Background: The addition of docetaxel (Doc) or abiraterone to androgen deprivation therapy (ADT) in men with mCSPC improves survival. Whether the triple combination of ADT, Doc and next generation endocrine therapy further improves patient outcome is unknown. Enzalutamide (Enz) is a potent anti-androgen that has activity in the advanced, castration-resistant setting. Preclinical data support the use of Enz in combination with Doc. Enz inhibits the ABCB1 drug efflux pump implicated in Doc resistance, and Doc may eradicate Enz-resistant clones harboring the androgen receptor splice variant 7 (ARv7). The combination of Enz with Doc at standard doses was safe in the phase I setting. This study tests the hypothesis that men with newly diagnosed mCSPC may benefit from adding Enz to standard Doc and ADT. Methods: This is a phase II, single arm trial of Enz plus Doc and ADT in men with newly diagnosed mCSPC. The study is designed to enroll 39 eligible participants who must have metastatic prostate adenocarcinoma with confirmed soft tissue and/or skeletal metastasis, ECOG 0-2, and PSA ≥ 5. Subjects who previously received up to 3 years of ADT with radiation for localized disease are eligible if ADT was discontinued > 6 months before diagnosis of mCSPC and testosterone recovery is confirmed. Prior treatment with cytotoxic chemotherapy or next generation endocrine therapy is not allowed. Patients will be stratified by volume of metastatic disease. Treatment consists of Doc 75 mg/m2 IV every 3 weeks for 6 cycles and Enz 160 mg daily commencing at enrollment and continued until radiographic progression or study withdrawal. Continuous ADT is required during the study period. The primary endpoint is 12-month PSA complete response rate. Secondary endpoints include adverse events, best PSA response, radiographic objective response, time to castration resistance, progression free and overall survival. Exploratory biomarker analysis includes sequential measurement of circulating tumor cell (CTC) levels and CTC ARv7 status during study treatment. Clinical trial information: NCT03246347