3145 Background: BRCA muts in CRC are associated with a higher tumor mutation burden irrespective of microsatellite instability, which highlights the possibility of using PARP-inhibitors(i) in CRC in the future. Early phase studies have shown that combination of PARP-i with oxaliplatin or irinotecan enhances tumor lysis in CRC. In this study, we investigated the influence of mutations in the Homologous Repair Pathway genes on survival outcomes among mCRC pts treated with oxaliplatin or irinotecan-based regimens. Methods: The impact of selected SNPs within 4 genes (BRCA1, BRCA2, RAD51, BARD1) on OS/PFS was analyzed through the OncoArray, a custom array manufactured by Illumina, on genomic DNA from blood samples of 431 pts enrolled in 2 randomized trials. TRIBE FOLFIRI/bev arm (n = 215, mPFS/OS: 9.7/26.2 mo) served as discovery cohort, FIRE-3 FOLFIRI/bev arm (n = 107, mPFS/OS: 11.5/31.4 mo) as validation and TRIBE FOLFOX/bev arm (n = 109, mPFS/OS: 10.8/26 mo) as control. Results: Significant associations were found among carriers of BRCA1 rs8176318 SNP, where C > A base change is known to reduce BRCA1 expression among CRC cells. In the discovery cohort, pts with A/A had shorter OS (22.4 vs 27.3 mo, P = .009) and PFS (7.5 vs 10.5 mo, P = .0006) compared to carriers of any C allele in both univariate and multivariate analysis. Same results were observed in pts with left-sided CRCs (PFS-7.5 vs 11 mo, P = .005; OS- 25.6 vs 32.3, P = .034) and among males (PFS- 7.5 vs 10.3 mo, P = .008; OS- 25.7 vs 31.3 mo, P = .008) in both uni and multivariate analysis. These results were also seen in the validation cohort: A/A carriers in left-sided CRCs had poor OS (26.1 vs 36.0 mo, P = .027) and PFS (9.5 vs 11.7 mo, P = .002. Males with A/A genotype also had poor OS (24.7 vs 32.5 mo, P = .028) and PFS 96.9 vs 12.2 mo; P = .0002). In the control cohort, A/A genotype carriers had poor tumor response in overall (P = .011) and left-sided disease (P = .034). These outcomes were independent of KRAS mutation status. No significant relationship was observed among females with mCRC. Conclusions: This is the first study to report that BRCA1 mut influence survival outcomes among mCRC pts, particularly among males and those with left-sided disease. Prospective trials are warranted to assess the utility of routine BRCA mut testing and the role of PARP-i in improving survival outcomes in this pt population.