Impact of homologous recombination repair gene mutations on survival in metastatic castration-sensitive prostate cancer (mCSPC) from an observational database.

Abstract

e17098 Background: Mutations in homologous recombination repair genes (HRRm) are known to increase the aggressiveness of prostate cancer (PCa). However, their prevalence varies depending on the HRR gene, and their impact on survival might be different. We report here, from the PROGENE observational database comprising 6000 PCa, the management and survival of 162 mCSPC patients between 2011-2023 and characterized for somatic and/or germline HRRm. Methods: HRRm were identified using next-generation sequencing of a panel of HRR genes. Ethnicity, comorbidities, clinico-pathological characteristics (such as PSA level, ISUP and TNM stage), and treatment lines were analysed by calculating the direct effect of each variable on survival using a Bayesian network. Multivariate Cox models and Kaplan Meier survival curves using propensity scores were produced and compared by log rank test. Results: HRR mutations were observed in 26 mCSPC patients (16.0%), ATM and BRCA2 were the most common ones (Table). Bayesian network identified HRRm status as an independent predictive factor of survival. In patients with HRRm (HRR+), a statistically significant decrease in overall survival was observed compared to non-mutated patients (HRR-) with median OS of 24 months [95% CI= 16.0; 41.0] for HRR+ patients versus 45.0 months [95% CI= 34.0; 69.0] for HRR- patients (p=0.038). Compared to HRR- patients, an earlier mortality was observed for BRCA2+ patients with median OS of 24.0 months [95% CI = 9.0; 40.0] (p=0.036), whereas there was no difference for ATM+ patients (median OS = 41 months; [95% CI= 15.0-87.0]). Similarly, BRCA2 mutations were associated with faster progression, with median progression free survival of 8 months [95% CI= 0.0; 14.0] for BRCA2+ patients versus 17 months [95% CI= 12.0; 20.0] for HRR- patients (p=0.006). No difference in progression was found between ATM+ and HRR- patients. Conclusions: BRCA2 and ATM are the most frequent HRR mutations in mCSPC patients. HRRm are associated with reduced overall survival. In addition, BRCA2 mutation is associated with reduced progression free survival. Specific management of early-stage PCa patients with those mutations is therefore justified given their unfavorable outcomes. List of the HRRm identified in the 162 mCSPC patients. HRR mutated gene/population HRR+ (N = 26) BRCA+ (N = 9) BRCA- (N = 153) HRR+/BRCA- (N = 17) BRCA1BRCA2CDK12CHEK2PALB2RAD51BATM 1 (3.8%)8 (30.8%)6 (23.1%)3 (11.5%)1 (3.8%)1 (3.8%)9 (34.6%) 1 (11.1%)8 (88.8%)0 (0.0%)0 (0.0%)0 (0.0%)1 (11.1%)1 (11.1%) 0 (0.0%)0 (0.0%)6 (3.9%)3 (2.0%)1 (0.7%)0 (0.0%)8 (5.2%) 0 (0.0%)0 (0.0%)6 (35.3%)3 (17.6%)1 (5.9%)0 (0.0%)8 (47.1%) Total 26 (100%) 9 (100.0%) 17 (11.1%) 17 (100.0%)