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.