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).
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.
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/m2) had better DCR, OS, EFS, TTPSAP, and TTRP than patients with BMI <25 kg/m2, independent of treatment arm (p < 0.009).
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.
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.
European urology oncology. 2026 Mar 19 [Epub ahead of print]
S Gillessen, K Gobat, R Cathomas, N Fischer, R Pereira Mestre, T Hermanns, S I Rothschild, N Mach, W Mingrone, M Ciriolo, B Müller, A Erdmann, C Schär, C Mamot, P Bohanes, A Omlin, S Bastian, K Ribi, L Mazzucchelli, J Barizzi, L G Horvath, T Scheinberg, R Mellor, S Schär, H-M Lin, R Lim, M Pollak, F Turco, C Rothermundt
EOC - Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland; USI - Faculty of Biomedical Sciences, Lugano, Switzerland. Electronic address: ., Competence Center of Swiss Cancer Institute (SCI), Bern, Switzerland., Division of Oncology/Hematology, Kantonsspital Graubünden, Chur, Switzerland., Department of Medical Oncology, Kantonsspital Winterthur, Winterthur, Switzerland., EOC - Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland., Department of Urology, Universitätsspital Zürich, Zürich, Switzerland., Department of Medical Oncology, Universitätsspital Basel, Basel, Switzerland; Department of Oncology/Hematology, Kantonsspital Baden, Baden, Switzerland., Department of Oncology, Hopitaux universitaires de Genève, Geneva, Switzerland., Department of Medical Oncology, Kantonsspital Olten, Olten, Switzerland., Department of Oncology/Hematology, Bürgerspital Solothurn, Solothurn, Switzerland., Department of Medical Oncology, Kantonsspital Luzern, Luzern, Switzerland., Department of Oncology/Hematology, Kantonsspital Baden, Baden, Switzerland., Competence Center of SAKK, Bern, Switzerland., Department of Medical Oncology, Kantonsspital Aarau, Aarau, Switzerland., Oncology Department, CCAC 2-Centre de Chimiothérapie Anti-cancéreuse, Lausanne, Switzerland., Department of Medical Oncology and Hematology, Kantonsspital St. Gallen, St.Gallen, Switzerland., Division of Oncology/Hematology, Kantonsspital Graubünden, Chur Switzerland., Quality of Life Office, International Breast Cancer Study Group, a Division of ETOP IBCSG Partners; Foundation, Bern; Careum School of Health, Part of the Kalaidos University of Applied Sciences, Zürich, Switzerland., EOC, Istituto Cantonale di Patologia, Locarno and USI, Università della Svizzera Italiana, Switzerland., EOC, Istituto Cantonale di Patologia, Locarno, Switzerland., Chris O'Brien Lifehouse, Sydney, Australia; University of Sydney, Sydney, Australia; Garvan Institute of Medical Research, Sydney, Australia; University of New South Wales, Sydney, Australia., Chris O'Brien Lifehouse, Sydney, Australia; University of Sydney, Sydney, Australia; Garvan Institute of Medical Research, Sydney, Australia., Chris O'Brien Lifehouse, Sydney, Australia; Garvan Institute of Medical Research, Sydney, Australia; University of New South Wales, Sydney, Australia., Competence Center of Swiss Cancer Institute (SCI), Bern Switzerland., EOC - Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland; Garvan Institute of Medical Research, Sydney, Australia., Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada., Departments of Oncology and Medicine, McGill University, Montreal, Canada., Department of Medical Oncology and Hematology, Kantonsspital St. Gallen, St. Gallen, and Luzerner Kantonsspital, Luzern, Switzerland.