High-grade serous ovarian cancer (HGSOC) is the most common ovarian cancer subtype. It originates from epithelial cells at the fimbrial end of the fallopian tube that seed onto the ovary and within the peritoneal cavity. Greater than 50% of HGSOC are homologous recombination deficient (HRD) as the result of mutated or epigenetically silenced genes encoding proteins including BRCA1 and BRCA2 that function in homologous recombination to repair double strand breaks. Targeting the base excision repair pathway with Poly(ADP-ribose) polymerase inhibitor (PARPi) in HRD tumours induces synthetic lethality, with PARPis shown to extend overall survival in patients with HRD ovarian cancer. HRD HGSOC cell lines COV362 (BRCA1 mutant; c.2611fs[exon11] and c.4095 +1 G>T) and OVCAR8 (hypermethylated BRCA1 promoter) are sensitive to PARPis. We have used these cell lines to create pre-clinical models of resistance to the PARPis olaparib and niraparib, generating cell lines with 2 to 7 fold increased resistance to these PARPis compared to parental cells. We then screened parental and olaparib resistant OVCAR8 cells pre-treated with olaparib (inhibitory concentration 20 (IC20)) for 48 hours, with the Tocris Epigenetics 3.0 Drug Screening Library (160 compounds) for 72h. Compounds constituting this drug library target epigenetic readers, writers, erasers and transcriptional modulators. Discoveries were validated using OVCAR8 cells made resistant to niraparib, as well as parental and PARPi (olararib and niraparib) resistant COV362 cells. Validation included cell viability of drug treated 3D bio-printed cells, clonogenic cell survival and proliferation studies, as well as cell cycle analyses, revealing a synergistic drug combination that increased sensitivity of HGSOC to PARPis. Future studies will expand analyses into an extensive panel of ovarian cancer cell lines characterised for HRD and sensitivity to PARPis to more broadly determine the potential of this synergistic drug combination to encompass targeting the epigenome to treat HGSOC.