Study Background and Disease Burden
Endometrial cancer represents one of the most common gynecologic malignancies, with a rising global incidence and significant mortality in advanced or recurrent stages. Patients with recurrent advanced/metastatic disease face limited effective therapeutic options beyond first-line treatments, and prognosis remains poor. Molecular profiling has revealed that endometrial cancers frequently harbor alterations in critical pathways including PI3K-AKT-mTOR, insulin-like growth factor 1 (IGF1), and DNA repair mechanisms. These molecular derangements drive tumor progression and confer resistance to conventional treatments. Consequently, a therapeutic strategy simultaneously targeting multiple dysregulated pathways holds promise to enhance treatment efficacy. The ENDOLA phase I/II clinical trial was thus designed to explore the combination of three agents — the PARP inhibitor olaparib, metronomic low-dose cyclophosphamide, and metformin, which acts as an inhibitor of PI3K-AKT-mTOR signaling — in women with recurrent advanced or metastatic endometrial carcinomas, aiming to improve disease control in a heavily pretreated population.
Study Design
The ENDOLA trial, registered under ClinicalTrials.gov identifier NCT02755844, employed a combined phase I/II design to evaluate safety, tolerability, and preliminary efficacy of the triplet regimen. Initially, a dose-escalation phase was conducted to define the recommended phase II dose (RP2D) of olaparib in combination with fixed doses of metronomic cyclophosphamide (50 mg daily) and metformin (1500 mg daily). Olaparib doses ranged from 100 to 300 mg administered twice daily (bid). Following the identification of RP2D, an expansion cohort evaluated the non-progression rate at 10 weeks (NPR-10w) as the secondary efficacy endpoint. Key eligibility criteria included women with histologically confirmed recurrent advanced or metastatic endometrial carcinoma who had received prior systemic therapies.
Key Findings
A total of 31 patients were treated across the dose-escalation and expansion phases. The RP2D of olaparib was established at 300 mg twice daily when combined with daily metronomic cyclophosphamide and metformin. The combination regimen demonstrated acceptable tolerability; however, grade 3-4 adverse events occurred in 51% of patients, primarily hematological toxicities such as anemia, neutropenia, or thrombocytopenia. Despite this, the safety profile was consistent with known effects of the individual agents, and the all-oral regimen was manageable in the outpatient setting.
Efficacy outcomes were encouraging in this difficult-to-treat cohort. The NPR-10w was 61.5%, indicating that nearly two-thirds of patients achieved disease stabilization or better at 10 weeks. The median progression-free survival (mPFS) was 5.2 months, notable given the heavily pretreated nature of the population.
A post-hoc analysis stratified patients by molecular subtypes and tumor genomic features to explore differential benefit. Patients with tumors displaying a non-specific molecular profile (NSMP, n=4) achieved an mPFS of 9.1 months. Similarly, patients whose tumors harbored both TP53 mutations and a high number of large genomic alterations (LGA ≥ 8, n=10) showed an mPFS of 8.6 months, suggesting particular molecular contexts in which the combination may be especially effective. These exploratory findings underscore the potential of molecular biomarkers to guide patient selection in future trials.
The study did not report detailed analyses of circulating biomarker kinetics or pharmacodynamic effects, which remain areas for further research to elucidate mechanisms of response and resistance.
Expert Commentary
The ENDOLA trial provides valuable insights into a novel combinatorial approach targeting complementary oncogenic pathways in recurrent endometrial cancer. Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, exploits tumor vulnerabilities in DNA repair defects, especially in homologous recombination deficiency contexts. Cyclophosphamide, administered metronomically at low dose, exerts immunomodulatory and antiangiogenic effects while minimizing toxicity. Metformin, widely used as an antidiabetic agent, inhibits the PI3K-AKT-mTOR axis — frequently activated in endometrial cancer — and may enhance antitumor immunity and metabolic reprogramming.
This multi-targeted strategy addresses important molecular hallmarks driving tumor progression and treatment resistance. The favorable benefit-toxicity ratio, particularly in a heavily pretreated cohort, highlights the regimen’s potential clinical relevance. Notably, the identification of NSMP and TP53/LGA genomic aberration subgroups with prolonged PFS advocates for precision oncology approaches in this heterogeneous disease.
Nevertheless, the study’s limitations include the modest sample size and absence of a randomized control arm, which restricts definitive conclusions regarding comparative efficacy. Additionally, the lack of reported biomarker dynamics and pharmacodynamic readouts prevents deeper mechanistic understanding.
Future studies should validate these findings in larger cohorts, incorporate comprehensive biomarker-driven stratification, and assess potential synergy with emerging immunotherapies or targeted agents to optimize patient outcomes.
Conclusion
The ENDOLA phase I/II trial demonstrates that the all-oral combination of olaparib, metronomic cyclophosphamide, and metformin is a feasible and active treatment option for women with recurrent advanced or metastatic endometrial cancer. The regimen’s safety profile and preliminary efficacy in a heavily pretreated population are promising. Moreover, molecular subtype analyses suggest potential predictive biomarkers to personalize therapy. This study paves the way for further biomarker-integrated randomized trials to define the role of this triplet combination within the evolving therapeutic landscape of endometrial carcinoma.
References
Piffoux M, Leary A, Follana P, Abdeddaim C, Joly F, Bin S, Bonjour M, Boulai A, Callens C, Villeneuve L, Alexandre M, Schwiertz V, Freyer G, Rodrigues M, You B. Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial. Nat Commun. 2025 Feb 20;16(1):1821. doi: 10.1038/s41467-025-56914-7. PMID: 39979249; PMCID: PMC11842746.
