BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype.

Background: Genomic alterations in DNA damage response (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC). Understanding how these genomic events impact prognosis and/or treatment response is vital for optimising clinical outcomes.
Methods: Targeted sequencing was performed on 407 plasma samples from 375 men with mCRPC. Using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay, pathogenic alterations in 152 key genes (including 27 DDR-related genes) were assessed, as was the presence and mechanisms of biallelic loss in BRCA2.
Findings: At least one DDR alteration was present in 34.5% (129/375) of patients (including monoallelic alterations). The most frequently altered DDR genes were BRCA2 (19%), ATM (13%), FANCA (5%), CHEK2 (5%) and BRCA1 (3%). Patients with BRCA alterations, especially BRCA2, had significantly worse progression-free survival (PFS) (Hazard ratio (HR) 3.3 [95% CI 1.9-6.0]; Cox regression p < 0.001), overall survival (HR 2.2 [95% CI 1.1-4.5]; Cox regression p = 0.02) and PSA response rates to androgen receptor (AR) pathway inhibitors (32% vs 60%, chi-square p = 0.02). BRCA-deficient tumours were also enriched for alterations within multiple genes including in the AR and PI3K pathways. Zygosity of BRCA2 alterations had no discernible impact on clinical outcomes, with similarly poor PFS for monoallelic vs biallelic loss (median 3.9 months vs 3.4 months vs copy neutral 9.8 months).
Interpretation: These data emphasise that the BRCA genes, in particular BRCA2, are key prognostic biomarkers in mCRPC. The clinical utility of BRCA2 as a marker of poor outcomes may, at least in cfDNA assays, be independent of the zygosity state detected. Enrichment of actionable genomic alterations in cfDNA from BRCA-deficient mCRPC may support rational co-targeting strategies in future clinical trials.
Funding: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.
Competing Interests: Declaration of interests M.K received travel/accommodation from Celgene; D.C, T.Z, P.D and S.J are stockholders in Predicine, Inc.; L.G.H received research funding from Astellas Pharma, travel/accommodation from Astellas Pharma and Pfizer, honoraria from Janssen and Astellas and is on the scientific advisory board from Imagion; Kate Mahon received travel/accommodation from Astellas Pharma; E.M.K received honoraria from Janssen, research funding from Astellas Pharma and AstraZeneca, and travel/accommodations from Astellas Pharma, Pfizer, and Ipsen; A.A.A is a consultant for Astellas Pharma, Janssen, Novartis and Aculeus Therapeutics, is on the speakers bureau for Astellas Pharma, Janssen, Novartis, Amgen, Ipsen, Bristol Myers Squibb, Merck Serono and Bayer, received honoraria from Astellas Pharma, Janssen, Novartis, Tolmar, Amgen, Pfizer, Telix, Sanofi, Astra Zeneca, Merck Serono, Bristol Myers Squibb, Ipsen, Bayer, Pfizer, Noxopharm, Merck Sharpe Dohme, and Aculeus Therapeutics, is on the Scientific Advisory Board for Astellas Pharma, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, Telix, Merck Serono, Janssen, Bristol Myers Squibb, Ipsen, Bayer, Merck Sharpe Dome, Amgen, and Noxopharm, travel/accommodations from Astellas, Merck Serono, Amgen, Novartis, Janssen, Tolmar, Pfizer and Bayer, and received research funding from Astellas (investigator), Merck Serono (investigator), Astra Zeneca (investigator), Bristol Myers Squibb (institutional), Astra Zeneca (institutional), Aptevo Therapeutics (institutional), Glaxo Smith Kline (institutional), Pfizer (institutional), MedImmune (institutional), Astellas (institutional), SYNthorx (institutional), Bionomics (institutional), Sanofi Aventis (institutional), Novartis (institutional), Ipsen (institutional), Exelixis (institutional), Merck Sharpe Dome (institutional), Janssen (institutional), Eli Lilly (institutional), Gilead Sciences (institutional), Merck Serono (institutional), Hinova (institutional).
(Copyright © 2023. Published by Elsevier B.V.)