This is a prospective randomized phase II clinical trial where patients who are receiving enzalutamide in the pre-chemotherapy space are randomized upon objective progression (radiographic and/or clinical per PCWG2 criteria) to docetaxel/prednisone alone or the same combination plus enzalutamide. The primary aim is to evaluate whether continuing enzalutamide in combination with docetaxel in patients who failed or progressed while on enzalutamide would increase progression-free survival (PFS) by 4 months. The secondary end points are PSA responses, percent of patients alive at 1 and 2 years, decline in circulating tumor cells (CTCs), and quality of life (QOL) using validated scales.
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Inclusion Criteria: * Willing and able to provide written informed consent and HIPAA authorization for the release of personal health information. NOTE: HIPAA authorization may be either included in the informed consent or obtained separately. * Males 18 years of age and above * Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features * Having documented disease progression on enzalutamide defined by 1 or more of the following criteria: * PSA progression according to PCWG2 criteria with 3 consecutive rising PSA measurements, all collected at least 1 week apart * Radiographic progression in soft tissue or bone by modified RECIST 1.1 for subjects with measurable disease; or * Bone disease progression defined by 2 or more new lesions on 2 consecutive bone scans in the absence of falling PSA * Patients who have not had a bilateral orchiectomy must have a plan to maintain effective GnRG-analogue therapy for the duration of the trial * Serum testosterone level \< 50 ng/dL at Screening visit * ECOG PS: 0-1 * Throughout the study, male patients and their female partners of childbearing potential must use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration. Two acceptable methods of birth control thus include the following: * Condom (barrier method of contraception even if having sex with a pregnant woman) * One of the following is required: * Established use of oral, injected, or implanted hormonal method of contraception by the female partner * Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female partner * Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female partner * Tubal litigation in the female partner * Vasectomy or other procedure resulting in infertility (eg, bilateral orchiectomy) for \>6 months * Patients must have adequate organ and marrow function as defined below * Leukocytes \>3,000/mm3 * absolute neutrophil count \>1,500/mm3 * platelets \>100,000/mm3 * total bilirubin within normal institutional limits (or \<2X the upper limit of normal in those with Gilbert's disease) * AST(SGOT)/ALT(SGPT) \<1.5 X institutional upper limit of normal * creatinine within normal institutional limits OR * creatinine clearance\* \>45 mL/min/1.73 m2 for patients with creatinine levels above institutional normal * Estimated life expectancy of \> 6 months * Able to swallow the study drug as prescribed and comply with study requirements Exclusion Criteria: * Prior treatment with docetaxel-based chemotherapy * Prior treatment with abiraterone acetate * Prior treatment with cabazitaxel * Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the patient inappropriate for enrollment * Ongoing investigational treatment * Medical conditions such as uncontrolled hypertension, uncontrolled diabetes mellitus, cardiac disease that would, in the opinion of the investigator, make this protocol unreasonably hazardous * Major surgery within 4 weeks of enrollment * Use of an investigational therapeutic agent with 4 weeks of enrollment * History of seizure or any condition that may predispose to seizure. * History of loss of consciousness or transient ischemic attack within 12 months of enrollment * Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease) within last 3 months * Grade \> 2 treatment-related toxicity from prior therapy * History of hypersensitivity to polysorbate 80 * Any known allergy to the compounds under investigation * Any other condition which, in the opinion of the Investigator, would preclude participation in this trial