Abstract CT005: Safety and efficacy of olaparib combined to metronomic cyclophosphamide and metformin in recurrent advanced/metastatic endometrial cancer patients: ENDOLA trial
Authors: You Benoit , Leary Alexandra , Rodrigues Manuel , Follana Philippe , Abdeddaim Cyril , Joly Florence , Bin Sylvie , Villeneuve Laurent , Alexandre Marine , Boutitie Florent , Maucort-Boulch Delphine , Schwiertz Verane , Freyer Gilles 
Published: June 2022

Abstract
Objectives: In patients with recurrent advanced endometrial carcinomas (EC), innovative treatments are needed after platinum chemotherapy. EC are characterized by frequent defective DNA repair, along with alterations of PI3K-AKT-mTor, and IGF1R pathways. In preclinical studies, the activity of PARP inhibitor is increased by the inhibition of PI3K-AKT pathway. Metformin inhibits the PI3K-AKT-mTor signaling pathway, and reduces IGF1 circulating levels. Metronomic cyclophosphamide may increase the activity of PARP inhibitors through DNA alkylating and anti-angiogenic effects. ENDOLA trial was meant to assess the safety and efficacy of the triplet olaparib (PARP 1-3 inhibitor) + metronomic cyclophosphamide + metformin in patients with advanced EC
Methods: ENDOLA trial (NCT02755844) was an academic French prospective multicenter phase I/II open-label dose-escalation study meant to assess the safety, the Recommended Phase II trial Dose (RP2D), and the efficacy of olaparib combined to metronomic cyclophosphamide 50 mg PO QD and metformin 500 mg PO TID in patients with recurrent advanced EC. In the phase I part, olaparib was dose-escalated from PO 150 mg to 300 mg BID with a continual reassessment method (CRM), aiming at defining the RP2D. In the phase II part, the cohort was expanded to assess the efficacy of the triplet in terms of non-progression rate at 10 weeks (H0= 20%; H1= 50%; 1-sided α risk=0.01; power = 90%).
Results: From Sept 2016 to Nov 2019, 35 patients enrolled, and 31 were assessable (median age: 69, IQR: 62-72; endometrioid: n=18 (51.4%); serous: n=11 (35.5%); carcinosarcoma: n=2 (6.5%)). In the phase I part (17 patients), 1 DLT (5.9%) was observed: grade 3 fatigue during cycle 1 at 150 mg. Dose-escalation was possible up to 300 mg BID, that was the RP2D. In the phase II part (14 patients), the overall response rate was 20.8%, and the disease-control rate was 66.6 %. The non-progression rate at 10 weeks was 61.5% (95% CI 42.8-80.2). The median PFS was 5.1 months, including 7.5 months (5.1-8.9) for endometrioid, and 4.3 months (2.7-5.8) for serous carcinomas. Treatment-related serious adverse-events (AEs) occurred in 3 patients (grade 3 fatigue; grade 4 lymphopenia; grade 4 lymphopenia & neutropenia). The most frequent grade 3-4 treatment-related AEs were lymphopenia (32.3%); anemia (16.1%); neutropenia (16.1%); and fatigue (12.9%).
Conclusions: In heavily pre-treated patients with advanced EC, olaparib 300 mg BID could be safely combined to metformin 1500 mg/day and metronomic cyclophosphamide 50 mg/day. With a 61.5% non-progression rate at 10 weeks, the 1st-objective was reached. The 5.1 month median PFS (7.5 for endometrioid and 4.3 for serous) is promising compared to those observed with chemotherapy or immunotherapy-based combination in KEYNOTE-775 (Colombo et al. Proc ESMO 2021). Investigation in phase III is warranted.
Citation Format: Benoit You, Alexandra Leary, Manuel Rodrigues, Philippe Follana, Cyril Abdeddaim, Florence Joly, Sylvie Bin, Laurent Villeneuve, Marine Alexandre, Florent Boutitie, Delphine Maucort-Boulch, Verane Schwiertz, Gilles Freyer. Safety and efficacy of olaparib combined to metronomic cyclophosphamide and metformin in recurrent advanced/metastatic endometrial cancer patients: ENDOLA trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT005.