This phase II trial studies how well hypofractionated radiation therapy works in treating participants with prostate cancer high-risk features following radical prostatectomy. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects.

PRIMARY OBJECTIVE:

I. To determine if stereotactic body radiation therapy (SBRT) would result in similar freedom from failure (FFF) than standard fractionation photon therapy.

EXPLORATORY OBJECTIVES:

I. After completion of radiation therapy, determine the incidence of grade 2 or greater genitourinary (GU) and gastrointestinal (GI) toxicity at 6 months (Common Terminology Criteria for Adverse Events [CTCAE] version 4).

II. After completion of radiation therapy, determine the incidence of grade 3 or greater GU and GI toxicity at 6 months (CTCAE version 4).

III. After completion of radiation therapy, determine the incidence of quality of life issues following completion of radiation therapy.

IV. After completion of radiation therapy, determine the incidence of impotence after the use of radiation therapy at 3 years.

V. After completion of radiation therapy, determine the incidence of freedom from biochemical failure (FFBF) at 5 years.

VI. After completion of radiation therapy, determine the incidence of clinical failure: local and/or distant at 5 years.

VII. After completion of radiation therapy, determine the incidence of salvage androgen deprivation use (SAD) at 5 years.

VIII. After completion of radiation therapy, determine the incidence of progression free survival: using clinical, biochemical and SAD as events at 5 years.

IX. After completion of radiation therapy, determine the incidence of overall survival at 5 years.

X. After completion of radiation therapy, determine the incidence of disease-specific survival at 5 years.

XI. Determine the impact of radiation therapy on quality of life. XII. Determine overall GI and GU toxicity. XIII. Determine prostate and normal structure movement during radiation therapy (RT) with the use of scans.

XIV. Correlate pathologic and radiologic findings with outcomes. XV. Correlate pre-RT prostate specific antigen (PSA) levels with outcomes. XVI. Correlate variation in proton therapy or x-ray dosimetry and outcomes. XVII. Develop a quality assurance process for prostate proton therapy. XVIII. Prospectively collect information that will help to define dose-volume relationships of normal structures with acute and chronic toxicity.

XIX. Allow for future research of pathologic risk factors that may influence prognosis; this information will help us to attempt to characterize their presence in prostate cancer with high risk features after prostatectomy and their potential effect on outcomes.

XX. Possibly compare dosimetric parameters of an IMRT plan with the proton therapy radiation plan.

OUTLINE: Participants are assigned to 1 of 3 groups.

GROUP I: Participants undergo hypofractionated radiation therapy over 15-30 minutes every other day over 2 weeks, for 5 treatments.

GROUP II: Beginning 8-10 weeks before radiation therapy, participants receive androgen suppression therapy subcutaneously (SC) or intramuscularly (IM) for up to 6 months (at the discretion of the treating physician). Participants then undergo hypofractionated radiation therapy as Group I.

GROUP III: Participants receive androgen suppression therapy as Group II for up to 18 months (at the discretion of the treating physician), then undergo hypofractionated radiation therapy over 15-30 minutes every other day over 1-2 weeks, for 1-5 treatments.

After completion of study treatment, participants are followed up at 3 and 12 months, annually for 4 years, then every 2 years thereafter.

Inclusion Criteria:

• Histologically confirmed prostate adenocarcinoma at the time of surgery
• Pathologic stages T2-T3b, N0-Nx-N1, M0-1 as staged by the pathology report (American Joint Committee on Cancer [AJCC] criteria 8th edition [Ed.])
• One or more high risk features including: seminal vesicle invasion, extracapsular extension, positive margins, or a PSA post surgery between 0.2 and < 2.0
• PSA values < 2 ng/ml within 90 days prior to enrollment. Obtained at least 6 weeks after surgery
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 assessed within 90 days of enrollment
• Patients must sign Institutional Review Board (IRB) approved study specific informed consent
• Patients must complete all required pre-entry tests within the specified time frames
• Patients must be able to start treatment (androgen suppression [AS] or radiation) within 120 days of study registration
• Members of all races and ethnic groups are eligible for this trial
• Patients from outside of the United States may participate in the study

Exclusion Criteria:

• Previous pelvic radiation
• Prior androgen suppression therapy for prostate cancer for more than 6 months
• Active rectal diverticulitis, Crohn's disease affecting the rectum or ulcerative colitis (non-active diverticulitis and Crohn's disease not affecting the rectum are allowed)
• Prior systemic chemotherapy for prostate cancer
• History of proximal urethral stricture requiring dilatation
• Current and continuing anticoagulation with warfarin sodium (coumadin), heparin, low- molecular weight heparin, Clopidogrel bisulfate (plavix), or equivalent (unless it can be stopped to manage treatment related toxicity, to have a biopsy if needed, or place markers)
• Major medical, addictive or psychiatric illness which in the investigator's opinion, will prevent the consent process, completion of the treatment and/or interfere with follow-up. (Consent by legal authorized representative is not permitted for this study)
• Evidence of any other cancer within the past 5 years and < 50% probability of a 5 year survival. (Prior or concurrent diagnosis of basal cell or non-invasive squamous cell cancer of the skin is allowed)
• History of myocardial infarction or decompensated congestive heart failure (CHF) within the last 6 months