Background: There are six agents that improve survival in mCRPC, each administered as a single agent. Combinations of agents with distinct mechanisms of action have the potential to improve outcomes. Methods: We performed a multi-institution phase I/II study to examine safety and efficacy of CAB plus ENZ with mandatory granulocyte-colony stimulating factor support in mCRPC. Results: A sample size of 3 to 12 subjects for the phase I portion and 33 for the phase II portion provided 82% power to detect PSA response rate (decrease ≥90%) of 50% compared to the null hypothesis of 24%. The main eligibility criteria allowed prior abiraterone/prednisone (AAP) and docetaxel (in the metastatic hormone sensitive setting). Baseline characteristics: median age 69 years (47 - 82), median PSA 20.2 ng/dl (0.2 - 966.3); 7 subjects had visceral disease, 10 received prior AAP, and 8 received prior docetaxel. In the phase I portion, there were no dose limiting toxicities using CAB 25 mg/m² IV Q3wks up to 10 cycles and ENZ 160 mg PO QD, hence this dosing was used for the phase II portion. 33 men with mCRPC were treated with CAB plus ENZ in the phase II arm. PSA response rates are listed in Table. Prior exposure to AAP decreased PSA response, but subjects who had prior AAP also had higher pre-treatment PSA. There were no treatment related deaths. Dose reduction of CAB to 20 mg/m² was needed in 7 subjects. Over the course of the study, 14 Grade 3 adverse events occurred that were deemed possibly related to treatment: fatigue (n=2, 6%), febrile neutropenia (n=2, 6%), leukopenia (n=2, 6%), thrombocytopenia (n=2, 6%), anemia (n=1, 3%), hypertension (n=1, 3%), leukocytosis (n=2, 6%), fracture (n=1, 3%), failure to thrive (n=1, 3%). Conclusions: CAB plus ENZ was tolerable and associated with promising anti-tumor activity, particularly in abiraterone-naïve subjects. Further evaluation of this regimen is warranted. This project was managed by the Prostate Cancer Clinical Trials Consortium and funded by Astellas Inc. and Sanofi.Clinical trial information: NCT02522715