Inclusion Criteria

- INCLUSION CRITERIA:

A. Histopathological documentation of prostate cancer confirmed in the Laboratory of
Pathology at the National Institutes of Health (NIH) Clinical Center, or Walter Reed
National Military Medical Center prior to enrollment. If no pathologic specimen is
available, patients may enroll with a pathologist?s report showing a histologic diagnosis
of prostate cancer and a clinical course consistent with the disease.

B. Biochemical progression defined as follows:

- For patients following definitive radiation therapy: a rise in PSA of greater than or
equal to 2 ng/mL above the nadir (per RTOG-ASTRO consensus criteria).

- For patients following radical prostatectomy: rising PSA after surgical procedure.
(Patients must have a PSA greater than or equal to 2ng/ml)

C. ECOG performance status of 0-1 (Karnofsky greater than or equal to 80%).

D. Patients must have a PSA doubling time of 12 months or less. E. Patients must have a
rising PSA as confirmed by 3 values done at least 1 week apart and over no less than 1
month.

F. Recovery from acute toxicity related to prior therapy, including surgery and radiation,
or no toxicity greater than or equal to grade 2.

G. Negative CT scan/MRI and bone scan for metastatic prostate cancer.

H. Hematological eligibility parameters (within 16 days before starting therapy):

Granulocyte count greater than or equal to 1000/mm(3)

Platelet count greater than or equal to 100 000/mm(3)

Hgb greater than or equal to 10 g/dL

I. Biochemical eligibility parameters (within 16 days before starting therapy):

Hepatic function: bilirubin less than or equal to 1.5 mg/dL (OR in patients with Gilbert?s
syndrome, a total bilirubin less than or equal to 3.0), AST and ALT less than or equal to
2.5 times upper limit of normal.

J. No other active malignancies within the past 36 months (with the exception of
nonmelanoma skin cancers or carcinoma in situ of the bladder) or life-threatening
illnesses

K. Willing to travel to the NIH for follow-up visits.

L. 18 years of age or older.

M. Able to understand and sign informed consent.

N. Baseline testosterone greater than or equal to lower limit of normal.

O. PSA less than or equal to 20 ng/mL.

P. The effects of enzalutamide, PSA-TRICOM or the combination 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.

EXCLUSION CRITERIA:

A. Immunocompromised status due to:

- Human immunodeficiency virus (HIV) positivity.

- Active autoimmune diseases such as Addison's disease, Hashimoto's thyroiditis,
systemic lupus erythematosus, Sjogren syndrome, scleroderma, myasthenia gravis,
Goodpasture syndrome or active Grave's disease. Patients with a history of
autoimmunity that has not required systemic immunosuppressive therapy or does not
threaten vital organ function including CNS, heart, lungs, kidneys, skin, and GI
tract will be allowed.

- Other immunodeficiency diseases

B. Chronic administration (defined as daily or every other day for continued use greater
than 14 days) of corticosteroids deemed systemic by investigator within 28 days before the
first planned dose of PSA-TRICOM. Use of inhaled steroids, nasal sprays, and topical
creams for small body areas is allowed.

C. Serious intercurrent medical illness that, in the judgment of the investigator, would
interfere with patient's ability to carry out the treatment program.

D. History of seizure, including any febrile seizure, loss of consciousness, or transient
ischemic attack, or any condition that may pre-dispose to seizure (e.g., prior stroke,
brain arteriovenous malformation, head trauma with loss of consciousness requiring
hospitalization).

E. Other medications used for urinary symptoms including 5-alpha reductase inhibitors
(finasteride and dutasteride) and alternative medications known to alter PSA (eg
phytoestrogens and saw palmetto)

F. History of prior chemotherapy

G. History of prior immunotherapy within the last 3 years

H. Major surgery within 4 weeks prior to enrollment (Day 1 visit).

I. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to enzalutamide or poxviral vaccines (e.g., vaccinia vaccine)

J. Known allergy to eggs, egg products, aminoglycoside antibiotics (for example,
gentamicin or tobramycin).

K. History of atopic dermatitis or active skin condition (acute, chronic, exfoliative)
that disrupts the epidermis

L. Previous serious adverse reactions to smallpox vaccination

M. Unable to avoid close contact or household contact with the following highrisk
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.

N. Receipt of an investigational agent within 30 days (or 60 days for an antibodybased
therapy) before the first planned dose of study drugs.

O. Patients who test positive for HBV or HCV

P. Use of herbal products that may decrease PSA levels (e.g. saw palmetto)

Q. Any gastrointestinal disease that could hinder the absorption of enzalutamide

R. Uncontrolled hypertension (SBP> 170/ DBP> 105)