Inclusion Criteria:

Men, ≥18years of age with documented asymptomatic or minimally symptomatic metastatic
castration-resistant prostate cancer.

Documented progressive disease post surgical castration or during androgen suppression
therapy, or during complete androgen blockade therapy and withdrawal. Documented by either
criterion a (Radiological progression), OR criterion b (PSA progression).

1. Radiological progression defined as any new/enlarging bone metastases or
new/enlarging lymph node disease, consistent with prostate cancer.

OR

2. PSA progression defined by sequence of rising values separated by > 1 week (2
separate increasing values) over a threshold minimum of 2.0 ng/ml. (PCWG2 PSA
eligibility criteria).

Chemotherapy naïve and Vaccinia-experienced (previous smallpox vaccination). Currently
using a GnRH agonist or antagonist (unless surgically castrated).

Exclusion Criteria:

Cancer-related pain requiring scheduled opioid narcotics for control (as needed, ≤ 2x per
week is allowed).

Metastasis to organ systems other than lymph nodes and/or bone. Estimated PSA doubling
time of <1 month as established within 6 months of the anticipated first dose of vaccine
or placebo.

Concurrent or prior Provenge (sipuleucel-T) immunotherapy for prostate cancer. Receipt of
an investigational agent within 30 days (or 60 days for an antibody-based therapy) of the
first planned dose of PROSTVAC-V/F.

History of prior malignancies other than prostate cancer within the past 3 years,
excluding successfully resected basal or squamous cell carcinoma of the skin.

Congestive heart failure (NYHA Class II, III, or IV), unstable angina, ventricular or
hemodynamically significant atrial arrhythmia, or cardiovascular disease such as stroke or
myocardial infarction (current or within the past 6 months) Confirmed positive for HIV,
hepatitis B, and /or hepatitis C. Immunodeficiency or splenectomy. History of or active
autoimmune disease, persons with vitiligo are not excluded. Diabetics are not excluded if
the condition is well controlled.

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