Enzalutamide Plus Metformin Versus Enzalutamide Alone in Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 2 Trial (SAKK 08/14)

Background and objective The aim of our study is to determine whether the addition of metformin to enzalutamide can improve the outcomes of men with metastatic castration-resistant prostate cancer (mCRPC). Methods From 2016 to 2021, patients with mCRPC were randomized to receive enzalutamide plus metformin or enzalutamide alone, with body mass index (BMI) as a stratification factor. Primary end point was disease-control rate (DCR) at 15 mo. Secondary end points included event-free survival (EFS), time to prostate-specific antigen progression (TTPSAP) or radiologic progression (TTRP), and overall survival (OS). Post hoc analyses include tumor phosphatase and tensin homolog (PTEN)–protein expression. Key findings and limitations Enzalutamide plus metformin ( n = 84) did not increase DCR or secondary end points compared with enzalutamide alone ( n = 82; DCR 52% vs 56%, p = 0.64). Post hoc analysis suggests that addition of metformin to enzalutamide may improve TTPSAP ( p = 0.0074) in patients with PTEN-expressing tumor ( n = 64), but not in patients with PTEN-negative tumor ( n = 65, p > 0.6). Patients who were overweight/obese at baseline (BMI ≥25 kg/m 2 ) had better DCR, OS, EFS, TTPSAP, and TTRP than patients with BMI