Effects of adjunctive metformin on recurrence-free survival and reproductive outcomes following progestin-based fertility-sparing treatment for endometrial neoplasia: Results from the FELICIA trial, a prospective, randomized, phase IIb trial with blinded central adjudication

OBJECTIVE: Metformin is a potential anticancer agent; however, evidence of benefit in endometrial neoplasia is limited. We evaluated whether adding metformin improved the outcomes of progestin-based fertility-sparing treatment. METHODS: In this multicenter, open-label, randomized, phase IIb trial using blinded central adjudication, women aged 18-42years with an institutional diagnosis of atypical endometrial hyperplasia (AEH) or presumed stage IA grade 1 endometrioid carcinoma were assigned (1:1:1) to medroxyprogesterone acetate (MPA) alone, MPA plus metformin 750mg/day, or MPA plus metformin 1500mg/day. Central pathological review reclassified baseline specimens according to the 2020 World Health Organization criteria and adjudicated remission and recurrence. The primary endpoint was the 3-year recurrence-free survival (RFS) rate from treatment initiation. Secondary endpoints included remission, pregnancy outcomes, and safety. RESULTS: Analysis included 154 patients. Median body mass index was 24.3 (range, 15.6-57.1) kg/m2. The Kaplan-Meier estimates of the 3-year RFS rate were 44.7% with MPA alone and 44.5% with the pooled metformin groups. The prespecified log-rank test showed no significant difference (P=0.825). Remission rates were 54.0%, 58.8%, and 50.9% in the MPA-alone, metformin 750mg, and metformin 1500mg groups, respectively. Among the 57 women who attempted to conceive, pregnancy occurred in 36.8%, 57.9%, and 42.1%, and live birth in 31.6%, 52.6%, and 31.6%, respectively. Metformin increased gastrointestinal adverse events and was associated with less MPA-associated weight gain; no new safety signals emerged. CONCLUSION: Adding metformin to MPA did not improve RFS or remission rates, suggesting limited benefit in fertility-sparing treatment of endometrial neoplasia.