Abstract Ovarian cancer (OC) is initially chemoresponsive but the majority of patients relapse after first line platinum-, taxane-based chemotherapy. Recurrence has been shown to be associated with increased DNA damage response (DDR) mediated by poly-(ADP)-ribose polymerase 1/2 (PARP1/2), which can be therapeutically targeted by PARP inhibitors (PARPi). Although PARPi are indicated for platinum-responsive, BRCA-mutated OC, most OC patients have BRCA-proficient disease. Based on our previous studies supporting a role for DNA methylation in chemoresistant OC, mediated by the enzyme DNA methyltransferase 1 (DNMT1), and reports on a functional role for DNMT1 in DNA double strand break repair mediated by BRCA1/2, we hypothesized that combining DNMTi and PARPi will impair BRCA-mediated DDR, resulting in cytotoxicity in OC cells. A panel of OC cell lines, including A2780 (platinum sensitive, BRCA-wild type (wt)), A2780-cp and HeyC2 (platinum resistant, BRCA-wt) and Kuramochi (platinum resistant, BRCA2 mutant) were examined for cell growth using colony formation assays after treatment with DNMTi SGI-110 (5, 20, or 100nM) and PARPi talazoparib (1 or 10nM), alone or in combination. Combination treatment schemas consisted of: 1) “priming”: SGI-110 for three days, 24 hour recovery, then talazoparib treatment on Day 5 or 2) “co-administration”: talazoparib administration on day 1 and SGI-110 treatment on days 1-3. Colony formation was inhibited by talazoparib alone in all cell lines but in a dose-dependent manner. Decreased colony formation after SGI-110 alone (20 or 100 nM) was observed only in Kuramochi cells. Combination drug treatments resulted in significant reductions in colony formation. For example, regardless of BRCA and platinum sensitivity status, co-administration of SGI-110 and talazoparib reduced (P<0.05) cell survival, albeit%survival was dependent on drug dose and OC cell line. In general, priming with SGI-110 prior to treatment with talazoparib reduced (P<0.05) survival of A2780, Kuramochi and HeyC2 (majority of combinations tested); however, decreased (P<0.05) survival of A2780-cp was observed only after priming with 100 nM SGI-110. In summary, talazoparib combined with SGI-110 displayed effective cytotoxicity in OC cell lines harboring either wt- or mutant-BRCA, indicating that this DNMTi-PARPi drug combination impairs BRCA-mediated DDR and may represent an effective treatment regimen for OC. Citation Format: Nicholas Pulliam, Pietro Taverna, John Lyons, Kenneth P. Nephew. Novel combination therapy of DNMT inhibitor SGI-110 and PARP inhibitor BMN-673 (talazoparib) for BRCA-proficient ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2943. doi:10.1158/1538-7445.AM2015-2943