Repurposing metformin as anticancer drug: Randomized controlled trial in advanced prostate cancer (MANSMED).

BACKGROUND: The proposal of metformin as an anticancer drug has been explored in many types of cancers. Metformin may act synergistically with standard prostate cancer therapies. However, there is still a debate about the effect of metformin on hormone sensitive prostate cancer (HSPC). PATIENTS AND METHODS: randomized controlled trial. Eligible patients were high risk locally advanced or metastatic HSPC. Patients were randomly assigned to receive either metformin plus standard of care or standard of care alone. The primary endpoint was castration-resistant prostate cancer-free survival (CRPC-FS). The secondary endpoints were overall survival, PSA level and adverse events. RESULTS: A total number of 124 patients underwent randomization where 62 patients were allocated in each arm. Over a median follow up of 22 months, the CRPC-FS was significantly improved with metformin (29 months, 95% CI 25-33 vs. 20 months 95% CI 16-24; P = 0.01). After subgroup analysis, the addition of metformin improved the CRPC-FS in patients with high risk localized disease (median not reached vs. 25 months, 95% CI 18-31; P = 0.02) and in patients with metastatic low tumor volume disease (median not reached vs. 15 months, 95% CI 5-25; P = 0.009). No significant difference in overall survival or PSA response in both treatment arms (P = 0.1 and 0.5, respectively). Metformin was not associated with significant adverse events apart from grade II diarrhea. CONCLUSION: Metformin is a safe and low-cost drug. Combining with androgen deprivation therapy improves the outcome in locally advanced or metastatic prostate cancer. Patients with low volume metastatic prostate cancer seem to drive more benefit.