Background: The treatment of advanced prostate cancer (PC) is challenging, with undesirable side effects that impact patient quality of life. Radioimmunotherapy (RIT) can localize therapy to specific tumor cells in multiple organs to reduce or eliminate damage to normal tissue. The cell surface glycoprotein prostate-specific membrane antigen (PSMA) is an ideal therapeutic target as it is highly expressed by malignant prostate cells. There is a strong rationale for further investigation of the ¹⁷⁷Lu-labeled, chelator-conjugated antibody, ¹⁷⁷Lu-DOTA-rosopatamab, as a potential RIT candidate for the treatment of PC. Methods: In this multinational, multicenter, prospective, randomized, open label phase 3 study (NCT04876651), 387 patients with PSMA-expressing metastatic castration-resistant PC (mCRPC) that have progressed despite prior treatment with a novel androgen axis drug will be enrolled in a 2:1 ratio to receive either the best standard of care (SoC) or 2 single intravenous (IV) injections of 76 milicuries (mCi) each (equivalent to a 45 mCi/m² dose in a standard 1.7m² individual) of ¹⁷⁷Lu-DOTA- rosopatamab, given 14 days apart, plus best SoC. Eligible patients must have received prior therapy with either enzalutamide or abiraterone plus prednisone, and 1 line of prior taxane therapy or have refused or are ineligible for taxanes. Patients must have adequate organ function including at least 150x10⁹ /L platelets, hemoglobin 10 g/dL, and have PSMA-positive disease on ⁶⁸Ga-PSMA-11 PET/CT imaging as confirmed by a central reader. Key exclusion criteria include small cell histology, increased risk of hemorrhage or bleeding, known brain or hepatic metastases, or history of stroke, seizure, or treatment with radioisotopes within 6 months prior to randomization. The primary endpoint is radiographic progression-free survival. Secondary endpoints include 5-year overall survival, tumor objective response rate, time to symptomatic skeletal event, progression free survival, and number of participants with treatment-related adverse events. Clinical trial information: NCT04876651.