TPS5120 Background: The concept of metastasis-directed therapy (MDT) using radiation or surgery for oligometastatic (OM) prostate cancer (pCa) has evolved from an anecdotal hypothesis to a promising approach that may optimally balance toxicity and oncologic efficacy. Recently, there have been multiple smaller phase II randomized trials that have shown a signal of efficacy for MDT in OM pCa. Most studies have compared MDT to observation alone as the control arm, included only recurrent OM patients, and included up to 3-5 sites of metastasis. It is in this context, that the VA STARPORT trial was initiated in 2021 to definitively determine the role of MDT in Veterans with oligorecurrent pCa in 1-5 sites. Yet, the diagnosis and management of metastatic pCa have since evolved. The SABR-COMET-10 trial recently completed enrollment and compares systemic therapy alone or with MDT in patients with 1-10 metastases from various histologies. While pCa PET/CT imaging was only available for Veterans with biochemical recurrence in 2021, PSMA PET/CT now allows for the improved diagnosis of OM in Veterans with de novo pCa—a growing cohort of patients without a clear standard of care. Therefore, to maximize the impact and generalizability of the trial, VA STARPORT has been amended to allow for de novoOM and 1-10 metastases. The primary goal of VA STARPORT is to determine if adding PET-directed local therapy (PDLT) to standard systemic therapy (SST) improves disease control compared to SST alone in Veterans with recurrent and de novooligometastatic pCa. Methods: VA STARPORT is a phase II/III randomized trial open at 18 VA medical centers comparing SST alone (Arm 1) or with PDLT (Arm 2) in Veterans with OM pCa. Key eligibility criteria include recurrent or de novohormone-sensitive metastatic pCa and 1-10 metastatic lesions on any FDA-approved pCa PET/CT. The primary endpoint is castration-resistant prostate cancer-free survival (CRPC-free survival). Secondary endpoints include radiographic PFS, clinical PFS, freedom from index lesion progression, toxicity, quality of life, and prostate cancer-specific and overall survival. SST is delivered using any NCCN guideline-concordant regimen in both arms. PDLT can be either radiation or surgery to all sites of cancer. Regarding local therapy, de novo patients in Arm 1 receive prostate-directed RT, and in Arm 2 receive PDLT to all metastases and the prostate. For recurrent patients in Arm 1 there is no local therapy, while in Arm 2 patients receive PDLT. All participants undergo somatic tumor sequencing using the VA National Precision Oncology Program. Assuming a hazard ratio of 0.60 for SST + PDLT vs SST, two-sided alpha = 0.05 and 90% power, a total of 464 participants will be randomized to generate 166 CRPC-free survival events by the end of the active study phase. Recruitment is ongoing and 150 patients have been enrolled. Clinical trial information: NCT04787744 .