Background: Node-positive prostate cancer comprises for approximately 13% of newly-diagnosed patients and represents an aggressive form of the disease, but has been historically understudied in therapeutic clinical trials. Cure rates remain suboptimal for these patients with early stage IV disease, so clinical trials to intensify systemic treatment are warranted. Abiraterone and apalutamide have each demonstrated efficacy in improving metastasis-free survival and/or overall survival in the advanced stage setting, including both castrate-resistant and metastatic castration-sensitive prostate cancer. The mechanisms of action of abiraterone and apalutamide are complementary, and combination therapy has been shown in a prior Phase Ib trial to be safe and well-tolerated. Methods: Patients with pathologic node-positive disease by radical prostatectomy and who subsequently have a detectable PSA are eligible for this randomized controlled trial. All patients are required to receive molecular imaging (FACBC, PSMA, or choline PET scan) at trial entry and must have no radiographic evidence of distant metastasis in order to remain eligible. Eligible patients are randomized 1:1 to (control arm) salvage radiation therapy with 2 years of ADT vs (experimental arm) addition of 2 years of abiraterone/prednisone and apalutamide. The primary endpoint is metastasis-free survival. With a sample size of 586 and with a potential for 10% loss to follow-up, the trial has 90% power with one-sided alpha=0.025 to detect a HR of 0.53 for the experimental arm vs control arm for the primary endpoint. Secondary endpoints include quality of life (EPIC-26, EQ5D-5L, Brief Pain Inventory, PROMIS-Fatigue), overall survival, time to castrate resistance, and other disease-related outcomes. In addition, data will be collected to validate the Decipher score and PAM50-based classification as predictive biomarkers in this node-positive patient population. Trial was activated on March 5, 2020, and is currently enrolling patients. This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA196067 (NRG Oncology Specimen Bank) from the National Cancer Institute (NCI) and Janssen and GenomeDX. Clinical trial information: NCT04134260