Androgen Deprivation Therapy and Apalutamide With or Without Radiation Therapy for the Treatment of Biochemically Recurrent Prostate Cancer, RESTART Study

Inclusion Criteria

• •Histologically confirmed prostate cancer
• •Signed informed consent form (ICF) indicating that the subject understands the purpose of, and procedures required for, the study and is willing to participate in the study
• •Consent to MD Anderson laboratory protocol Lab02-152
• •Available tumor tissue sample (recently collected +/- archival)
• •Biochemically recurrent prostate cancer following definitive treatment with radical prostatectomy or / and external beam radiation therapy. Patient may have received prior androgen deprivation with or without other treatments in the neoadjuvant, adjuvant or salvage setting as long as \>= 6 months from discontinuation have elapsed at the time of randomization
• •Progression based on the following criteria:
• •* PSA progression: For patients with prior radical prostatectomy (+/- radiation), PSA progression defined by a minimum of two rising PSA levels with an interval of at least 1 week between each determination and a PSA of \>= 0.5 ng/ml at screening. For patients with only prior definitive radiation of the prostate, PSA recurrence is defined as PSA \>= nadir+2 ng/mL
• •* PSA doubling time of =\< 12 months at the time of study entry. Calculation of PSA doubling time should include the use of all available PSA values obtained within past 12 months prior to randomization, with a minimum of 3 values \>= 0.1 ng/mL PSA values obtained prior to localized therapy will be excluded. PSA doubling time to be estimated using Memorial Sloan Kettering Cancer Center online calculator
• •* Identification of up to 5 metastatic lesions or/and pelvic node recurrent sites by advanced imaging technology (PSMA PET/CT or fluciclovine PET/CT). In case of inconsistency between the two imaging modalities, up to 5 lesions in the PSMA/PET will be accepted. All sites should be eligible to be treated with definitive intent. At least one of these lesions will be histologically confirmed. Symptomatic metastatic disease or disease impending symptoms (e.g. brain metastasis, painful bone metastasis, and spine disease) can be treated with definitive local therapy prior to enrollment. This lesion will be counted towards the total number of metastatic lesions
• •Must be able to receive luteinizing hormone-releasing hormone (LHRH) agonist or antagonist during the course of the study
• •Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1
• •Must be able to swallow tablets
• •To avoid risk of drug exposure through the ejaculate (even men with vasectomies), patients must agree while on study drug and for 3 months following the last dose of study drug to:
• •* Use a condom during sexual activity
• •* Not donate sperm
• •Absolute neutrophil count (ANC) \>= 1.0 x 10\^9/L
• •Hemoglobin \>= 9.0 g/dL
• •Platelet count \>= 75 x 10\^9/L
• •Serum albumin \>= 3 g/dL
• •Calculated creatinine clearance \>= 40 mL/min using the Cockcroft-Gault equation
• •Serum total bilirubin =\<1.5 x upper limit of normal (ULN) or direct bilirubin =\< 1.5 x ULN (Note: in subjects with Gilbert's syndrome, if total bilirubin is \> 1.5 x ULN, measure direct and indirect bilirubin, and if direct bilirubin is =\< 1.5 x ULN, subject may be eligible)
• •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 3.0 x ULN
• •Testosterone \> 150 ng/dL. For patients treated with ADT with or without short-term first generation anti androgens (e.g. bicalutamide) up to 4 weeks prior to randomization, a testosterone measurement prior to the ADT treatment will be used to determine eligibility, and must have been \> 150 ng/dL. If no testosterone level is available from before luteinizing hormone-releasing hormone analogue (LHRHa) injection and within 6 weeks of randomization, the patient will be ineligible