Abstract A022: FAK and PARP coinhibition in maintenance therapy for homologous recombination-proficient (HRP) high grade serous ovarian cancer

Abstract High-grade serious ovarian cancer (HGSOC) is the most common subtype of ovarian cancer, accounting for the most deaths. HGSOC is diagnosed at more advanced stages; less than 40% of patients survive more than 5 years following diagnosis. Standard approach is cytoreductive surgery with chemotherapy including paclitaxel and platinum-based drugs. Homologous recombination (HR)-deficient cancers are treated additionally with PARP inhibitors, while HR-proficient cancers are treated with bevacizumab, with either drug typically extending into a maintenance therapy. More than 70% of HGSOC cases present gains in the PTK2 gene, which codes for the focal adhesion kinase (FAK) protein. FAK-targeting drugs (defactinib) are now approved in combination therapy in LGSOC. FAK plays key roles in cell adhesion, migration, and survival and is critical for angiogenesis. FAK overexpression in HGSOC is associated with chemotherapy resistance and poor patient outcome. While PARP inhibitors are used in HR-deficient cancer based on their biologic activity, we tested whether FAK inhibitors could act as a maintenance therapy in HR-proficient disease due to effects on both angiogenesis and tumor cell survival. We found that maintenance therapy with FAK inhibitor (Narmafotinib) yielded sustained suppression of disease post-chemotherapy in an HR-proficient mouse model, while PARP inhibitors (Niraparib) had no effect. Surprisingly, the use of PARP inhibitors together with FAK inhibitors in maintenance therapy yielded the most effective control of disease. In vitro, there were additive effects between narmafotinib and niraparib. Mechanistically, narmafotinib treatment impacted PARP expression, cleavage, and PARylation. Narmafotinib did not increase DNA lesions measured by gH2AX, but the intensity of individual lesions trended higher. Taken together, these results offer insight into the possible use of narmafotinib in maintenance therapy in HGSOC patients. Citation Format: Caree R. Carson, Dwayne Stupack. FAK and PARP coinhibition in maintenance therapy for homologous recombination-proficient (HRP) high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A022.