STEP 0: REGISTRATION ELIGIBILITY CRITERIA

Patient must be male and >= 18 years of age

Patient must have had a radical prostatectomy (RP) as definitive therapy for histopathologically-proven prostatic adenocarcinoma

Patient must have biochemical recurrence (BCR) after RP, meeting one of the criteria below:
* PSA level of ≥ 0.2 ng/mL at any time after RP if patient had first detectable PSA within 12 months after RP. First detectable = first non-zero value reported, any value higher than the lower limit of normal for that assay
(Note: Patients with a persistent post-RP PSA reading of ≥ 0.2 ng/mL are automatically eligible).  
OR
* PSA level of ≥ 0.5 ng/mL at any time after RP if patient had first detectable PSA more than 12 months after RP. First detectable = first non-zero value reported, any value higher than the lower limit of normal for that assay.
OR
* NO minimum PSA requirement if the patient has a detectable PSA (any value higher than the lower limit of normal for that assay) at any time after RP AND has an eligible baseline SOC PET (PET1) with at least one positive lesion in any body location

Effective Addendum #11, if subjects have previously performed baseline CIM within 26 weeks prior to step 0 registration, the CIM should have no definite evidence of extrapelvic metastatic disease. (CIM is CT abdomen/pelvis or magnetic resonance imaging [MRI] abdomen/pelvis or bone scintigraphy or equivalent)
* If patient does not have previously performed baseline CIM:
** Obtaining CIM is optional if the study-eligible PET is positive for extrapelvic lesions. A low-dose CT without IV contrast obtained as the CT component of the PET/CT can be considered as CIM of sufficient diagnostic quality if the affected soft tissue or bone lesion are definitively visualized and able to be characterized anatomically. Similarly, diagnostic quality MRI obtained as part of a PET/MRI will be accepted if it is a multi-parametric MRI obtained with gadolinium intravenous contrast
** Obtaining baseline CIM is not required if the study-eligible PET is negative for extrapelvic lesions
*** NOTE: 
**** Extra-pelvic metastases are defined as extrapelvic soft tissue, lymph node and organ metastases, and/or any osseous metastases in any location; extra-pelvic is defined as superior to common iliac bifurcation, and/or outside of standard fields for prostate bed + whole pelvis nodal RT field
**** Non-osseous pelvic lesions (e.g. prostate bed, seminal vesicle, and pelvic lymph nodes (N1)) seen on CIM (CT abdomen/pelvis or MRI abdomen/pelvis) are allowed if they can be adequately encompassed within the standard salvage radiation treatment field (prostate bed + whole pelvis nodal)

Patient must be a candidate for SOC post-prostatectomy radiation therapy (RT) to the prostate bed and pelvic nodes with androgen deprivation therapy (ADT)

Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible

Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Patient must not have started short term ADT for biochemical recurrence prior to baseline PET (PET1), but may start short term ADT after PET and up to 7 days prior to study registration.
* NOTE:  A short course (e.g., ~ 4-6 weeks) of low-dose anti-androgen (e.g. bicalutamide), generally started after PET1, either before or after study registration, is also permitted as a brief temporizing measure/bridge to protocol-approved SOC short term ADT

Patient must not be actively receiving treatment in another therapeutic clinical trial

Patient must be able to lie flat and still for approximately 20-30 minutes or otherwise tolerate a PET scan and radiation treatment planning and delivery

Patients undergoing a PET/MR must meet local institutional safety guidelines for MRI

Patient must not have history of seizures or known condition that may cause predisposal to seizures (e.g., stroke or head trauma resulting in loss of consciousness) within 1 year prior to registration

Patient must not have history of inflammatory bowel disease or gastrointestinal disorder affecting absorption that is expected to increase risk of complication from radiotherapy to an unacceptable level, per institutional standard

Hemoglobin (Hgb) >= 9.0 g/dL (independent of transfusion and/or growth factors within 3 months prior to Step 0 registration) (obtained within 8 weeks prior to Step 0 registration)

Leukocytes >= 3,000/mcL (obtained within 8 weeks prior to Step 0 registration)

Absolute neutrophil count >= 1,500/mcL (obtained within 8 weeks prior to Step 0 registration)

Platelets >= 100,000/mcL (obtained within 8 weeks prior to Step 0 registration)

Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (patients with Gilbert’s syndrome, if total bilirubin is > 1.5 x ULN, must have a direct bilirubin of < 1.5 x ULN to be eligible) (obtained within 8 weeks prior to Step 0 registration)

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained within 8 weeks prior to Step 0 registration)

Creatinine < 1.5 x institutional ULN (or measured creatinine clearance > 30 mL/min) (obtained within 8 weeks prior to Step 0 registration)

Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class I or II (by patient symptoms) or A or B (by objective assessment)

Patient must not have completed a course of prior pelvic external beam radiation therapy that would overlap with SOC RT fields used in this protocol, such that normal tissue constraints cannot be met

Patient must agree not to father children while on study, as part of their radiotherapy treatment and consent

Patient must be English or Spanish speaking to be eligible for the QOL component of the study
* NOTE: Sites cannot translate the associated QOL forms

STEP 1: RANDOMIZATION ELIGIBILITY CRITERIA

Patient must have completed a baseline SOC PET/CT or PET/MR (PET1 scan) using an FDA approved radiotracer to establish presence or absence of extra-pelvic metastases on PET (positive or negative). The PET1 must have been completed after Step 0 registration and prior to Step 1 randomization OR up to 16 weeks prior to Step 0 registration

For patients with PET scan results that are negative for extra-pelvic metastases, PET-imaging status of intra-pelvic nodes must be known (positive or negative)

For patients with PET scan results that are equivocal or positive for extra-pelvic metastases [defined as any PET positive lesions outside of standard salvage RT fields (prostate bed +/- typical whole pelvis)], the disease site of extra-pelvic metastases [lymph node site(s) only vs any non-lymph node site(s)] must be known
* NOTE: A lesion seen on PSMA PET should be considered positive if felt at least likely secondary to prostate cancer (e.g. PSMA-Reporting and Data System [RAD] score 3 or higher)

PRIMARY OBJECTIVES:
I. For patients without PET-evidence of extrapelvic metastases, to evaluate whether the addition of enhanced systemic therapy to standard of care (SOC) salvage radiation therapy (RT) could prolong progression-free survival (PFS).
II. For patients with PET-evidence of extrapelvic metastases, to evaluate the distribution of PFS in each arm.

SECONDARY OBJECTIVES:
I. To evaluate overall survival in each arm.
II. To evaluate event-free survival in each arm.
III. To evaluate time to prostate-specific antigen (PSA) progression in each arm.
IV. To assess the incidence of adverse events with the addition of enhanced systemic therapy in patients without PET-evidence of extrapelvic metastases.
V. To assess the incidence of adverse events with local ablative metastasis-directed RT for PET-positive metastatic disease in patients with PET-evidence of extrapelvic metastases.
VI. To estimate the detection rate of baseline PET at the patient and regional level, and to evaluate its concordance with the follow-up imaging at time of PSA progression or radiologic progression as outlined (whichever occurs first).
VII. To determine the distribution of PET-positive lesions among anatomic sites (prostate fossa, intrapelvic soft tissue/lymph node, extrapelvic soft tissue/lymph node, and bone metastases) in patients with post-radical prostatectomy (RP) biochemical recurrence (BCR), correlated with PSA and other relevant clinical parameters.

EXPLORATORY OBJECTIVE:
I. To determine the value of repeat PET (PET2) at time of second PSA progression or 12 months after completion of enhanced systemic therapy, whichever comes first to assess response to therapy (enhanced systemic therapy +/- focal RT and/or androgen deprivation therapy [ADT]) compared to available standard response assessments (PSA and/or any available conventional imaging modalities [CIM]).
 
QUALITY OF LIFE (QOL) PRIMARY OBJECTIVES:
I. To compare overall quality of life, measured by Functional Assessment of Cancer Therapy- Prostate (FACT-P) total score, at 6 months between arms A and B.
II. To evaluate the distribution of overall quality of life, measured by FACT-P total score, at 6 months in arms C and D.

QOL SECONDARY OBJECTIVES:
I. To compare the change in overall QOL, measured by FACT-P total score, from baseline to 6 months between arms A and B.
II. To compare patient-reported fatigue (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue scores) at 6 months between arms A and B.
III. To compare patient-reported overall QOL (FACT-P scores), fatigue (FACIT-Fatigue scores) and pain interference (Patient Reported Outcomes Measurement Information System [PROMIS] Pain Interference Short Form 4a) between arms A and B at the time of disease progression.

QOL EXPLORATORY OBJECTIVES:
I. To compare cognitive function, measured by FACT-Cognitive Function (Cog) PCI and total scores, between the three treatment arms receiving enhanced systemic treatment with ADT and apalutamide (Arms B, C, and D) and ADT alone (Arm A) at 6 and 12 months.
II. To compare the change in cognitive function, measured by change in FACT-Cog PCI and total scores, from baseline to 6 and baseline to 12 months, between the three treatment arms receiving enhanced systemic treatment with ADT and apalutamide (Arms B, C, and D) and ADT alone (Arm A) at 6 and 12 months.
III. To characterize longitudinal change in cognitive function between baseline and 24 months in patients with prostate cancer receiving treatment for BCR and define clinical and disease related characteristics associated with greater cognitive change by the FACT-Cog PCI and total scores.

OUTLINE: 

STEP 0: Patients undergo SOC PET/computed tomography (CT) or PET/MR scan at baseline. A subset of patients randomized to Arms C or D and receiving fluciclovine F18 intravenously (IV) or flotufolastat F-18 gallium IV undergo a repeat PET2 at time of PSA progression or clinical concerns for progression or 12 months after completion of enhanced systemic therapy, whichever occurs first. Patients in Arm C or D using any other Food and Drug Administration (FDA)-approved tracer for PET1 do not undergo PET2. 

STEP 1: Patients are randomized to 1 of 4 arms based on results of PET/CT or PET/MR in Step 0.

ARM A (PET NEGATIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC external beam radiation therapy (EBRT) for 6 months. Patients also receive goserelin acetate subcutaneously (SC), leuprolide acetate intramuscularly (IM), triptorelin IM, relugolix orally (PO), or degarelix SC for 6 months starting anytime between 7 days prior to Step 0 Registration and 14 days after Step 1 Randomization. All treatment continues for 6 months in the absence of disease progression or unacceptable toxicity.

ARM B (PET NEGATIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix PO, or degarelix SC as in Arm A. Patients also receive apalutamide PO once daily (QD) for 6 months in the absence of disease progression or unacceptable toxicity.

ARM C: (PET POSITIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix PO, or degarelix SC as in Arm A. Patients also receive apalutamide PO QD as in Arm B.

ARM D (PET POSITIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix PO, or degarelix SC as in Arm A and apalutamide PO QD as in Arm B. Patients also undergo stereotactic body radiation therapy (SBRT) or 3-dimensional (3D) conformal radiation therapy (CRT), intensity-modulated radiation therapy (IMRT) (including volume modulated arc therapy [VMAT]), and intensity-modulated proton therapy (IMPT) over 3-10 fractions in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for the first 2 years, every 6 months for years 3-5, and then annually for years 5-10.