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

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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 <25 kg/m 2 , independent of treatment arm ( p < 0.009). Conclusions and clinical implications The addition of metformin to enzalutamide did not improve the study end points in the whole study cohort. PTEN status as a potential predictive biomarker and the obesity paradox warrant further investigation. Patient summary This study found that adding the diabetes drug metformin to standard treatment with enzalutamide did not improve outcomes in men with advanced prostate cancer. However, men whose tumors express PTEN protein seemed to benefit from metformin. Interestingly, overweight/obese men lived longer than those of normal weight.

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