The metastatic capacity of prostate cancer (PCa) behaves along a spectrum of disease that contains an oligometastatic state where metastases are limited in number and location. The importance of radiation consolidation of all tumor deposits in oligometastatic PCa to forestall further metastatic dissemination is now backed by small randomized studies in the recurrent setting, but the utility in the de novo space is unknown. Our Baltimore ORIOLE randomized trial of stereotactic ablative radiation (SABR) alone, highly focused, high-dose radiation, versus observation in oligometastatic PCa demonstrated a progression-free survival (PFS) benefit of SABR alone. Furthermore, using state-of-the-art genomic profiling techniques we demonstrated that radiation resulted in a systemic immune response that could possibly predict patient benefit from SABR. Total consolidative radiation approaches have not been tested in the de novo oligometastatic space for PCa. Thus, we propose this first-in-man opportunity to understand the interplay between micrometastatic disease and the primary PCa following radiation consolidation of macroscopic disease has the potential to: (1) uncover novel radiobiology implications on the metastatic process; and (2) provide a curative paradigm for patients with de novo oligometastatic PCa. For this proposal, we will leverage resources from a soon to be activated randomized trial of total radiation consolidation for de novo oligometastatic men – Phase 2 randomized Total Eradication of metastatic lesions following definitive Radiation to the Prostate in de novo oligometaStatic prostate cancer (TERPS) trial. TERPS is a phase II non-blinded, randomized 1:1 trial of men with de novo oligometastatic PCa treated with best systemic therapy (BST) + primary prostate radiation (XRT) versus BST+XRT+ stereotactic ablative radiation metastasis-directed therapy (SABR MDT). Now, strategies to define the patients who may benefit the most from SABR metastasis-directed therapy (MDT) are needed using biomarkers. This current U54 ROBIN Oligometastasis (ROBIN OligoMET) Molecular Characterization Trial (MCT) proposal is to conduct correlative studies from this first-in-man randomized trial of SABR MDT in men with de novo oligometastatic prostate cancer. We hypothesize macroscopic prostate tumors support the growth of and help nurture future distant metastases. In addition, we hypothesize that tissue, imaging and circulating biomarkers can identify men with de novo PCa oligometastasis that benefit the most from SABR. AIM #1 – To validate prognostic-predictive ability of tissue and liquid biomarkers using the first-in-man randomized trial of stereotactic ablative radiation (SABR) consolidation in men with de novo oligometastatic castration-sensitive prostate cancer. AIM #2 – To validate prognostic-predictive ability of radiomics using the first-in-man randomized trial of stereotactic ablative radiation (SABR) consolidation in men with de novo oligometastatic ca...