Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial

Max Piffoux, Alexandra Leary, Philippe Follana, Cyril Abdeddaim, Florence Joly, Sylvie Bin, Maxime Bonjour, Anais Boulai, Celine Callens, Laurent Villeneuve, Marine Alexandre, Verane Schwiertz, Gilles Freyer, Manuel Rodrigues and Benoit You ()
Additional contact information
Max Piffoux: France; GINECO
Alexandra Leary: France; GINECO
Philippe Follana: France; GINECO
Cyril Abdeddaim: France; GINECO
Florence Joly: France; GINECO
Sylvie Bin: Hospices Civils de Lyon
Maxime Bonjour: Hospices Civils de Lyon
Anais Boulai: Institut Curie and Paris Sciences Lettres University
Celine Callens: Institut Curie and Paris Sciences Lettres University
Laurent Villeneuve: Hospices Civils de Lyon
Marine Alexandre: Hospices Civils de Lyon
Verane Schwiertz: Hospices Civils de Lyon
Gilles Freyer: France; GINECO
Manuel Rodrigues: Institut Curie
Benoit You: France; GINECO

Nature Communications, 2025, vol. 16, issue 1, 1-9

Abstract: Abstract Endometrial cancers are characterized by frequent alterations in the PI3K-AKT-mTor, IGF1 and DNA repair signaling pathways. Concomitant inhibition of these pathways was warranted. ENDOLA phase I/II trial (NCT02755844) was designed to assess the safety/efficacy of the triplet combination of the PARP inhibitor olaparib, metronomic cyclophosphamide (50 mg daily), and PI3K-AKT-mTor inhibitor metformin (1500 mg daily) in women with recurrent endometrial carcinomas. Olaparib dose-escalation (100-300 mg twice-a-day (bid)) was used to determine the recommended-phase II-trial-dose (RP2D, primary endpoint), followed by an expansion cohort to determine the non-progression rate at 10 weeks (NPR-10w, secondary endpoint). 31 patients were treated. Olaparib RP2D was defined as 300 mg bid. The tolerability was acceptable, and grade 3-4 adverse events (51% patients) were mainly hematological. The NPR-10w was 61.5%, and the median progression-free survival (mPFS) was 5.2 months. In a post-hoc analysis, when explored by molecular subtypes/alterations, longer PFS were observed in patients with tumors characterized by a non-specific-molecular-profile (NSMP, n = 4; mPFS, 9.1 months), and by both TP53 altered & high number of large genomic alterations (LGA ≥ 8)(n = 10, mPFS, 8.6 months)). The analyses about kinetics of circulating biomarkers and pharmacodynamic effects are not reported here. In total, the benefit/toxicity ratio of the all-oral olaparib/cyclophosphamide/metformin regimen was favorable in heavily pretreated patients with recurrent endometrial cancer.

Date: 2025
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DOI: 10.1038/s41467-025-56914-7

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