Homologous recombination deficiency and genomic alterations in advanced prostate cancer: insights for precision therapy

Abstract Background the homologous recombination deficiency signature (HRDsig) is emerging as a novel potential predictor of PARP-inhibitor (PARPi) response. We compared genomic alterations (GA) across BRCA2-loss, BRCA2 short variant–mutated (svmut), and BRCA2–wild type (wt) clinically advanced prostate carcinoma (CAPC) samples, combined with an assessment of HRDsig status to gain a better understanding of these biomarkers. Methods Comprehensive genomic profiling (CGP) was performed on 22 061 CAPC cases to evaluate all classes of GA. Microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic ancestry, were derived from sequencing data. HRDsig status was calculated using genome-wide copy number features. PD-L1 expression was assessed by IHC. Comparisons were performed using Fisher’s exact test with Benjamini–Hochberg correction for false discovery. Results Among 22 061 CAPC cases, 10.2% were HRDsig+. HRDsig+ and were enriched for BRCA2, RB1, MYC, RAD21, and AR alterations, while SPOP, MSI-high, high TMB, and MMR signatures were more frequent in HRDsig− cases. Across BRCA2-defined subgroups, 597 (2.7%) were BRCA2-loss, 1085 (4.9%) BRCA2-svmut, and 20 379 (92.4%) BRCA2-wt. Both BRCA2-loss and BRCA2-svmut were associated with higher GA burden and enrichment for RB1 alterations. BRCA2-loss cases displayed lower TMB-high incidence, while BRCA2-svmut showed higher MSI-high and TMB-high incidence. Most BRCA2 alterations were bi-allelic, with concurrent alterations in other HRR genes being rare. Conclusions BRCA2-loss CAPC displays a distinct genomic landscape, marked by robust HRD features, suggesting the potential of higher sensitivity to PARPi. These findings highlight the relevance of HRDsig, and routinely use of CGP in refining patient selection for PARPi and guiding the design of future clinical trials.