Two Studies for Patients With Unfavorable Intermediate Risk Prostate Cancer Testing Less Intense Treatment for Patients With a Low Gene Risk Score and Testing a More Intense Treatment for Patients With a Higher Gene Risk Score, The Guidance Trial

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of adenocarcinomaof the prostate within 270 days prior to registration

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

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

• PSA 10-20 ng/mL

• Clinical stage T2b-c (digital rectal examination [DRE] and/or imaging) byAmerican Joint Committee on Cancer (AJCC) 8th edition

• Gleason score 7 (Gleason 3+4 or 4+3 [ International Society of UrologicalPathology (ISUP) Grade Group 2-3])

• Has ONE or more of the following 'unfavorable' intermediate-risk designators:

• > 1 immature reticulocyte fraction (IRF)

• Gleason 4+3=7 (ISUP Grade Group 3)

• >= 50% of biopsy cores positive

• Biopsies may include 'sextant' sampling of right/left regions of theprostate, 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 otherapproaches). A targeted lesion that is biopsied more than once anddemonstrates cancer (regardless of number of targeted cores involved)should count as a single additional positive core sampled andpositive. In cases of uncertainty, count the biopsy sampling assextant core(s)

• Absence of high-risk features

• Appropriate stage for study entry based on the following diagnostic workup:

• History/physical examination within 120 days prior to registration;

• Negative bone imaging (M0) within 120 days prior to registration; Note: Tc-99mbone scan or sodium fluoride (NaF) positron emission tomography (PET) areallowed. Equivocal bone scan findings are allowed if plain films X-ray,computed tomography (CT) or magnetic resonance imaging (MRI) are negative formetastasis at the concerned site(s). While a negative fluciclovine, choline, orprostate specific membrane antigen (PSMA) PET may be counted as acceptablesubstitute for bone imaging, any suspicious findings must be confirmed andcorrelated with conventional imaging (Tc-99m bone scan, NaF PET, CT, X-ray, orMRI) to determine eligibility based on the latter modalities (e.g. M0 based onconventional imaging modalities)

• Clinically negative lymph nodes (N0) as established by conventional imaging (pelvic +/- abdominal CT or MR), within 120 days prior to registration.Patients with lymph nodes equivocal or questionable by imaging are eligible ifthe nodes are =< 1.0 cm in short axis and/or if biopsy is negative.

Note: While a negative fluciclovine, choline, or prostate specific membrane antigen (PSMA) PET may be counted as acceptable substitute for pelvic imaging, any suspicious findings must be confirmed by conventional imaging (CT, MRI or biopsy). If the findings do not meet pathological criteria based on the latter modalities (e.g. node =< 10 mm in short axis, negative biopsy), the patient will still be eligible

• Age >= 18

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 120 daysprior 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 >= 8.0 g/dL, independent of transfusion and/or growth factors (within 120days prior to registration)

• Platelet count >= 100,000 cells/mm^3 independent of transfusion and/or growthfactors (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 specifically whose renal function is notconsidered adequate by the formula above, an alternative formula that takesrace into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPIformula) should be used for calculating the related estimated glomerularfiltration rate (GFR) with a correction factor for African American racecreatinine clearance for trial eligibility, where GFR >= 30 mL/min/1.73m^2 willbe considered adequate

• Total bilirubin: 1.5 =< institutional upper limit of normal (ULN) (within 120 daysprior to registration) (Note: In subjects with Gilbert's syndrome, if totalbilirubin is > 1.5 x ULN, measure direct and indirect bilirubin. If direct bilirubinis less than or equal to 1.5 x ULN, subject is eligible)

• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) andalanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]): =< 2.5x institutional ULN (within 120 days prior to registration)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy 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 HBVviral 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 unlessthe viral load becomes undetectable on suppressive therapy. Patients who areimmune 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 beentreated 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 unlessthe viral load becomes undetectable on suppressive therapy

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

Exclusion Criteria:

• Previous radical surgery (prostatectomy) or any form of curative-intent ablationwhether focal or whole-gland (e.g., cryosurgery, high intensity focused ultrasound [HIFU], laser thermal ablation, etc.) for prostate cancer

• Definitive clinical or radiologic evidence of metastatic disease (M1)

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease freefor a minimum of 3 years. History of or current diagnosis of hematologic malignancyis not allowed

• Prior radiotherapy to the prostate/pelvis region that would result in overlap ofradiation therapy fields

• Previous bilateral orchiectomy

• Previous hormonal therapy, such as luteinizing hormone-releasing hormone (LHRH)agonists (e.g., leuprolide, goserelin, buserelin, triptorelin) or LHRH antagonist (e.g. degarelix), anti-androgens (e.g., flutamide, bicalutamide, cyproteroneacetate). ADT started prior to study registration is not allowed

• Prior use of 5-alpha-reductase inhibitors is allowed, however, it must be stoppedprior to enrollment on the study with at least a 30 day washout period beforebaseline study PSA measure and registration

• Active testosterone replacement therapy; any replacement therapy must be stopped atleast 30 days prior to registration

• Severe, active co-morbidity defined as follows:

• Current severe or unstable angina;

• New York Heart Association Functional Classification III/IV (Note: Patientswith known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment ofcardiac function using the New York Heart Association FunctionalClassification)

• History of any condition that in the opinion of the investigator, wouldpreclude participation in this study

• Inability to swallow oral pills

• High risk features, which includes any of the following:

• Gleason 8-10 [ISUP Grade Group 4-5]

• PSA > 20

• cT3-4 by digital exam OR gross extra-prostatic extension on imaging [indeterminate MRI evidence will not count and the patient will be eligible]