Xu, Conway

e15125 Background: Endometrial cancer (EC) is the most common gynecologic malignancy, with endometrioid being the most prevalent histology. Approximately 75% of high-grade endometrioid tumors are TP53 wild-type. During studies testing a novel combination of the PARP inhibitor rucaparib and TOP1 poison SN38 in high-risk primary patient serous and serous-like ECs, a subset of non-serous ECs with normal p53 expression showed unexpected synergy. This suggests broad efficacy in EC, warranting in vivo studies to assess tolerability and efficacy. Given potential overlapping toxicity, a novel formulation, pegylated SN38 (PLX038A), was tested. Methods: Primary patient tumors (n=4) were treated with rucaparib (0µM-25 µM) and SN38 (0µM-0.5 µM) in 3D cell culture experiments. RealTime Glo assessed viability after 3-5 days of drug exposure. Combination indices were determined using the Chou-Talalay method. Tolerability and efficacy were assessed in female SCID-beige mice (n=45) injected with intraperitoneal EC PDX tumors. Mice were randomized to controls, PLX038A (15 mmol/µmol IP, every 14 days), rucaparib (150 mg/kg daily gavage), or combination (same dose and schedule) for 8 weeks. Tolerability was assessed by daily animal weight and total condition score (TCS) from 1 (emaciated, non-ambulatory) to 13 (obese). Weight change more than -20% or TCS < 5 defined moribund criteria. Weekly ultrasound measurements assessed tumor response. Results: All four primary patient tumors exhibited synergy, with a combination index less than 1. Moribund criteria were not met in any mice across all cohorts. The average percent weight change and lowest TCS across cohorts were: rucaparib (-8.51%, min/max -19 to +14%; TCS 6.25, range 5-8, n=8), PLX038A (-3.97%, min/max -19 to +5%; TCS 6.8, range 6-9, n=10), the combination (-5.52%, min/max -15 to +1.8%; TCS 7.18, range 6-8, n=11), and control (+1.61%, range -6 to +8%; TCS 6.5, range 6-7, n=4). Scores were similar between groups, but the slightly lower TCS in the rucaparib cohort was associated with higher tumor burden from ineffective therapy. Tumors in the rucaparib monotherapy group grew similarly to controls. In contrast, the combination therapy cohort exhibited significant regression below baseline during treatment. Conclusions: These findings suggest that the combination of rucaparib and SN38 (PLX038A) is effective in EC primary patient tumor organoids and PDXs with wild-type TP53. No significant negative physiological effects on animal TCS and weight change were observed. No drug-related toxicity was observed in mice receiving combination treatment. Mice receiving combination treatment displayed significant tumor regression below baseline compared to both single agents and control. These data support future exploration of this combination therapy in ECs.

Abstract 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 &lt; 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.