Background: Salvage radiation therapy (sRT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). PET imaging with recently FDA-approved agents in this setting (18F-Fluciclovine, 18F-DCFPyL and 68Ga-PSMA-11), have shown improved accuracy for detection of metastases not identified with conventional imaging (CIM). Given the greater sensitivity and specificity of PET, its findings are being increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for different treatment intensification approaches. In metastatic prostate cancer, metastasis-directed RT (MDT) has been used to avoid or delay systemic therapy in men with oligometastatic disease. Apalutamide (Apa) is an androgen receptor signaling inhibitor that has been shown to improve outcomes when added to ADT in mCSPC. This study will evaluate whether patients with PET-detected lesions outside the pelvis will benefit from addition of MDT to treatment intensification with STAD/Apa, and whether patients with no PET-detected lesions outside the pelvis will benefit from addition of Apa to standard sRT/STAD. Methods: PC pts with post-RP BCR (PSA > 0.5ng/mL; > 0.2ng/mL if first detectable within 12 mos of RP) and no extrapelvic metastases on CIM who are candidates for SOC ST (sRT to prostate bed and pelvic nodes with STAD) are eligible. Pts will undergo SOC baseline PET using a FDA-approved tracer. Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic metastases). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- MDT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death, whichever occurs first. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of MDT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish a 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified logrank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish a 5-year PFS rate of 76.5% in the experimental arm from 61.5% in the control arm. Secondary endpoints include overall and event-free survival, toxicity, PET progression and quality of life. Clinical trial registry number: NCT04423211. Clinical trial information: NCT04423211.