This phase III trial studies how well hypofractionated radiation therapy works compared to the conventional one in treating patients with prostate cancer. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. 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 assess the gastrointestinal (GI) and genitourinary (GU) toxicities in patients treated with hypo-fractionated postoperative radiotherapy relative to the conventional postoperative radiotherapy.

SECONDARY OBJECTIVES:

I. To report patient outcome to include local control, loco-regional control, distant metastases, biochemical progression-free survival, prostate-cancer specific survival (PCSS), time to salvage therapy.

Ia. To compare freedom from biochemical failure (FFBF) and time to progression (TTP) with definition of post prostatectomy nadir + 2 ng/mL in both treatment arms.

II. To evaluate patient reported quality of life outcomes with hypo-fractionated compared to standard fractionated postoperative radiotherapy using validated surveys (Expanded Prostate Cancer Index Composite [EPIC]-26, Short Form [SF]-12, EuroQol 5 dimensional [EQ-5D]) and use of erectile dysfunction medications/devices.

III. To compare patient reported GU symptoms using the Common Terminology Criteria for Adverse Events (CTCAE) version 5 (specifically GU symptoms) and quality of life reports with EPIC-26, SF-12, EQ-5D survey at end of radiation therapy (RT), 6, 12, 24 and up to 60 months from the end of radiation therapy.

IV. To compare patient reported GI symptoms using CTCAE version 5 (specifically GI symptoms) and quality of life reports with the EPIC-26 SF-12, EQ-5D survey at end of RT, 6, 12, 24, and up to 60 months from the end of radiation therapy.

V. To report health economics with cost and time based driven activity (TDABC) in delivering shorter hypofractionated courses of radiotherapy compared to standard course (indirect and direct cost).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo conventional radiation therapy daily over 7 weeks after standard of care surgery.

ARM II: Patients undergo hypofractionated radiation therapy over 4.5 weeks after standard of care surgery.

After completion of study treatment, patients are followed up at 3-6 months, and then every 6-12 months for up to 5 years.

Inclusion Criteria:

• Men age 18 or older
• Patient has diagnosis of pathologically confirmed prostate cancer, treated with radical prostatectomy. Any type of radical prostatectomy will be permitted, including retropubic, perineal, laparoscopic, or robotically assisted
• Patient has pathologic T2-T3M0 stage. Patients can have 5 or less metastatic pelvic lymph nodes confirmed by pathology
• For patients radiated in the post-operative salvage setting: pathology can demonstrate any of the following features but not required, positive margin, extracapsular extension, or seminal vesicle involvement with detectable prostate-specific antigen (PSA) of >= 0.1. PSA >= 0.1 after radical prostatectomy: most recent PSA value within 12 months of registration and prior to initiating any androgen deprivation therapy (ADT)
• Patient diagnosed with Gleason score of 6-10
• Eastern Cooperative Oncology Group (ECOG) performance 0-2
• Patients may receive 6 months and up to 24 months of androgen deprivation therapy. Patients may have received androgen deprivation therapy up to 12 months prior to postoperative radiotherapy
• If the patient has a prior history of any cancer other than prostate cancer, he must have completed treatment within 1 year of study registration and the patient must have no evidence of disease of this prior non-prostate cancer

Exclusion Criteria:

• Prior radiation therapy to prostate/seminal vesicle fossa or postoperative region
• Neoadjuvant chemotherapy before or after prostatectomy
• History of lupus, scleroderma, or calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST) syndrome
• History of severe active co-morbidity or uncontrolled diabetes
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
• Transmural myocardial infarction within the last 6 months
• Severe hepatic disease, defined as a diagnosis of Child-Pugh class B or C hepatic disease
• End-stage renal disease (i.e., on dialysis or dialysis has been recommended)