Enzalutamide With or Without Vaccine Therapy for Advanced Prostate Cancer

* INCLUSION CRITERIA: * Patients must have histologically or cytologically confirmed prostate cancer confirmed by either the Laboratory of Pathology at the National Institutes of Health (NIH) Clinical Center or Walter Reed National Military Medical Center at Bethesda prior to starting this study. If no pathologic specimen is available, patients may enroll with a pathologist's report showing a histological diagnosis of prostate cancer and a clinical course consistent with the disease. * Castrate testosterone level (\<50ng/dl or 1.7nmol /L) * Metastatic disease documented by one of the following: * Metastatic bone disease on an imaging study, or * Soft tissue disease documented by computed tomography (CT)/magnetic resonance imaging (MRI), or * Progressive disease at study entry defined as one or more of the following criteria occurring in the setting of castrate levels of testosterone: i. Radiographic progression defined as any new or enlarging bone lesions or growing lymph node disease, consistent with prostate cancer OR ii. Prostate-specific antigen (PSA) progression defined by sequence of rising values separated by \>1 week (2 separate increasing values over a minimum of 2ng/ml (Prostate Cancer Clinical Trials Working Group (PCWG2) PSA eligibility criteria). If patients had been on flutamide, PSA progression is documented 4 weeks or more after withdrawal. The requirement for a 4-6 weeks 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. * Asymptomatic or mildly symptomatic from prostate cancer; no use of regularly scheduled opiate analgesics for prostate cancer-related pain * Patients must agree to continue to continuation of androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone analogue/antagonist or bilateral orchiectomy * Age greater than or equal to 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky greater than or equal to 80%). * Patients must have normal organ and marrow function as defined below: * absolute neutrophil count greater than or equal to 1,500/mcL * platelets greater than or equal to 100,000/mcL * total bilirubin within normal institutional limits; for patients with Gilbert's syndrome, total bilirubin less than or equal to 3.0mg/dL * Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transferase (SGPT) less than or equal to 2.5 times institutional upper limit of normal * creatinine within 1.5 X normal institutional limits, OR * creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal by Cockcroft-Gault Equation * 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 and 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. * Ability of subject to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: * 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 * 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, Hashimoto's thyroiditis, Crohn's or Grave's disease). Patients with type 1 diabetes mellitus or vitiligo are not excluded if the condition is well controlled. * Patients with a history of brain/leptomeningeal metastasis * Patients who have been treated with abiraterone will be excluded * 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. * 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. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to enzalutamide or poxviral vaccines (e.g., vaccinia vaccine) * Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, gentamicin or tobramycin), * History of atopic dermatitis or active skin condition (acute, chronic, exfoliative) that disrupts the epidermis * Previous adverse reactions to smallpox vaccination * Unable to avoid close contact or household contact with the following high-risk individuals for three weeks after the Day 1 vaccination: (a) children less than or equal to 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or concurrent extensive eczema or other eczematoid skin disorders, or (d) immunocompromised individuals, such as those with human immunodeficiency virus (HIV). * 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. * Patients with prior chemotherapy for nonmetastatic prostate cancer within a year are excluded. * Receipt of an investigational agent within 28 days (or 56 days for an antibody-based therapy) before the first planned dose of study drugs. (Immune checkpoint inhibitors that are antibody-based will only require 28 days before enrollment) * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension (systolic blood pressure (SBP)\>170/ diastolic blood pressure (DBP)\>105) or psychiatric illness/social situations within 12 months that would limit compliance with study requirements. * Use of herbal products that may decrease PSA levels (e.g., saw palmetto) * Any gastrointestinal disease that could hinder the absorption of enzalutamide. * Patients who have had chemotherapy for metastatic castration-resistant prostate cancer. (Patients who have had docetaxel for metastatic castration sensitive disease per Chemo-hormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) Data35 may enroll as long as they did not have progressive disease while on docetaxel and are 6 months removed from treatment, with all treatment related toxicities resolving to at least grade 1.) * Patients who have received radiation therapy, radionuclide therapy or undergone surgery within certain duration (4 weeks) of enrollment