Investigation of Metformin in Patients With Castration Resistant Prostate Cancer in Combination With Enzalutamide vs. Enzalutamide Alone

Inclusion Criteria: * Written informed consent according to ICH/GCP regulations before registration and prior to any trial-related investigations * Histologically or cytological confirmed adenocarcinoma of the prostate without small cell carcinoma or small cell components * Asymptomatic or minimally symptomatic patients in relation to disease * Metastatic adenocarcinoma of the prostate documented by imaging (CT/MRI and/or bone scan) * Ongoing androgen deprivation therapy with Gonadotropin-releasing hormone GnRH analogues or bilateral orchiectomy (i.e. surgical or medical castration) * Total testosterone levels ≤ 1.7 nmol/L (corresponding to ≤ 50 ng/dL) * Tumor progression at the time of registration, defined as per protocol. * Completed baseline QoL and pain questionnaires * Male patients ≥ 18 years * WHO performance status 0-2 * Adequate hematologic values: hemoglobin ≥ 90 g/L, neutrophils ≥ 1.0 x 109/L, platelets ≥ 75 x 109/L * Adequate hepatic function: ALT and AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN (exception if Gilbert's syndrome ≤ 2.5 x ULN) * Adequate renal function: calculated creatinine clearance ≥ 50 mL/min, according to the formula of Cockcroft-Gault * Patient is able to swallow the trial drugs and comply with trial requirements * Patient agrees not to father a child during participation in the trial and during 3 months thereafter * Patient agrees to participate to the mandatory translational research part of the trial with exception of Pyruvate dehydrogenase sub-study. Exclusion Criteria: * Known or suspected Central nervous system CNS metastases or active leptomeningeal disease * Previous malignancy within 2 years prior to registration, with the exception of localized non-melanoma skin cancer and Ta and Tis bladder cancer * Prior treatment for prostate cancer with * novel endocrine agents (including abiraterone acetate, enzalutamide, TAK-700, TAK-683, TAK-448, VT464, darolutamide, apalutamide), * radioisotopes, * TKI and other small molecules, * immunotherapy, * chemotherapy (with the exception of docetaxel chemotherapy in hormone sensitive prostate cancer) * Treatment with experimental drugs or treatment within a clinical trial within 30 days prior to registration (except the clinical trial SAKK 96/12, PEACE-4 and/or the biobank project SAKK 63/12) * Clinically significant cardiovascular disease including: * Myocardial infarction within 6 months prior to registration, * Uncontrolled angina within 3 months prior to registration, * Congestive heart failure NYHA class III or IV, * QTc interval \> 480 ms, * History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes), * History of Mobitz II second or third degree heart block without a permanent pacemaker in place, * Uncontrolled hypertension as indicated by systolic blood pressure \> 170 mmHg OR diastolic blood pressure \> 105 mmHg * Severe concurrent disease, infection, or co-morbidity that, in the judgment of the investigator, would make the patient inappropriate for enrollment (e.g. uncontrolled or acute severe infection, advanced chronic obstructive pulmonary disease, heart failure) * Known history of HIV, hepatitis B, hepatitis C * Major surgery within 4 weeks prior to registration * Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within 3 months prior to registration) * Treatment with metformin within the last 6 months prior to registration * Patients on pharmacotherapy for diabetes mellitus * History of diabetic ketoacidosis, diabetic coma and pre-coma * Known history of seizures or any conditions that may predispose to seizure. History of loss of consciousness or transient ischemic attack within 12 months prior to registration * Concurrent anticoagulation with rivaroxaban or warfarin * Known hypersensitivity to the IMPs or hypersensitivity to any of their components * Any concomitant drugs contraindicated for use with the IMPs according to the Swissmedic approved product information * Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol and follow-up.