Background: Preclinical models have shown that autophagy is a resistance mechanism of enzalutamide (enza), a small molecule suppressing the androgen pathway approved for treatment of CRPC. Metformin, an autophagy inhibitor, enhances preclinical therapeutic responses when combined with Enza, thus prompting a Phase I clinical trial evaluating the combination. We present results to date. Methods: Eligible patients (pts) had established CRPC, ECOG 0-2, adequate hematologic and organ function, and ≤ 2 prior treatments for CRPC. Major exclusion criteria included prior enza or metformin treatment, presence of brain metastases, history of DM2 or seizures. An initial cohort of 3 pts were treated with enza 160 mg PO qdaily and metformin 500 mg PO bid (DL1), with metformin dose escalated to 1000 mg PO bid (DL2) in subsequent 3 pts if dose-limiting toxicity (DLT) was observed in ≤1 pt in DL1. Primary objective was to establish the maximum tolerated dose (MTD), with secondary objectives of evaluating PSA response of ≥ 50%, PSA progression, and safety. Results: A total of 12 pts have been enrolled to date; mean age was 77 (range 60-95). No DLTs were observed at DL1; 1 DLT due to Grade 3 abdominal pain was observed at DL2, with an additional 6 pts subsequently enrolled in expansion. The only adverse effects ≥ Grade 3 were: syncope (1/12), hallucinations (1/12), and abdominal pain (2/12). One pt withdrew consent, 2 required dose reduction of metformin, and 1 died of progressive disease. Of 10 evaluable pts, PSA response was seen in 8 pts. Conclusions: The combination of enza 160 mg qdaily and metformin 1000 mg PO bid is safe and well-tolerated. Efficacy results to date support continued study of the combination in pts with CRPC. Clinical trial information: NCT02339168