A randomized phase II study of aromatase inhibitors plus metformin in pre-treated postmenopausal patients with hormone receptor positive metastatic breast cancer

BACKGROUND: Everolimus significantly improves progression-free survival (PFS) and has been approved to use in aromatase inhibitor pretreated patients with hormone receptor positive advanced breast cancer. Metformin has been shown to inhibit mTOR pathway, with more favorable safety profile, leading to this hypothesis-generating trial to assess whether metformin enhances the efficacy of aromatase inhibitors. METHODS: 60 postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer were randomly assigned 1:1 to aromatase inhibitor (exemestane 25mg/d or letrozole 2.5mg/d depending on the most recent treatment) plus metformin (0.5g bid, orally) or placebo. The primary endpoint was PFS, and secondary endpoints were objective response rate, clinical benefit rate, overall survival and safety. RESULTS: Median PFS was 4.7 months in the combination group and 6.0 months in the control group (hazard ratio, 1.2; 95% confidence interval [CI], 0.7 to 2.1; P =0.48). ORR was 6.7% in the combination group and 0% in the control group (odds ratio for ORR not available; P =0.99), and CBR was 33.3% and 50.0%, respectively (OR for CBR 0.5; 95% CI, 0.2 to 1.4; P=0.15). No significant difference in overall survival was observed between the combination and control groups (median OS, 30.9 vs. 32.4 months; P = 0.81). Subgroup analyses didn't find any specific population favoring the combination treatment. No substantial difference in incidence or severity of adverse events was seen between the two treatment groups. CONCLUSION: This randomized phase II clinical trial failed to show an improved efficacy with the addition of metformin to endocrine therapy, although with excellent tolerability.