Abstract 5495: Combination therapy with poly (ADP-ribose) polymerase inhibitor in endometrial cancer

Objective: Endometrial cancer (EC) is the most common gynecologic malignancy and serous histology is the second most common subtype. It is associated with poorer outcomes as recurrent disease tends to be resistant to chemotherapy. Given the dearth of proven targeted therapies in this setting and the tendency for serous ECs to have homologous recombination deficiency (HRD), this study aimed to test the synergy between poly (ADP-ribose) polymerase inhibitors (PARPis) and SN38, an active metabolite of DNA topoisomerase I, irinotecan. PARPis are currently FDA approved in ovarian cancer and have their greatest efficacy in tumors with HRD while topoisomerase inhibitors are a standard chemotherapy option for recurrent cancer. Methods: A genomic instability score (GIS) was derived from low-pass whole genome sequencing-based bioinformatics analysis according to three previously reported HRD metrics: telomeric allelic imbalance, large state transitions, and loss of heterozygosity. GIS was calculated for 34 patient derived xenograft (PDX) tumors, of which eight had serous histology. PARPi, rucaparib, and SN38 were used to treat EC PDX tumors in ex vivo 3D cell culture experiments using RealTime Glo for viability after 4-5 days of drug exposure. Synergy was assessed by calculating the combination index (CI) using Chou-Talalay method. Results: GIS ≥ 42 was noted in 62.5% (5/8) of serous EC PDX tumors and only 19.2% (5/26) of non-serous EC PDX tumors. Synergy (CI < 1.0) between rucaparib and SN38 was demonstrated in 85.7% (6/7) of serous EC PDX ex vivo 3D cell culture experiments, but only 62.5% (10/16) of non-serous EC PDX tumors. Conclusions: Most serous EC PDX tumors had a high GIS, consistent with HRD, when compared to a minority of non-serous histologies. Furthermore, combination therapy of rucaparib and SN38 had a synergistic effect in almost all serous EC PDX models, while still being effective in a majority of non-serous models. Additional PDX tumors need to be assessed to establish the predictive value of a GIS on synergy between rucaparib and SN38. Further in vivo studies are also needed to confirm these ex vivo findings of synergy. Ultimately, the hope is to generate preclinical data which justifies the use of PARPis in serous ECs as monotherapy or in combination with other anticancer therapies. Citation Format: Conway Xu, Xiaonan Hou, Erik Jessen, Chen Wang, S. John Weroha. Combination therapy with poly (ADP-ribose) polymerase inhibitor in endometrial cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5495.