Inclusion Criteria

- INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed prostate cancer
confirmed by the Laboratory of Pathology at the 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 CT/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. 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)

- 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.

- 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

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
normal

- creatinine within 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. 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,
Hashimotos thyroiditis, Crohns or Graves 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 eczemoid skin disorders, or (d)
immunocompromised individuals, such as those with 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 30 days (or 60 days for an antibody-based
therapy) before the first planned dose of study drugs.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, uncontrolled hypertension (SBP> 170/ 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 disease.

- Patients who have received radiation therapy, radionuclide therapy or undergone
surgery within certain duration (4 weeks) of enrollment