Inclusion Criteria:

• Patients post-prostatectomy with baseline Gleason ≥ 7 (per prostatectomy pathology) and baseline PSA nadir ≥ 0.2 ng/ml obtained prior to step 1 registration
• Baseline testosterone level obtained post prostatectomy prior to step 1 registration
• Pathologically (histologically) proven diagnosis of adenocarcinoma of the prostate as confirmed at time of prostatectomy; prostatectomy must have been performed ≤ 365 days (1 year) prior to step 1 registration
• Primary treatment with radical prostatectomy
• Any type of radical prostatectomy is permitted, including retropubic, perineal, laparoscopic or robotically assisted
• Prior ablative treatment for treatment of benign prostatic hypertrophy or focal high-intensity focused ultrasound therapy (HIFU) prior to prostatectomy is allowed
• Prior androgen deprivation (luteinizing hormone-releasing hormone [LHRH] agonist and/or non-steroidal anti-androgen) is allowed if discontinued at least 90 days prior to study enrollment and given for ≤ 90 days duration; finasteride or dutasteride must be stopped before treatment but should not determine eligibility; for patients on prior LHRH analogs, the discontinuation date should be calculated based the expected duration of the sustained release injection, not simply the injection date of the drug
• Pathologically proven to be lymph node negative by pelvic lymphadenectomy (pN0) or lymph node status pathologically unknown (undissected pelvic lymph nodes [pNx])
• Any pT-stage based on American Joint Committee on Cancer 7th edition is acceptable for study entry based on the following diagnostic workup:
  • History/physical examination within 60 days prior to step 1 registration
  • No distant metastases, based upon the following minimum diagnostic workup:
  • A computed tomography (CT) scan of the abdomen and pelvis (with contrast if renal function is acceptable; a CT without contrast is permitted if the patient is not a candidate for contrast) or magnetic resonance imaging (MRI) of the pelvis within 120 days prior to step 1 registration; lymph nodes will be non-metastatic unless they measure more than 1.5 cm short axis;
  • Bone scan within 120 days prior to step 1 registration (a sodium fluoride [NaF] positron emission tomography/computed tomography [PET/CT] is an acceptable substitute); if the bone scan is suspicious, a plain x-ray, CT scan, NaF PET/CT and/or MRI must be obtained to rule out metastasis
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 within 90 days prior to step 1 registration
• Platelets ≥ 1 X 10^6 cells/mm^3 (100,000) based upon complete blood count (CBC)
• Hemoglobin ≥ 10.0 g/dl based upon CBC (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is not allowed)
• Absolute neutrophil count greater than 1.5 x 10^9/L (1500)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 1.5 x the upper limit of normal
• Total bilirubin normal unless history of Gilbert's syndrome
• The patient or a legally authorized representative must provide study-specific informed consent prior to step 1 registration
• Available surgical formalin-fixed paraffin-embedded (FFPE) specimen for genomic analysis on DECIPHER Genomic Resource Information Database (GRID) platform

Exclusion Criteria:

• Definitive clinical or radiologic evidence of metastatic disease
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 2 years) Ta bladder cancer is not considered invasive
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable if completed more than two years prior to step 1 registration; prior androgen deprivation is allowed
• Prior whole gland ablative therapy (i.e. cryoablation or high intensity focused ultrasound [HIFU]) for prostate cancer is allowed; prior focal HIFU or treatment for benign prostatic hypertrophy is allowed
• Prostatectomy performed greater than 365 days (1 year) prior to step 1 registration
• Severe and/or active co-morbidity defined as follows:
  • History of inflammatory bowel disease
  • History of active hepatitis B or C; blood tests are not required to determine if the patient has had hepatitis B or C, unless the patient reports a history of hepatitis
  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  • Transmural myocardial infarction within the last 6 months
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 1 registration
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization within 15 days of step 1 registration or precluding study therapy at the time of step 1 registration
  • Uncontrolled severe illness or medical condition (including uncontrolled diabetes), which in the judgment of the treating physician would make the administration of chemotherapy inadvisable
  • Concurrent or planned treatment with strong inhibitors (e.g. ketoconazole, clarithromycin, etcetera [etc]) or strong inducers (e.g. carbamazepine, phenytoin, rifampin, phenobarbital, efavirenz, tipranavir, St. John's wort) of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments)
• Human immunodeficiency virus (HIV) positive with cluster of differentiation 4 (CD4) count < 200 cells/microliter; note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to step 1 registration; note also that HIV testing is not required for eligibility for this protocol