Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis with a median overall survival (OS) less than 12 months. Using whole exome NGS, 26 (49%) pts in a 53 pt cohort had either DNA damage repair (DDR) pathway mutations (somatic and/or germline, n = 18), or isocitrate dehydrogenase 1 (IDH1) mutations (n = 8), and may have potentially benefited from PARP inhibition. Further, disruption of the mutated DDR pathways with a PARP inhibitor may result in increased mutational burden and neoantigens leading to immunogenicity, thus providing the rationale for combination with a PD-1 antibody. This phase 2 trial is designed to investigate the role of a PARP inhibitor in combination with a PD-1 antibody in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed advanced, unresectable biliary adenocarcinoma (intra- or extra-hepatic, and gallbladder) without progression after 4-6 months of 1^st line platinum-based systemic chemotherapy, measurable disease per RECIST v1.1, ECOG PS 0-1, Child-Pugh A or B7, and absence of autoimmune disease or chronic steroid use. Primary objective is to evaluate progression-free survival (PFS) rate at 4 months. Secondary objectives include evaluation of objective response rate per immune related (ir)RECIST criteria, median PFS and OS, and safety in this patient population. Exploratory objectives include identification of predictive biomarkers of response and mechanisms of resistance through serial biopsies and blood collection (pre, on and post therapy), including sequential whole exome/transcriptomic analysis with immune cell subset analysis. Treatment includes rucaparib 600 mg PO BID on days 1-28 with nivolumab 240 mg on days 1, 15 Q4 weeks. In absence of disease progression, pts may continue therapy up to 2 years. Accrual goal is 32 evaluable pts. Using a null hypothesis value of a 63% PFS rate at 4 months, and an 85% alternative hypothesis, this ongoing study has 80% power, with a one-sided alpha of 0.05 to identify treatment efficacy in the study arm. Clinical trial information: NCT03639935