A Trial of Androgen Deprivation, Docetaxel, and Enzalutamide for Metastatic Prostate Cancer

Inclusion Criteria: * Histologically or cytologically confirmed adenocarcinoma of the prostate without evidence of small cell carcinoma or greater than 50% neuroendocrine differentiation. Metastatic disease must be present including soft tissue, and/or bone metastases OR nonregional lymph node involvement prior to study enrollment. If the subject has regional lymph node involvement, there must be at least one additional site of disease including visceral, non-regional nodal or skeletal metastases. * ADT with surgical castration with bilateral orchiectomy or medical castration with LHRH agonist or LHRH antagonist therapy may have been initiated no greater than 112 days (16 weeks) prior to enrollment date. Subjects who initiated ADT prior to consent, are not eligible if PSA has risen ≥ 25% and ≥ 2 ng/ml above nadir value since initiation of ADT prior to consent. * At least one PSA level of ≥ 5 ng/ml within 90 days prior to consent. * Prior ADT for non-metastatic disease with LHRH agonist or LHRH antagonist therapy in the neoadjuvant/adjuvant setting is permitted if: 1. Total duration of therapy did not exceed 36 months 2. 6 months have elapsed since completion of therapy prior to consent, 3. Serum testosterone \> 50 ng/dl within 28 days prior to reinitiation of ADT for metastatic disease 4. Prior ADT for non-metastatic disease must have accompanied definitive local therapy for curative intent. * Age ≥ 18 years. * ECOG performance status 0-2. * Adequate liver function: AST and ALT \<1.5x upper limit of normal, total bilirubin \< 1x upper limit of normal. * Adequate bone marrow function: Platelets \>100,000 cells/mm3, Hemoglobin \> 8.0g/dL and ANC \> 1,500 cells/mm3. * Adequate renal function with a creatinine clearance (based on Cockcroft-Gault formula) ≥ 30 mL/min. * Ability to understand and the willingness to sign a written informed consent document. * Able to swallow and retain oral medication Exclusion Criteria: * Personal history of seizure. * Personal history of conditions that may predispose to seizure activity including cortical cerebrovascular accident or brain trauma. * Known central nervous system metastases, including involvement of brain parenchyma and leptomeninges. * Personal history of any condition that may impair absorption of enzalutamide. * Prior or current therapy with ketoconazole, abiraterone, enzalutamide, apalutamide (ARN-509, JNJ-56021927), darolutamide (ODM-201, BAY1841788) or cytotoxic chemotherapy such as docetaxel, cabazitaxel, cyclophosphamide. * Prior therapy with bicalutamide, nilutamide or flutamide within 14 days of enrollment. * Within 28 days of major surgery and/or lack of recovery from prior surgical procedure or 14 days of palliative radiation prior to enrollment. * Prior or current therapy with an investigational agent for metastatic prostate cancer. * Known hypersensitivity to drugs formulated with polysorbate 80. * Personal history of posterior reversible encephalopathy syndrome. * CTCAE version 4.0 grade 2-4 peripheral sensory neuropathy. * Human immunodeficiency virus infection or active hepatitis B or C infection. * Uncontrolled and current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements in the opinion of the investigator. * Presence of any of the following within the previous 3 months prior to enrollment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack. * History of an additional active malignancy within 12 months prior to the date of consent (except non-melanoma skin cancer). * Current use of strong CYP2C8 inhibitors, CYP3A4 inducers or CYP3A4, CYP2C9 or CYP2C19 substrates with a narrow therapeutic range as listed in Section 7.2.1. * Any condition that requires the use of prednisone \> 10mg daily, or equivalent daily glucocorticoid dose, for greater than 14 days