The Impact of Pathogenic Variants of BRCA1, BRCA2, and other DNA-Repair Genes on the Survival Benefits Conferred by PARP Inhibitors-Single-Centre Experience from Quebec.

Poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have transformed the way we treat patients with ovarian cancer (OC) which are homologous recombinant deficient. However, real-world data on response rates is contrasting. We studied the impact of BRCA pathogenic variants (PVs) type on progression-free survival (PFS) and overall survival (OS) in high-grade serous patients with OC treated with PARPi maintenance therapy. A retrospective study of patients who had PV and were treated with maintenance PARPi between 2011 and 2024. Our primary outcome was the PFS and OS of patients treated with PARPi. Overall, we included 22 (44%) BRCA1, 19 (38%) BRCA2, and 9 patients (18%) with other DNA repair-related genes-7 (14%) RAD51C/D, 1 (2%) PALB2, and 1 (2%) CHEK2. The median follow-up time was 27 months. Groups were balanced with respect to body mass index, proportions of patients with complete cytoreduction, stage at diagnosis, treatment setting, and PARPi treatment (niraparib, olarapib, and rucaparib). At 24 months since starting PARPi, 34% of patients with BRCA1 were disease free, 71% of patients with BRCA2, and 77% with other DNA repair-related genes, log rank = 0.019. The median PFS was inferior for BRCA1 mutation carriers when compared to BRCA2 (hazard ratio [HR] 2.85; 95% CI 1.09-7.69), and when compared to other DNA repair-related genes (HR 4.34; 95% CI 0.97-20.0). The proportion of patients who progressed while on maintenance therapy was higher among BRCA1 15 (68.2%) versus 6 (31.6%) in BRCA2 and 2 (22.2%) in other DNA repair-related genes, P = 0.018. In a Cox regression analysis for PFS, including PV type, R0 cytoreduction, and stage of disease, the only independently associated factor with PFS was the implicated gene, with BRCA2 having superior PFS when compared to BRCA1, adjusted HR 0.34 (95% CI 0.13-0.90), and other DNA repair-related genes (adjusted HR 0.21; 95% CI 0.05-0.95) when compared to BRCA1. We observed a potential differential response to maintenance PARPi according to PV status, with a signal toward shorter PFS among patients with BRCA1 PVs.