Enzalutamide With or Without Vaccine Therapy for Advanced Prostate Cancer

Background: * Enzalutamide is a well-tolerated, modern androgen receptor antagonist (ARA) with more enhanced anti-tumor activity compared to previous ARAs. Phase III trial has demonstrated a 4.8 month improvement in survival and a 37% risk reduction in death in metastatic castration resistant prostate cancer (mCRPC) patients who have had previous docetaxel. * PROSTVAC is a therapeutic cancer vaccine which is designed to induce an anti-tumor immune response. In a randomized controlled Phase 2 trial, PROSTVAC (rilimogene galvacirepvec/rilimogene glafolivec) therapy was associated with a prolongation of survival by 8.5 months in men with metastatic castrate-resistant prostate cancer. An international Phase 3 trial is on-going. * Preclinical data has demonstrated that hormonal therapies such as ARAs can enhance the immune response through multiple mechanisms. Specifically, our group has shown that enzalutamide can increase thymic production of na(SqrRoot) ve T-cells, which could be activated by a cancer vaccine. Together, these data provide an important rationale to combine enzalutamide with PSA-TRICOM in mCRPC. * Data from the clinical trials with these therapies suggest that they are very well tolerated and without overlapping toxicity. Objective: -Determine if prostate-specific antigen (PSA)-TRICOM combined with enzalutamide will increase time to progression (as defined by Prostate Cancer Clinical Trials Working Group 2 criteria, incorporated in section 5.2) in chemotherapy-naive metastatic castration resistant prostate cancer patients compared to enzalutamide alone. Design: * The study will randomize chemotherapy-naive, mCRPC patients to either enzalutamide alone or enzalutamide with PSA-TRICOM. Enzalutamide will be given at the standard dose of 160 mg daily. * PSA-TRICOM will be administered identical to the Phase III dosing with vaccine given week 1 (vaccinia-PSA-TRICOM, 2x10(8) units subcutaneously) and then week 3, 5 and then monthly fowlpox-vaccine (1x10(9) units subcutaneously). * After completing 6 months of vaccine, fowlpox-vaccine (1x10(9) units subcutaneously will be administered every 3 months. Patients will be treated until radiographic progression on scans using Prostate Cancer Working Group Criteria. Eligibility: * mCRPC patients with rising PSA or progressive disease despite castration levels of testosterone. * Chemotherapy-na(SqrRoot) ve with minimal or no symptoms related to prostate cancer. * Patients with history of autoimmune disease, brain/leptomeningeal metastasis, a second malignancy within 3 years of enrollment, or a severe co-morbid condition will be excluded. * Patients who have received abiraterone will be excluded * Patients will be stratified based on previous immunotherapy used as cancer treatment.