Real-World Landscape of BRCA Deleterious Alterations in Advanced Prostate Cancer: Insights From a Nationwide Genomic Database.

BACKGROUND: The clinical characteristics of BRCA1 and BRCA2 (BRCA) deleterious alterations in advanced prostate cancer-considering age, family history, co-occurring gene alterations, and variant type-remain incompletely understood in patients undergoing tumor-only panel testing. MATERIALS AND METHODS: We analyzed 2,815 patients who underwent comprehensive cancer genomic profiling (CGP) using a tissue-based tumor-only panel from December 2020 to November 2024. Eligible patients had metastatic prostate cancer resistant to standard therapies or androgen-indifferent prostate cancer, including neuroendocrine prostate cancer. Data were obtained from the Center for Cancer Genomics and Advanced Therapeutics, a nationwide CGP database in Japan. RESULTS: Median age at CGP testing was 72 years (range 23-93 years). BRCA deleterious alterations were detected in 428 patients (15.2%), decreasing with age: 24.2% (< 50 years), 25.4% (50-59 years), 16.3% (60-69 years), 14.3% (70-79 years), and 9.3% (≥ 80 years). A family history of breast or ovarian cancer independently predicted BRCA alterations (odds ratio 1.901 and 3.016; both p < 0.05). RB1 alterations and MYC amplification were significantly enriched as co-occurring alterations in BRCA2 (6.9% vs. 14.9%, 15.4% vs. 23.1%; both p < 0.05). Stratified by BRCA2 variant type, patients with homozygous deletion (HD) had longer overall survival than those with truncating alterations following olaparib treatment (median 30.6 vs. 16.9 months; hazard ratio 0.373; 95% CI 0.220-0.633). CONCLUSIONS: In advanced, therapy-resistant prostate cancer, BRCA deleterious alterations were more frequent in younger patients and those in with a family history of breast and ovarian cancer. BRCA2 HD was significantly associated with a favorable response to olaparib.