• Pathologically proven diagnosis of adenocarcinoma of the prostate within 270 days prior to registration.

• Unfavorable intermediate risk prostate cancer, defined as having ALL the following bulleted criteria:

  • Has at least one intermediate risk factor (IRF):

    • Prostate-specific antigen (PSA) 10-20 ng/mL
    • Clinical stage tumor (T)2b-c (digital rectal exam \[DRE\] and/or imaging) by American Joint Committee on Cancer (AJCC) 8th edition
    • Gleason Score 7 (Gleason 3+4 or 4+3 \[International Society of Urological Pathology \[ISUP\] grade group 2-3])

  • Has one or more of the following "unfavorable" intermediate-risk designators:

    • > 1 IRF

    • Gleason 4+3=7 (ISUP grade group 3)

    • ≥ 50% of biopsy cores positive

      • Biopsies may include "sextant" sampling of right/left regions of the prostate, often labeled base, mid-gland and apex. All such "sextant" biopsy cores should be counted. Men may also undergo "targeted" sampling of prostate lesions (guided by MRI, ultrasound or other approaches). A targeted lesion that is biopsied more than once and demonstrates cancer (regardless of number of targeted cores involved) should count as a single additional positive core sampled and positive. In cases of uncertainty, count the biopsy sampling as sextant core(s).

    • Absence of high-risk features

• Appropriate stage based on the following diagnostic workup:

  • History/physical examination within 120 days prior to registration
  • Negative bone imaging (M0) with Tc-99m bone scan or fluciclovine (18F) sodium fluoride (NaF) positron emission tomography (PET) within 120 days prior to registration
  • Clinically negative lymph nodes (N0) as established by conventional imaging (pelvic +/- abdominal CT or MRI), within 120 days prior to registration (lymph nodes equivocal or questionable by imaging are eligible if the nodes are ≤ 1.0 cm in short axis and/or if biopsy is negative)
  • Prostate specific membrane antigen (PSMA) or fluciclovine PET negative for nodal or distant metastatic disease is an acceptable substitute for the above bone and pelvic imaging

• Age ≥ 18

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 120 days prior to registration.

• Non-castrate testosterone level (> 50 ng/dL) within 120 days prior to registration.

• Absolute neutrophil ≥ 1,000 cells/mm^3 (within 120 days prior to registration)

• Hemoglobin ≥ 10 g/dL (within 120 days prior to registration)

• Platelet count ≥ 100,000 cells/mm^3 (within 120 days prior to registration)

• Creatinine clearance (CrCl) ≥ 30 mL/min estimated by Cockcroft-Gault Equation (within 120 days prior to registration)

  • For African American patients, CrCl ≥ 30 mL/min is estimated by the alternative formula that takes race into account

• Total bilirubin: 1.5 ≤ institutional upper limit of normal (ULN) (within 120 days prior to registration)

• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)(serum glutamic-pyruvic transaminase \[SGPT\]) ≤ 2.5 × institutional ULN (within 120 days prior to registration)

• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Note: HIV testing is not required for eligibility for this protocol.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B).

• For patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

  • Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy.

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.