This phase II trial tests how well risk based de-escalated hormone therapy (i.e., fewer treatments) with radiation works in treating patients with prostate cancer. Androgen deprivation therapy (ADT), such as gonadotropin-releasing hormone analogs (LHRH) and abiraterone acetate (Zytiga), lower the amount of the male hormone, testosterone, made by the body. This may help kill or stop the growth of tumor cells that need testosterone to grow. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Research has shown that long-term ADT is beneficial for patients with high-risk prostate cancer. However, there are few studies that determine ADT treatment based on risk factors. Giving risk based de-escalated ADT with radiation therapy may be as effective as giving more ADT in treating high-risk prostate cancer.

PRIMARY OBJECTIVE:

I. Recovery of the Expanded Prostate Cancer Index Composite (EPIC) hormonal domain to baseline levels at 2-years.

EXPLORATORY OBJECTIVES:

I. After completion of radiation therapy, determine the incidence of:

Ia. Grade 2 or greater genitourinary (GU) and gastrointestinal (GI) toxicity at 6 months (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0); Ib. Grade 3 or greater GU and GI toxicity at 6 months (CTCAE version 5.0); Ic. Patient-reported quality of life; Id. Impotence after the use of radiation therapy at 3 years; Ie. Freedom from biochemical failure (FFBF) at 5 years; If. Clinical failure: local and/or distant at 5 years; Ig. Salvage androgen deprivation use (SAD) at 5 years; Ih. Progression free survival: using clinical, biochemical and SAD as events at 5 years; Ij. Overall survival at 5 years; Ik. Disease-specific survival at 5 years. II. Determine overall GI and GU toxicity.

OUTLINE: Patients are assigned to 1 of 3 risk groups.

GROUP I (LOW RISK): Patients undergo radiation therapy to the prostate bed over 2 - 6 weeks.

GROUP II (INTERMEDIATE RISK): Patients receive ADT subcutaneously (SC) or intramuscularly (IM) for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy to the prostate bed over 2 - 6 weeks starting on week 8-10 of ADT hormone therapy.

GROUP III: (HIGH RISK): Patients receive ADT SC or IM with or without abiraterone acetate for up to 18 months in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy to identified areas over 2 - 6 weeks starting on week 8-10 of ADT hormone therapy.

Additionally, patients undergo positron emission tomography (PET), computed tomography (CT) or magnetic resonance imaging (MRI), and blood sample collection throughout the trial.

After completion of study treatment, patients are followed up at months 3 and 12, then yearly for up to year 5 followed by every 2 years.

Inclusion Criteria:

• Histologically confirmed high risk prostate adenocarcinoma
• Pathologic stages T1c-T4, N0-Nx-N1, M0-1 as staged by the pathology report (AJCC Criteria 8th Edition [Ed].)
• One or more high risk features including Gleason 8-10, T3-T4, prostate specific antigen (PSA) ≥ 20
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Patients must sign institutional review board (IRB) approved study specific informed consent
• Patients must complete all required pre-entry tests
• Patients must be at least 18 years old
• Oligometastatic prostate cancer defined as disease in up to 5 distant or regional areas (group 3 only)

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