A recorder is available during non-working hours. 2.4 BASELINE EVALUATION The following parameters will be obtained within 16 days prior to start of treatment: 2.4.1 Clinical Evaluation History and physical examination ECOG performance status (see APPENDIX A ) Height, Weight Baseline electrocardiogram (EKG) on all patients, and appropriate cardiologic evaluation, as clinically indicated, to provide baseline function and identify any patients who should be monitored closely for cardiac risks associated with vaccinia vaccination 2.4.2 Laboratory studies Complete blood count plus differential and platelet count Acute care panel Hepatic panel Mineral panel LDH, CK, Uric Acid, Total Protein urinalysis Serum PSA Serum CEA level 24 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 Lymphocyte phenotyping CD4/CD8 HLA class I expression (results will not be required prior to enrollment) 2.4.3 Leukapheresis Optional for HLA-A2 positive patients. 3 STUDY IMPLEMENTATION 3.1 STUDY DESIGN The study will randomize chemotherapy-naïve, mCRPC patients to either enzalutamide alone or enzalutamide with PSA-TRICOM. Enzalutamide will be given at the standard dose of 160 mg daily [5]. PSA-TRICOM will be administered identical to the Phase III dosing with vaccine given week 1 (vaccinia-PSA-TRICOM, 2x108 infectious units subcutaneously) and then fowlpox-vaccine (1x109 infectious units subcutaneously) given in week 3, week 5 and then every 4 weeks through week 21 [35]. After completing 6 months of vaccine, fowlpox-vaccine (1x109 infectious units subcutaneously) will be administered every 3 months based on previous clinical trial experience with PSA- TRICOM [17]. Patients will be treated until radiographic progression on scans using Prostate Cancer Working Group Criteria [23] (Response Criteria in this protocol have incorporated the Response Criteria and are discussed in section 5.3). Re-staging will be done every 3 months similar to the AFFIRM trial [ 5]. For patients who have stable disease beyond 2 years and a PSA less than 1.0 ng/ml, they can defer restaging scans, based on investigator discretion. The primary endpoint of this trial will be TTP, with secondary endpoints including overall survival, and exploratory analysis evaluating immunologic responses to vaccine with enzalutamide and to enzalutamide alone. 25 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 FOR THE FIRST 18 CYCLES OF TREATMENT: BEYOND 18 CYCLES OF TREATMENT: Beyond 18 cycles of treatment, cycle length will increase to 42 days. Patients will return for follow up every 6 weeks instead of every 4 weeks. For those patients beyond 18 cycles of treatment receiving the PROSTVAC vaccine, they will receive a dose every second cycle instead of every third cycle, however, the number of weeks between doses of vaccine will remain unchanged at 12 week intervals. (To allow for the transition between 4 and 6 week cycles, one dose of vaccine will be given at a 10 week interval). Similarly, for patients who have been on treatment more than 18 cycles, restaging scans will be every second cycle instead of every third cycle, however, the number of weeks between restaging scans will remain unchanged at 12 weeks intervals. For patients who have stable disease beyond 2 years and a PSA less than 1.0 ng/ml, they can defer restaging scans, based on investigator discretion. 3.2 ADMINISTRATION Patients who have been treated for less than 18 cycles will receive enzalutamide 160mg orally, daily on days 1 – 28 in a 28-day cycle, and will continue this dosing throughout the cycle. Patients who have been treated for more than 18 cycles will receive enzalutamide 160mg orally, daily on days 1 – 42 in a 42-day cycle, and will continue this dosing throughout the cycle. The study drug will be dispensed by the NIH Clinical Center Pharmacy.