Background: The current first-line treatment for patients with CRPC and disease progression is either treatment with abiraterone acetate/prednisone, ENZ, or treatment with docetaxel in more symptomatic patients. There is preclinical data on synergism of ENZ and the biguanide MET: studies on mice orthotopically implanted with ENZ-resistant cells demonstrated that the combination of ENZ and clomipramine or MET significantly reduced tumor growth compared to control groups. Rothermundt et al. previously reported favorable effects of single agent MET in a phase 2 trial: objective PSA responses, disease stabilization and improvement of metabolic endpoints in patients with CRPC. Therefore addition of MET to ENZ might have positive impact on tumor progression, on body composition and insulin sensitivity. Methods: This is a prospective 1:1 randomized multicenter phase 2 trial. Primary endpoint is disease control (DC) at 15 months. Progression is defined as having 2 of the following events: radiographic progression, symptomatic/clinical progression, or PSA progression. Secondary endpoints include overall response according to modified RECIST v1.1 and PCWG2 recommendations, event-free survival, adverse events, quality of life, pain and overall survival. Translation research comprises liquid biopsy, metabolomics, hyperglycemia, and pyruvate dehydrogenase substudies. Assuming a 20% difference in the DC rate at 15 months (50% vs. 70% in the combination arm) with alpha 0.10 and power 80%, 168 patients are required in total. Eligibility criteria are as follows: asymptomatic or minimally symptomatic mCPRC (adenocarcinoma) documented by imaging, ongoing androgen deprivation therapy (ADT) with GnRH agonists or antagonists or bilateral orchiectomy, total testosterone levels ≤ 1.7 nmol/L, tumor progression at the time of registration, no prior treatment for mCRPC other than ADT, no history of diabetes and metformin use, and adequate organ function. Patients receive either ENZ 160mg qd in combination with MET 850mg bd or ENZ 160mg qd alone. 62 patients have been enrolled since accrual began in March, 2016. Clinical trial information: NCT02640534