The purpose of this study is to describe the 2 year progression-free survival in men with recurrent PSA-only disease after prostatectomy receiving combined enzalutamide and standard androgen-deprivation therapy (ADT) with salvage radiation therapy. Eligible men will have recurrent PSA-only prostate cancer within 4 years of prostatectomy, and a PSA of 0.2 - 4 in the absence of metastatic disease on CT and bone scans. In addition to standard ADT and radiation therapy, research participants will take enzalutamide once daily for six months. It is primarily hypothesized the 2 year PFS rate will be improved with the combined therapy compared to the historical control data in a similar patients setting.

Inclusion Criteria:

• Histologically confirmed diagnosis of prostate adenocarcinoma. Variants of prostate cancer, including neuroendocrine features and small cell carcinoma of the prostate, are not permitted.
• Gleason sum of 7, 8, 9, or 10 at the time of prostatectomy.
• PSA relapse within 4 years of prostatectomy defined by persistently detectable or rising PSA after surgery.
• Evidence of disease recurrence or progression as evidenced by a PSA > 0.20. This requires 2 consecutive rises in PSA, at least 1 week apart, over the post-prostatectomy nadir or one PSA value above 0.20 ng/mL if the patient failed to achieve a post-prostatectomy nadir of < 0.2 ng/mL.
• Age ≥ 18 years
• Karnofsky performance status ≥ 70
• Adequate laboratory parameters
• Adequate bone marrow function: ANC ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hb >9g/dL
• AST/SGOT and ALT/SGPT ≤ 2.5 x Institutional Upper Limit of Normal (ULN)
• Serum bilirubin ≤ 1.5 x Institutional ULN
• Serum creatinine ≤ 1.5 x Institutional ULN or 24-hour clearance ≥ 50 mL/min
• A minimum of 4 weeks from any major surgery prior to registration.
• Ability to swallow, retain, and absorb oral medication.
• Ability to understand and the willingness to sign a written informed consent document.
• Must use a condom if having sex with a pregnant woman.
• Male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration.

Exclusion Criteria:

• Radiographic evidence of metastatic disease. Patients with node-positive disease (<2 positive nodes) at the time of radical prostatectomy are eligible. Patients with pelvic nodes up to 2 cm by short axis at the time of screening are eligible. Patients with any enlarged lymph nodes in the retroperitoneum or above the aortic bifurcation or with pelvic nodes ≥ 2 cm must be excluded.
• PSA > 4.0 ng/mL.
• Testosterone level ≤ 100 ng/dL.
• More than 1 month of prior hormone exposure or hormone exposure within 30 days of registration. Prior enzalutamide, ketoconazole, abiraterone, or TAK700 prohibited. Prior 5α reductase inhibitors are allowed.
• Prior immunotherapy including sipuleucel-T.
• Prior systemic chemotherapy (docetaxel, cabazitaxel, estramustine, other cytotoxic agents)
• History of solid organ or stem cell transplantation.
• History of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, prior head or traumatic brain injury with loss of consciousness, prior or current space-occupying lesion in the brain). Also, history of loss of consciousness or transient ischemic attack within 12 months of Day 1 visit.
• Known or suspected brain metastasis or active leptomeningeal disease.
• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of enzalutamide or increase the risk of radiation (e.g., uncontrolled nausea, vomiting, diarrhea, malabsorption syndromes, prior small bowel resection, or inflammatory bowel disease).
• Patients who have received prior prostate or pelvic radiotherapy, including external beam or brachytherapy.
• Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy prior to registration.
• Patients unable or unwilling to abide by the study protocol or cooperate fully with the investigator.

3 years