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PURPOSE: Up to 25% of pancreatic adenocarcinomas (PDACs) harbor mutations in the homologous recombination DNA damage response (HR-DDR) pathway. Although known to affect responsiveness to DNA-damaging chemotherapy, the prognostic relevance of these mutations is unclear and outcomes in patients with PDAC who harbor HR-DDR mutations beyond BRCA1/2 remain unexplored. METHODS: We evaluated 820 patients with PDAC enrolled in the Know Your Tumor program for whom we had collected comprehensive genomic testing results and longitudinal clinical outcomes. Patients were categorized as having resected versus advanced disease, and as having received platinum-based therapy versus being platinum naïve. Tumor genomic profiles were categorized as HR-DDR mutated (HR-DDRmut) or proficient (pHR-DDR) on the basis of the presence of pathogenic mutations of somatic or germline origin in BRCA1/2 or PALB2 (group 1); ATM/ATR/ATRX (group 2); or BAP1, BARD1, BRIP1, CHEK1/2, RAD50/51/51B, or FANCA/C/D2/E/F/G/L (group 3). Overall survival was measured from the date of diagnosis until death. RESULTS: Median overall survival (mOS) was similar in all resected patients irrespective of exposure to platinum-based therapy, whereas for platinum-treated patients with advanced disease, mOS was significantly longer for HR-DDRmut versus pHR-DDR (2.37 years v 1.45 years, respectively). Of importance, no difference was identified in platinum-naïve patients. mOS in patients with mutations in all three HR-DDRmut groups was greater than that for pHR-DDR patients, but this difference was lost in platinum-naïve patients. CONCLUSION: Patients with advanced HR-DDRmut have improved mOS when treated with platinum-based therapy compared with pHR-DDR patients. In platinum-naïve patients, there is no mOS difference, which suggests that HR-DDR status has no pure prognostic value. These findings support the need to test all patients with advanced PDAC to ensure that HR-DDRmut patients receive the benefit of treatment with platinum-based therapy. [ABSTRACT FROM AUTHOR]