Impact of HRR Gene Subclass on Clinical Outcomes of PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer.

This retrospective study evaluates the clinical significance of mutations in effector genes (BRCA1, BRCA2, PALB2, RAD51, FANCD2) versus sensor genes (ATM, ATR, CHEK1, CHEK2, NBS1) in patients with metastatic castration-resistant prostate cancer (mCRPC) classified as homologous recombination deficiency (HRD)-positive. The study assesses their predictive value for response to poly(ADP-ribose) polymerase inhibitors (PARPi) combined with androgen receptor signaling inhibitors (ARSi). A multicenter, retrospective real-world study conducted across 6 oncology hospitals in Bulgaria. Patient data were obtained through a formal request to the Ministry of Health's United Information Portal, an electronic health records repository. The analysis included mCRPC patients treated with olaparib plus abiraterone who underwent next-generation sequencing (NGS) between January 1, 2022, and January 1, 2025, conducted in a certified national reference laboratory, with a median follow-up of 16 months. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Of the 210 mCRPC patients screened via NGS, 28% (n = 58) harbored mutations in at least one HRR gene, classified as sensor (n = 27) or effector (n = 31). Patients with effector mutations demonstrated a statistically significant improvement in PFS compared to those with sensor mutations (median PFS: 20 vs. 14 months, HR = 0.48, 95% CI: 0.252-0.914, P = .0294). Similarly, overall survival (OS) was significantly prolonged in the effector group. While the median OS for the sensor group was 19 months, the effector group had not yet reached median OS at the time of analysis (HR = 0.38, 95% CI, 0.154-0.945, P = .0373). Logistic regression analysis and PSM supported findings. Patients with mCRPC harboring effector HRR mutations derive greater clinical benefit from PARPi plus ARSi than those with sensor mutations. These findings highlight the heterogeneous predictive value of HRR gene alterations and suggest that mutation sub-class should guide treatment decisions in HRD-positive mCRPC.