Parp Inhibition In Combination With Pembrolizumab Enhances Cytotoxicity In Ovarian Cancer Patient-Derived 3d Spheroids

Poly(ADP-ribose) polymerase (PARP) inhibitors have shown impressive clinical activities for ovarian cancer patients with BRCA mutations and have altered the paradigm for ovarian cancer treatment. Despite the utility that PARP inhibitors provide, intrinsic and acquired resistance often limit their effectiveness as a monotherapy, and therefore combination treatment is an attractive alternative for more durable responses. Checkpoint inhibitors have shown impressive efficacy in numerous solid tumor types, but have failed to show meaningful response in ovarian cancer. The role PARP inhibitors play as immune modulators to enhance checkpoint blockade efficacy has just recently emerged indicating that their combination with checkpoint inhibitors may be beneficial over either single agent. A recent phase I/II clinical trial by researchers at the Dana-Farber Cancer Institute demonstrated niraparib in combination with pembrolizumab produced complete or partial responses in 18% of patients with recurrent platinum-resistant ovarian cancer compared to less than a 5% response rate with PARP inhibitors alone (JAMA Oncol. 2019;5(8):1141-1149). Further understanding of the immune modulatory capacity of PARP inhibitors alone and in combination with checkpoint blockade will aid in the prediction of patient response or resistance to therapy. To address this lack in knowledge, we evaluated therapeutic responses to PARP inhibitors, checkpoint inhibitors, and combinations using ovarian cancer patient-derived 3D tumor spheroids. Primary tumor samples were evaluated for PD-L1 and EpCAM expression, and tumor infiltrating lymphocyte (TILs) populations were assessed for T-cell activation and CD8+:Treg ratios. Immune-mediated antitumor activity was investigated by monitoring changes in PD-L1 and MHC class-I expression in the tumor cell populations following PARP inhibition, pembrolizumab treatment, and in combination. The effects of pembrolizumab alone and in combination for enhanced T-cell mediated tumor cell killing were also tested. PD-L1 expression was associated with response to pembrolizumab, and pembrolizumab induced tumor cell killing was T-cell dependent. Despite detection of cytotoxic activity by olaparib and pembrolizumab as single agents, increased tumor cell killing was detected when olaparib and pembrolizumab were used in combination. In summary, we detected therapy related modulation of tumor cells as well as the immune composition which results in decreased tumor spheroid viability in the presence of PARP inhibition in combination with checkpoint blockade. These results highlight the potential benefit of PARP/checkpoint inhibitor combination therapy and of patient-derived 3D spheroids as a platform to help identify subsets of cancer patients who would likely respond to immunotherapies as single agents or in combination with other approved agents. Citation Format: Kathryn M. Appleton, Ashley Elrod, Stephen Shuford, Teresa M. DesRochers. PARP inhibition in combination with pembrolizumab enhances cytotoxicity in ovarian cancer patient-derived 3D spheroids [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 2244.