Homologous recombination repair (HRR) mutation in de novo metastatic hormone sensitive prostate cancer (mHSPC).

243 Background: Genomic alterations are becoming increasingly important to understand progression of disease and determine treatment in mHSPC. Homologous Recombination Repair (HRR) genes are of particular interest as they lead to decreased ability to repair DNA double-stranded breaks and can be used as a therapeutic target. We sought to understand the prognostic significance of HRR alterations in metastatic prostate cancer. Methods: In this retrospective study, we analyzed patients in the Veterans Health Administration with de novo hormone-sensitive prostate cancer from January 1 st , 2013 to December 31 st , 2022 that have undergone genomic sequencing. Veterans with HRR alterations included pathogenic alterations in BRCA1/2, CDK12, PALB2, CHEK2, and ATM. Tumor-suppressor gene (TSG) included TP53, PTEN, and RB1. Age, Charlson comorbidity index (CCI), PSA at diagnosis, first line therapy, and BMI were collected and used in multivariate models. Survival analyses were performed using the Kaplan-Meier method and Cox regression. Results: In 2027 veterans, there were 412 with HRRalt, 1040 with TSGalt, and 774 with neither. There was a decrease in median progression-free survival (PFS) from 32.4 months to 20.4 months in the HRR population (p<0.001) compared to veterans without HRR or TSG alterations. Similarly, there was a decrease in median overall survival (OS) from 70.2 months to 47.7 months in HRRalt (p<0.001). For comparison, individuals with a TSGalt had a median overall survival of 42.2 months On multivariate Cox regression analysis, HRR mutation was associated with increased risk of progression (HR 1.44, CI 1.19-1.74, p<0.001) and increased mortality (HR 1.41, CI 1.12-1.76, p=0.003), independent of first-line therapy choice, comorbidity index score, age, BMI, and PSA response. HRR mutation is also significantly associated with higher volume of disease compared to that of HRR-wild type (76.5% vs. 65.9%, p=0.007). Conclusions: HRR alterations were associated with shorter overall survival and progression-free survival in patients with metastatic hormone sensitive prostate cancer without TSG alterations. Genetic results are important for both estimating risk of adverse outcomes and predicting response to therapies.