Abstract Introduction: Homologous recombination deficiency (HRD) is an emerging biomarker for DNA-damage-response (DDR)-targeted therapies in pancreatic cancer (PDAC). There are different methods available to identify HRD in other cancers, however these have not been evaluated comprehensively in PDAC for their response prediction to first-line platinum-based therapies (1L-platinum). Methods: Patients with advanced (stage 3-4) PDAC who had germline and somatic MSK-IMPACT were included. We evaluated genetic methods for HRD and their association with clinical outcomes on 1L-platinum or 1L-non-platinum therapies. Homologous recombination (HR)-genes included: ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, PALB2, RAD50, RAD51, RAD51C, RTEL1. We evaluated the status of pathogenic HR-gene mutations (HRm): (1) germline vs. somatic HRm; (2) core HRm (cHRm) (BRCA1, BRCA2, PALB2) vs. non-core (ncHRm); (3) zygosity (monoallelic vs. biallelic HRm). Additionally, HRD genetic signatures using large-scale state transition (LST) and signature 3 (Sig3) were evaluated. Results: Two-hundred and sixty-two patients with advanced PDAC who received care at Memorial Sloan Kettering were included. There was no difference in overall survival (OS) for patients with either germline or somatic HRm, hence they were analyzed together as HRD. Median [95% CI] follow-up among surviving patients (n=75) was 21.9 [1.4-57.0] months, median OS was 15.5 [14.6-19] months, and median progression-free survival (PFS) was 7 [6.1-8.1] months. The effect of HRD on PFS was dependent on whether the patient received 1L-platinum or not. After controlling for stage at diagnosis, patients with HRD had a reduced risk of progression or death compared to patients without HRD when treated with 1L-platnium (HR: 0.44 [95%CI: 0.29-0.67], p<0.01). Biallelic HRm and cHRm were associated with higher LST and tumor mutation burden. Sig3-positive patients were also associated with improved PFS compared to Sig3-negative patients when treated with 1L-platinum. Conclusion: Patients who have PDAC with HRD defined by HRm had better OS irrespective of 1L-platinum, although they had better PFS when treated with 1L-platinum compared to 1L-non-platinum. Among methods to identify HRD, pathogenic HR-gene mutations remain the standard when using a targeted-sequencing approach. Further investigation is warranted. Citation Format: Wungki Park, Jiapeng Chen, Joanne F. Chou, Christine Iacobuzio-Donague, Nadeem Riaz, Eileen M. O'Reilly. Genetic algorithms to identify homologous recombination deficiency (HRD) in pancreas adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3557.