Highlights
- Randomized trials show metformin addition to chemotherapy does not improve progression-free or overall survival in advanced ovarian and endometrial cancers.
- Meta-analyses suggest metformin may reduce mortality and improve progression-free survival in endometrial cancer patients with type 2 diabetes but lacks preventive benefit on cancer incidence.
- Limited and inconclusive data exist regarding metformin’s role in cervical cancer and as adjunct therapy in early-stage endometrial cancer with levonorgestrel IUDs.
- Statins, not metformin, display a survival benefit in ovarian cancer per systematic reviews, underscoring the need for further clinical trials to clarify metformin’s oncologic potential.
Background
Gynecologic malignancies, including cervical, ovarian, and endometrial cancers, contribute substantially to female morbidity and mortality worldwide. Despite advances, especially in ovarian cancer therapies, overall prognosis remains poor for advanced-stage disease. Metformin, a widely used antihyperglycemic agent, has garnered interest for potential anticancer effects based on epidemiologic observations and preclinical data implicating AMPK activation, mTOR inhibition, and reduced insulin-mediated proliferation in tumor suppression. This review synthesizes evidence from clinical trials and meta-analyses (2017-2025) regarding metformin’s efficacy and safety in gynecologic cancers.
Key Content
1. Metformin in Endometrial Cancer
Randomized Controlled Trials
A pivotal NRG Oncology/GOG phase II/III RCT (PMID 40056832, 2025) evaluated metformin (850 mg BID) added to standard paclitaxel/carboplatin chemotherapy in advanced and recurrent endometrial cancer (stages III-IV and recurrent). The phase II portion suggested potential benefit, but the phase III interim analysis led to early trial termination for futility. Hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) were 0.814 (90% CI 0.635–1.043) and 1.088 (90% CI 0.803–1.475), respectively, indicating no significant advantage with metformin addition.
A 2021 phase II randomized trial (PMID 33762086) assessed levonorgestrel IUD efficacy combined with metformin (500 mg BID) or weight loss versus observation in obese women with clinical stage 1 endometrial adenocarcinoma or atypical hyperplasia. Pathological complete response rates at 6 months were similar across groups (metformin 57%, weight loss 67%, observation 61%), suggesting metformin did not enhance response rates in early-stage disease under these conditions.
Systematic Reviews and Meta-Analyses
A comprehensive 2024 meta-analysis (PMID 38246042) pooling data from 28 studies evaluated metformin’s association with incidence, mortality, and prognosis in endometrial cancer patients with type 2 diabetes mellitus (T2DM). Interestingly, metformin use was linked with a slightly increased risk of endometrial cancer incidence (HR=1.17, 95% CI 1.09–1.26). However, it significantly decreased all-cause mortality (HR=0.62, 95% CI 0.52–0.74) and improved PFS (HR=0.55, 95% CI 0.44–0.68) in this patient population. These data support a survival benefit rather than preventive efficacy. Prior meta-analyses (PMID 28760367, 2017) also corroborated metformin’s potential to reduce cellular proliferation and improve overall survival despite heterogeneity and study limitations.
2. Metformin in Ovarian Cancer
A recent randomized phase II placebo-controlled trial (PMID 39923680, 2025) assessed metformin (850 mg BID) combined with first-line platinum/taxane chemotherapy in patients with advanced ovarian cancer. The primary endpoint, PFS, showed no significant difference: median PFS was 15.4 months vs. 14.3 months for metformin and placebo arms (HR=0.87, 95% CI 0.56–1.36, p=0.31). OS was also comparable, and toxicity profiles did not differ, indicating metformin addition was safe but without clinical efficacy in this setting.
Additionally, a 2020 systematic review and meta-analysis (PMID 32317171) examining common medications including metformin in ovarian cancer survival concluded that only statin use was associated with improved survival. No significant survival benefit was evident for metformin users, possibly biased in earlier studies by immortal time bias. This underscores the current lack of robust evidence supporting metformin as an adjuvant in ovarian cancer therapy.
3. Evidence in Cervical Cancer
Limited direct clinical trial data on metformin in cervical cancer were identified within the search scope. Preclinical studies have hinted at potential anti-proliferative effects, but high-quality clinical evidence remains lacking. Future RCTs are warranted for definitive conclusions.
Expert Commentary
Metformin has biological plausibility as an anticancer agent due to its effects on metabolic and proliferative pathways; however, clinical data in gynecologic cancers present a complex picture. For endometrial cancer, meta-analyses favor survival benefits in diabetic patients but no clear preventive impact; randomized trials in advanced disease show no added benefit when combined with chemotherapy. The discrepancy may reflect confounding factors in observational studies and heterogeneity within patient populations (e.g., diabetic vs. non-diabetic). Moreover, dose, timing, and cancer stage may critically influence metformin’s effect, necessitating stratified analyses.
In ovarian cancer, recent rigorously designed RCTs negate prior observational suggestions of benefit, highlighting the need to interpret retrospective data cautiously, especially regarding immortal time biases. The absence of improved survival despite good tolerability also calls into question metformin’s utility as an anticancer adjunct in ovarian cancer.
In early-stage endometrial cancer, metformin did not improve pathological complete response rates when added to hormonal intrauterine devices, suggesting limited benefit in fertility-sparing or low-grade disease settings.
Clinically, current guidelines do not endorse metformin for gynecologic cancer treatment beyond diabetes management. Its use should be confined to well-designed clinical trials. Further research exploring molecular subsets of patients who might benefit, optimal dosing strategies, and combination with targeted agents is crucial.
Conclusion
Metformin remains a promising but unproven therapeutic adjunct in gynecologic oncology. Recent high-quality RCTs in advanced ovarian and endometrial cancers fail to demonstrate survival advantages when added to standard chemotherapy, while meta-analyses suggest mortality benefits primarily in diabetic endometrial cancer patients. No preventive role has been substantiated. Ongoing research must clarify metformin’s precise clinical utility, including patient selection and mechanistic biomarkers. Until then, metformin should not replace established treatments in gynecologic cancers.
References
- How J, et al. A randomized phase II/III study of paclitaxel/carboplatin/metformin versus paclitaxel/carboplatin/placebo as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: An NRG oncology/GOG study. Gynecol Oncol. 2025;195:66-74. doi:10.1016/j.ygyno.2025.03.003. PMID:40056832
- Buckanovich RJ, et al. Metformin for patients with advanced stage ovarian cancer: A randomized phase II placebo-controlled trial. Gynecol Oncol. 2025;194:18-24. doi:10.1016/j.ygyno.2025.02.001. PMID:39923680
- Wang Q, et al. Associations of metformin therapy treatment with endometrial cancer risk and prognosis: A systematic review and meta-analysis. Gynecol Oncol. 2024;182:15-23. doi:10.1016/j.ygyno.2024.01.007. PMID:38246042
- Schuler KM, et al. Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial. Gynecol Oncol. 2021;161(1):143-151. doi:10.1016/j.ygyno.2021.01.029. PMID:33762086
- Elsulaimani H, et al. Common medications and survival in women with ovarian cancer: A systematic review and meta-analysis. Gynecol Oncol. 2020;157(3):678-685. doi:10.1016/j.ygyno.2020.03.028. PMID:32317171
- Vargas MP, et al. Effects of metformin on endometrial cancer: Systematic review and meta-analysis. Gynecol Oncol. 2017;147(1):167-180. doi:10.1016/j.ygyno.2017.07.120. PMID:28760367
