Patients randomized to Arm B will receive vaccines at the NIH Clinical Center. The vaccines will be prepared and placed in syringes by the Clinical Center Pharmacy personnel at the NIH. Please see section 3.1 for dose, schedule and route of administration. Dosing and administration of PSA-TRICOM will be performed in the Day Hospital. Patients will be monitored with vital signs (blood pressure, heart rate, respiratory rate, temperature) prior to and within 1 hour after the initial vaccine treatment. Patient will be monitored with vital signs prior to subsequent vaccine treatments, and will remain in the Day Hospital for at least 30 minutes following 26 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 administration of vaccine for observation of adverse reactions. (Post-vaccine vital signs will not be required except for the first vaccination.) 3.3 DOSE MODIFICATIONS/DELAYS 3.3.1 Vaccine Dose Modification: None 3.3.2 Enzalutamide Dose Modification If a patient experiences a ≥ Grade 3 non-hematologic toxicity attributable to enzalutamide or an intolerable side effect attributable to enzalutamide, withhold dosing for one week or until symptoms improve to ≤ Grade 2, then resume at the same dose if clinically appropriate. Treatment may be held if clinically appropriate as determined by the investigator and may be restarted as long as patient has not demonstrated radiographic disease progression as defined in the protocol. If toxicity recurs and or in the judgment of the investigator dose reduction is appropriate, lower dose levels (120 mg /DL-1 or 80 mg/DL-2), may be considered. 3.3.2.1 Enzalutamide Dose Delay If the planned enzalutamide dose is missed due to scheduling or logistical issues (e.g., vacation, weather) during a cycle or delay in starting a cycle, it may be started within 14 days of the appointed time. 3.3.3 Criteria for individual patient re-treatment 3.3.3.1 Patients with grade 3 non-autoimmune toxicity due to the treatment regimen, may resume treatment provided that the toxicity has decreased to baseline or grade 2 toxicity within 60 days from the last day of treatment. See section 3.6.1 Criteria for removal from protocol therapy. 3.3.3.2 Patients receiving vaccine with ≥ grade 3 autoimmune toxicity will not be treated and will be removed from study. 3.3.3.3 Patients who develop any grade 4 toxicity attributable to protocol treatment will be removed from the protocol treatment and followed for resolution of toxicity 3.3.3.4 Patients who develop grade 3 injection site reactions will have their vaccine held until injection site reaction resolves to grade 2 or less. 3.3.3.5 If a schedule vaccine dose is missed due to scheduling or logistical issues, the vaccine may be given within 14 days of the appointed time. 27 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 3.4 STUDY CALENDAR Screening and BaselineTreatment 1 cycle = 28 days; C=Cycle; D=Day D -56 to D1 C1 D1C1 D15C2 D1C3 D1C4 D1C5 D1C6 D1C7 D1C8 D1C9 D1C10+ D113End of Study Informed Consent / RegistrationX NIH Advance Directives Form11X Randomization X TREATMENT Enzalutamide1X X X X X X X X X X2 rV-PSA-TRICOM3X rF-PSA-TRICOM3X X X X X X X4 EVALUATION History and PE, Height (height only at baseline) and WeightX X X X X X X X X X X5X ECOG Performance ScoreX X X X X X X X X X X5X Pathologic confirmation of dxX6 Laboratory Testing CBC with differential12X X X X X X X X X X X5X Acute Care Panel, Mineral Panel, Hepatic Panel, LDH, CK, Uric Acid, Total Protein12X X X X X X X X X X X5X Urinalysis X Serum PSA12X X X X X X X X X X X5X Serum CEA12X 28 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 Screening and BaselineTreatment 1 cycle = 28 days; C=Cycle; D=Day D -56 to D1 C1 D1C1 D15C2 D1C3 D1C4 D1C5 D1C6 D1C7 D1C8 D1C9 D1C10+ D113End of Study Hep B/HepC, HIV X7 Lymphocyte Phenotyping TBNK12X X X X X X X X X X5X HLA testing (results not required prior to enrollment)X ECG X8 Tc 99 scintigraphy12X8X X X9 CT-C/A/P, or MRI12X8X X X9 Immunology Assays10, 12X X X Adverse Events X Concomitant MedicationsX Footnotes: 1 For patients in Arms A and B 2 Cycle length will increase from 28 days to 42 days at cycle 19 day 1. Enzalutamide 160mg p.o. daily will be given every 28 days/ cycle until cycle 19 day 1 and then every 42 days/cycle thereafter. For patients who have had stable disease beyond 2 years and no SAEs related to the treatment, patients may be followed up in clinic at intervals of 12 weeks (consistent with clinical practice.) Vaccine dosing may be adjusted to accommodate the new schedule as long as it is not given at less than a 28-day interval. 3 Only for patients randomized to Arm B (Enzalutamide + Vaccine). 4 rF-PSA-TRICOM, will be given every 12 weeks after cycle 6 day 1 (To allow for the transition between 4 and 6 week cycles at cycle 19, one dose of vaccine will be given at a 10 week interval). 5 HPE, ECOG, CBC, Chem, PSA, and Lymphocyte Phenotyping will be obtained every cycle. 29 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 6 Pathologic confirmation will be obtained any time prior to enrollment. 7 HepB/HepC/HIV status will be obtained within 8 weeks prior to enrollment. 8 Baseline ECG, Tc99 scintigraphy and CT-CAP or MRI will be obtained within 30 days prior to enrollment. 9 Restaging will be done every 12 weeks or earlier if clinically indicated. For patients who are on-study beyond 24 months who do not have a rising PSA, CT and bone scan can be deferred based on clinical judgement of the investigator. 10 After C4D1, samples may be collected prior to treatment at C13, C19, then every 6 months at restaging while on-study. 11 As indicated in section 11.3, all subjects will be offered the opportunity to complete an NIH Advance Directives form. This should be done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained.