PSA progression defined by sequence of rising values separated by >1 week (2 separate increasing values over a minimum of 2ng/ml (PCWG2 PSA eligibility criteria). If patients had been on flutamide, PSA progression is documented 4 weeks or more after withdrawal. For patients on bicalutamide or nilutamide disease progression is documented 6 or more weeks after withdrawal. The requirement for a 4-6 week withdrawal period following discontinuation of flutamide, nilutamide or bicalutamide only applies to patients who have been on these drugs for at least the prior 6 months. For all other patients they must stop bicalutamide, nilutamide or flutamide the day prior to enrollment. 2.1.1.5 Asymptomatic or mildly symptomatic from prostate cancer; no use of regularly scheduled opiate analgesics for prostate cancer-related pain 2.1.1.6 Patients must agree to continue to continuation of androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone analogue/antagonist or bilateral orchiectomy 2.1.1.7 Age >18 years. 2.1.1.8 ECOG performance status <1 (Karnofsky >80%, see (APPENDIX A). 20 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 2.1.1.9 Patients must have normal organ and marrow function as defined below: absolute neutrophil count >1,500/mcL platelets >100,000/mcL total bilirubin within normal institutional limits; for patients with Gilbert’s syndrome, total bilirubin <3.0mg/dL AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal creatinine within 1.5 X normal institutional limits OR creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal by Cockcroft-Gault Equation In the equation above, the factor for “Sex” equals 0.85 for females and 1 for males 2.1.1.10 The effects of enzalutamide alone or in combination with PSA-TRICOM on the developing human fetus are unknown. For this reason, men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for three (3) months after the last dose of enzalutamide. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately. 2.1.1.11 Ability of subject to understand and the willingness to sign a written informed consent document. 2.1.2 Exclusion Criteria 2.1.2.1 Patients who are immunocompromised as listed as follows: Human immunodeficiency virus positivity due to the potential for decreased tolerance and may be at risk for severe side effects Chronic administration (defined as daily or every other day for continued use >14 days) of systemic corticosteroids (including steroid eye drops) or other immune suppressive drugs, within 28 days before the first planned dose of PSA-TRICOM. Nasal, or inhaled steroid, and topical steroid creams for small body areas are not excluded. Patients who have undergone allogeneic peripheral stem cell transplantation, or solid organ transplantation requiring immunosuppression History of splenectomy 2.1.2.2 History of, or active autoimmune disease (such as Autoimmune neutropenia, thrombocytopenia, or hemolytic anemia, systemic lupus erythematosis, Sjogrens syndrome, scleroderma, myasthenia gravis, Goodpasture’s syndrome, Addisons disease, Hashimotos thyroiditis, Crohns or Graves disease). Patients with type 1 diabetes 21 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 mellitus or vitiligo are not excluded if the condition is well controlled. 2.1.2.3 Patients with a history of brain/leptomeningeal metastasis 2.1.2.4 Patients who have been treated with abiraterone will be excluded 2.1.2.5 Patients with history of seizure as an adult including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). Also, current or prior treatment with anti-epileptic medications for the treatment of seizures or history of loss of consciousness. Also transient ischemic attack within 12 months prior to randomization will not be permitted. 2.1.2.6 Patients with second malignancy within 3 years of enrollment; Patients curatively treated non-melanoma skin cancers or carcinoma in situ of the bladder, are not excluded. 2.1.2.7 History of allergic reactions attributed to compounds of similar chemical or biologic composition to enzalutamide or poxviral vaccines (e.g., vaccinia vaccine) 2.1.2.8 Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, gentamicin or tobramycin), 2.1.2.9 History of atopic dermatitis or active skin condition (acute, chronic, exfoliative) that disrupts the epidermis 2.1.2.10 Previous adverse reactions to smallpox vaccination 2.1.2.11 Unable to avoid close contact or household contact with the following high-risk individuals for three weeks after the Day 1 vaccination: (a) children ≤ 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or concurrent extensive eczema or other eczemoid skin disorders, or (d) immunocompromised individuals, such as those with HIV. 2.1.2.12 Any condition which, in the opinion of the investigator, would prevent full participation in this trial (including the long-term follow-up), or would interfere with the evaluation of the trial endpoints.