Background: The treatment of advanced prostate cancer (PC) is challenging, with no curative therapy to date and undesirable side effects that may impact patient quality of life. Monoclonal antibodies enable high specificity with low rates of off-target organ exposure, prolonged retention in PSMA+ tumors, and a predictable safety profile. There is a strong rationale for further investigation of the ¹⁷⁷Lu-labeled, chelator-conjugated antibody, ¹⁷⁷Lu-DOTA-rosopatamab (hereafter, TLX591), with prior studies demonstrating a favorable safety profile and efficacy, particularly with a fractionated (dose-dense) regimen Phase 1 ProstACT SELECT preliminary results demonstrate consistent uptake between TLX591 and ⁶⁸Ga-PSMA-11 imaging and reinforces advantages of this first-in-class radio-antibody drug conjugate investigational therapy. Methods: In this multinational, multicenter, prospective, randomized, open label phase 3 study, patients (N=400) with PSMA-expressing metastatic castration-resistant PC (mCRPC) that have progressed despite prior treatment with an androgen-receptor pathway inhibitor (ARPI) will be enrolled in a 2:1 ratio to receive best protocol-defined standard of care (SoC) with or without 2 intravenous injections of 2.8 GBq of TLX591, given 14 days apart. SoC may be alternative ARPI or docetaxel. Eligible patients must have received 1 prior ARPI in the mCSPC, nmCRPC, or 1L mCRPC setting. Patients must have 150x10⁹ /L platelets, and have PSMA-positive disease on ⁶⁸Ga-PSMA-11 PET/CT imaging. The primary endpoint is radiographic progression-free survival. Secondary endpoints include 5-year overall survival, tumor objective response rate, time to symptomatic skeletal event, health-related quality of life, and treatment-related adverse events count. An alpha control and 95% confidence intervals will be used; patients will be substratified between TLX591 + 2^nd ARPI or TLX591 + docetaxel. This study is currently enrolling. This study is funded by Telix Pharmaceuticals. Clinical trial information: NCT04876651.