Background: Little is known about the clinical course of patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) who harbor alterations in the homologous recombination repair (HRR) pathway. Here, we examine the outcomes of men with mHSPC with HRR alterations. Methods: Single center, retrospective analysis of men with mHSPC who underwent next generation sequencing from 2015-2020. The primary endpoint was to assess the time from diagnosis of mHSPC to onset of castrate resistance (mCRPC), as defined by PCWG3 criteria, in pts with HRR alterations vs wild type (WT). Both somatic and germline HRR alterations were permitted. Univariate and multivariate Cox regression were used to assess the effect of HRR alterations on time to mCRPC. Secondary endpoints included time to mCRPC stratified by HRR gene and time to treatment failure (TTF) in HRR altered vs WT pts, stratified by therapy. Results: We identified 151 men with mHSPC for the study. Median age was 66 years and 62% (n = 93) had de novo metastatic disease. 25% (n = 37) had HRR alterations detected and the most common alterations were in BRCA2 (n = 15), ATM (n = 10), CDK12 (n = 7). 78.4% (n = 29) of alterations were somatic and 13.5% (n = 5) of pts had co-alterations in 2 HRR genes. Time to mCRPC was significantly decreased in pts with HRR alterations vs WT (12.7 vs 16.1 mos, HR- 1.95, p- 0.02). In multivariate analysis, the effect of HRR alterations on time to mCRPC remained statistically significant when adjusting for age, mHSPC therapy, presence of visceral metastases, and PSA (adjusted HR- 1.69, p-0.02). Stratified by individual HRR gene, pts with BRCA2, CDK12, or co-occurring alterations had significantly decreased time to mCRPC compared to other HRR alterations (Table). In terms of mHSPC therapy, 45.7% were treated with ADT alone, 27.8% with an androgen receptor signaling inhibitor (ARSI), and 26.5% with docetaxel. TTF was inferior in HRR altered vs WT pts (10.8 vs 13.8 mos, p-0.004, HR- 1.84). Stratified by therapy, TTF was inferior in HRR altered vs WT pts treated with ADT alone (8.9 vs 13.3 mos, p- 0.019, HR-1.94) and there was no significant difference in TTF in HRR altered vs WT pts treated with either the addition of an ARSI or docetaxel. Conclusions: HRR alterations are associated with worsened outcomes in mHSPC patients. Given the established role of PARP inhibitors in mCRPC, these data highlight an opportunity to explore the use of PARP inhibitors in mHSPC to potentially improve outcomes.

* ATM/CDK12, BRCA1/BRCA2, BRCA2/CDK12, BRCA2/CHEK2 ** CHEK2, PPP2R2A, RAD50.