Metformin for patients with advanced stage ovarian cancer: A randomized phase II placebo-controlled trial

Objective: The primary aim of this study was to determine if metformin, an oral biguanide administered with first-line chemotherapy and continued as maintenance therapy, improves progression-free survival (PFS) for patients with advanced-stage ovarian cancer. Methods: Patients with pathologically confirmed advanced-stage ovarian cancer undergoing primary debulking or neoadjuvant platinum-based chemotherapy followed by surgery were eligible to participate. Patients were randomized 1:1 to receive platinum/taxane-based chemotherapy with metformin 850 mg orally twice per day or placebo, followed by maintenance therapy (metformin or placebo) for two years from the date of randomization. Results: 108 evaluable patients were enrolled; 54 were randomly assigned to metformin, and 54 to placebo. Sixty-six percent (n = 71) received neoadjuvant therapy, 31 % (n = 33) primary debulking surgery, and 88 % (n = 93) had tumors of high-grade serous histology. The primary endpoint, PFS, was not significantly different between the treatment groups (1-sided p-value = 0.31; adjusted hazard ratio [HR] = 0.87, 95 % confidence interval [CI]: 0.56–1.36). Median PFS was 15.4 months (95 % CI: 11.2–23,5) for metformin and 14.3 months (95 % CI: 11.6–18.0) for placebo. Overall survival (OS) was not significantly different (2-sided p-value = 0.21; adjusted HR = 1.49, 95 % CI: 0.86–2.59), with a median of 40.7 months (95 % CI: 28.0–48.2) for metformin versus 43.8 months (95 % CI: 35.3–57.2) for placebo. The addition of metformin was well tolerated, and there were no differences in toxicity between the two groups. Conclusion: Although it was well-tolerated, adding metformin to first-line platinum/taxane-based therapy does not improve PFS or OS for patients with newly diagnosed advanced stage ovarian cancer.