ProstACT GLOBAL: A phase 3 study of ¹⁷⁷ Lu-rosopatamab (TLX591) with and without the best standard of care for patients with PSMA expressing metastatic castration-resistant prostate cancer progressing despite prior treatment with a novel a

TPS303 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 177 Lu-labeled, chelator-conjugated antibody, 1 77 Lu-rosopatamab, as a potential first-line RIT candidate for the treatment of PC. Methods: This multinational, multicenter, prospective, randomized, open label phase 3 study will have 2 parts: a dosimetry and safety lead-in (n=30) and a randomized treatment expansion (n=490). In Part 1, patients will be divided into 3 groups (n=10 each) to receive 2 single intravenous (IV) injections of 76 millicuries (mCi) each, 14 days apart, of 177 Lu-rosopatamab with best standard of care (SoC) combinations with abiraterone, enzalutamide, or docetaxel to fully characterize biodistribution and safety profiles of 177 Lu-DOTA-rosopatamab + SoC combinations. SoC received will be determined prior to treatment with 177 Lu-rosopatamab. In Part 2, patients will be enrolled in a 2:1 ratio to receive either the best SoC or 2 single IV injections of 76 mCi each (equivalent to a 45 mCi/m 2 dose in a standard 1.7m 2 individual) of 177 Lu-rosopatamab, given 14 days apart, plus best SoC. SoC will be determined prior to randomization, and a change in planned SoC will not be permitted. Eligible patients must have PSMA-expressing metastatic castration-resistant PC (mCRPC) that have progressed despite 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 150x10 9 /L platelets, hemoglobin 10 g/dL, and have PSMA-positive disease on 68 Ga-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. Key secondary endpoint is OS. Additional secondary endpoints include 5-year overall survival, tumor objective response rate, time to symptomatic skeletal event, and health-related quality of life. Clinical trial information: NCT04876651 .