Background: Despite recent treatment advances, mCRPC remains a challenging disease associated with significant mortality and morbidity. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed in most prostate adenocarcinomas. Radiolabelled peptides which bind PSMA receptors induce internalization of the ligand-receptor complex, allowing concentration of PSMA-bound isotopes within targeted prostate cancer cells. ¹⁷⁷Lutetium (¹⁷⁷Lu) bound to PSMA ligands has a favorable therapeutic-toxic ratio and yields PSA responses in 30-70% of selected patients. However, responses are often partial and acquired resistance common, suggesting a need to augment the clinical benefit of beta-radiation. Idronoxil is an inhibitor of external NADH oxidase type 2, and has a variety of downstream actions including radiosensitization. Given the reassuring safety data of idronoxil as a single agent, we initiated a phase 1 clinical trial of ¹⁷⁷Lu-PSMA plus idronoxil. Methods: Sixteen patients will be recruited. Participants will receive up to 6 doses of ¹⁷⁷Lu-PSMA at 6-weekly intervals; the first 8 patients will also receive 400mg idronoxil daily for 10 days from day 1 of each cycle, while subsequent patients will receive 800mg daily for 10 days if no major adverse events are noted. Entry criteria include (i) failure of, or (ii) ineligibility to receive both docetaxel and a second-generation androgen pathway inhibitor. Imaging criteria include a PSMA PET that shows significant uptake at all sites of disease with no discordant disease on FDG PET. The primary endpoint is the toxicity (safety, tolerability) of the combination as assessed by CTCAE criteria. Secondary endpoints include PSA response, radiological response, changes in quality of life, radiation dosimetry, overall survival and progression-free survival. Plasma for ctDNA testing will be collected to explore whether DNA repair defects are predictive biomarkers for response and/or mechanisms of resistance. Four of 16 patients have been enrolled, with no significant toxicities or safety concerns as yet.