Laurent Villeneuve

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

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.

Feasibility of ERAS guidelines for cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (CRS-HIPEC): An international multicenter study

Enhanced Recovery After Surgery (ERAS) protocols aim to optimize perioperative care and improve recovery after major surgery. While ERAS pathways are well established in several oncologic disciplines, their feasibility and consistency in the setting of cytoreductive surgery, with or without hyperthermic intraperitoneal chemotherapy (CRS ± HIPEC), remain uncertain due to the complexity and heterogeneity of these procedures. A prospective multicenter observational study was conducted across 10 expert CRS-HIPEC centers to assess the feasibility and real-world implementation of the ERAS Society guidelines for cytoreductive surgery, with or without hyperthermic intraperitoneal chemotherapy. Perioperative practices were compared before (PRE-ERAS) and after (POST-ERAS) structured ERAS guideline implementation. ERAS adherence, clinical outcomes, and predictors of 90-day postoperative complications and prolonged length of stay were analyzed using multivariable logistic regression models. In addition, a predefined subgroup analysis compared outcomes between ovarian and non-ovarian primary tumors. Between 2021 and 2022, 497 patients were included (PRE-ERAS: 288; POST-ERAS: 209). Baseline characteristics were similar except for more ovarian primaries in POST-ERAS (26.4% vs 44%, p = 0.004). POST-ERAS patients showed higher adherence to anemia screening (60% vs 69%, p = 0.042), carbohydrate loading (4% vs 30%, p 70% ERAS adherence (OR 0.19, 95% CI 0.06-0.54, p = 0.003) predicted fewer complications. Ovarian primary (OR 0.50, 95% CI 0.28-0.87, p = 0.016), >70% adherence (OR 0.33, 95% CI 0.12-0.82, p = 0.025), and POST-ERAS status (OR 0.61, 95% CI 0.37-0.99, p = 0.046) correlated with shorter LOS. ERAS implementation for CRS ± HIPEC shortened hospital stay but remained incomplete and was associated with increased readmissions, without reducing complication rates. These findings highlight the need to focus on a pragmatic set of high-impact ERAS elements to improve feasibility in complex cytoreductive surgery.

Safety and Efficacy of Metronomic Cyclophosphamide, Metformin and Olaparib in Endometrial Cancer Patients

Endometrial cancer ranks 11th in terms of incidence (7275 / year) and mortality (2025 deaths/ year). The 5-year overall survivals of patients at diagnosis with locally advanced and metastatic carcinomas are about 50% and 15% respectively. Beyond first line treatment with platinum-based chemotherapy, there is lack of effective drug in this disease, which explains the poor prognosis of patients. The prognosis of metastatic endometrial cancer patients is poor, and few drugs have been shown to be effective beyond first chemotherapy line. Endometrial carcinomas are characterized by frequent alterations of PI3K-AKT-mTor; IGF1R and of DNA repair pathways. Phosphatase and tensin homologue (PTEN)-phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTor) and DNA repair pathways interact, and inhibition of PI3K-AKT-mTor signaling pathway may alter DNA damage repair. Metronomic cyclophosphamide regimen may increase the anti-proliferative effects of olaparib because it is an alkylating agent, and it exerts anti-angiogenic effects, with a favorable toxicity profile. Metformin may increase the anti-proliferative effects of olaparib because it downregulates IGF1R and PI3K-AKT-mTor pathways, with no additive toxicity.