A prospective study exploring genomic correlates of clinical outcome in patients with metastatic castration-sensitive prostate cancer receiving enzalutamide.

244 Background: The genomic landscape of metastatic castration-sensitive prostate cancer (mCSPC) in Asian populations remains poorly characterized. Epidemiological studies have shown that while the incidence and mortality of prostate cancer are lower in Asian men compared to Western populations, Asian patients often present with higher-grade tumors at diagnosis. Furthermore, Asian men may exhibit comparable or even superior survival outcomes in response to androgen deprivation therapy (ADT), suggesting potential ethnic differences in tumor biology. This study investigated somatic alterations and their association with clinical outcomes in Japanese patients with mCSPC receiving ADT plus enzalutamide. Methods: We conducted a prospective, multicenter study of Japanese mCSPC patients treated with ADT plus enzalutamide. Tumor biopsy specimens obtained from 76 Japanese patients with mCSPC were analyzed by whole-exome sequencing. Somatic mutations were identified using the Genomon pipeline with matched germline DNA. The primary endpoint was time to castration-resistant prostate cancer (CRPC) progression, assessed by Kaplan-Meier survival analysis and Cox proportional hazard models. Results: Over a median follow-up of 29 months, 22 of 76 patients (29%) progressed to CRPC. FOXA1 emerged as the most frequently mutated gene (36%), followed by CYB561D1 (32%). Twenty genes were mutated in 10% or more of cases. Hotspot clustering was observed in 17 genes. BIRC5 (HR 4.09, 95 CI 1.70-9.80, p<0.01) and DUOXA1 (HR 3.18, 95% CI 1.17-8.64, p=0.02) hotspot mutations were significantly associated with time to CRPC in the univariate analysis. In contrast, FOXA1 wing2 domain mutations were associated with favorable prognosis (HR 0.22, 0.05-0.93, p=0.04). Additionally, EOD grade ≥ 3 was a clinical predictor of early progression (HR 4.19, 1.75-10.04, p=0.01). Multivariate analysis confirmed BIRC5 hotspot mutation (HR 3.71, 1.17-11.81, p=0.03) as an independent predictor of CRPC progression. Conclusions: This prospective genomic study revealed a somatic mutation profile derived from Japanese mCSPC. The BIRC5 hotspot mutation was identified as a novel predictor of CRPC progression in patients with mCSPC receiving androgen signaling inhibitors.