ApalutamidePROSTATE-IQ: Parallel RandOmized STudy of Personalized Apalutamide Treatment and Evaluation to Improve Quality of Life in Post-Operative Radiation With Androgen Axis Suppression. A Phase III Multi-center Study for Men With Detectable PSA After Prostatectomy for Prostate Cancer.

Inclusion Criteria:

1. Histologically confirmed prostate cancer.
2. PSA ≥ 0.1 after radical prostatectomy.
3. Candidate for salvage radiation and ADT treatment, as determined by treating physician.
4. Age >18 at the time of consent.
5. ECOG Performance Status ≤ 2.
6. Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 90 days of registration.

System Laboratory Value

Hematological:

Platelet count (plt) = ≥ 100,000/µL

Hemoglobin (Hgb) = ≥ 9 g/dL

Renal:

eGFR = ≥ 30 mL/min using MDRD Formula

Hepatic and Other:

Bilirubin2 = ≤1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) = ≤ 2.5 x ULN Alanine aminotransferase (ALT) = ≤ 2.5 x ULN Serum Albumin = > 3.0 g/dL Serum potassium = ≥ 3.5 mmol/L 2In subjects with Gilbert's syndrome, if total bilirubin is >1.5 x ULN, measure direct and indirect bilirubin; if direct bilirubin is ≤ 1.5 x ULN, subject may be eligible.
7. Ability to understand and comply with study procedures for the entire length of the study as determined by the site investigator or protocol designee.
8. Ability to understand English or Spanish language as determined by the site investigator or protocol designee. Since the primary outcome is a questionnaire available in English and Spanish.
9. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Participants must have the ability to understand and willingness to sign the written informed consent document.

Exclusion Criteria:

1. Use of post-prostatectomy testosterone suppression prior to registration (use of GnRH agonist or antagonist, with or without an anti-androgen). However, participants with testosterone recovery after post-prostatectomy testosterone suppression are eligible (testosterone recovery defined as total testosterone > 190 ng/dL) regardless of how long their testosterone was suppressed.
2. Use of testosterone suppression prior to prostatectomy if the ArteraAI Prostate Test (Post-RP) is required to risk stratify patients (those patients with PSA ≤0.5 and no evidence of nodal involvement require ArteraAI Prostate Test (Post-RP) to stratify).
3. Confirmed extrapelvic or bone disease based on conventional imaging
4. History of any of the following:

• Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1 year prior to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy).
• Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization. Any condition that in the opinion of the investigator, would preclude participation in this study.

5. Current evidence of any of the following:

• Uncontrolled hypertension (consistently >160 systolic or >100 diastolic)
• Gastrointestinal disorder affecting absorption
• Active infection (eg, human immunodeficiency virus \[HIV\] or viral hepatitis).
• Any condition that in the opinion of the investigator, would preclude participation in this study.

6. Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

8\) Medications known to lower the seizure threshold (listed in section 5 below) must be discontinued or substituted 4 weeks prior to C1D1 of study treatment for participants on arms receiving apalutamide.