6). D use associated with poorer outcomes. In MVA, the HR(PFS) for BRCA+ in NSAA arm was 1.47 (95% CI 0.71-3.04, p=0.3) vs ENZA arm: HR 0.98, (95% CI 0.31-3.08, p=0.97). Vol and GS were independently significant in both arms. Conclusions: In one of the largest germline genetic studies from a phase III mHSPC trial, we observed recurrent DDR and BRCA PVs at a lower rate than institutional cohorts. Germline BRCA PVs are associated with a shorter PFS on ADT+NSAA – an effect which may be mitigated by ENZA. Validation in independent trial cohorts is ongoing. Outcomes by arm/docetaxel and BRCA status. n 5y-OS % (95% CI) 3y-PFS % (95% CI) NSAA only BRCA- 238 56.6 (50.0-62.7) 42.9 (36.5-49.1) NSAA only BRCA+ 3 66.7 (5.4-94.5) 66.7 (5.4-94.5) NSAA+D BRCA- 176 54.7 (47.0-61.8) 32.5 (25.7-39.6) NSAA+D BRCA+ 6 33.3 (4.6-67.6) 16.7 (0.8-51.7) ENZA only BRCA- 228 70.6 (64.2-76.0) 73.3 (67.0-78.5) ENZA only BRCA+ 7 71.4 (25.8-92.0) 71.4 (25.8-92.0) ENZA+D BRCA- 187 60.7 (53.2-67.3) 62.3 (54.9-58.8) ENZA+D BRCA+ 2 NE 50.0 (0.6-91.0)
Hamid et al. (Wed,) studied this question.