Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes, warranting the development of new effective therapies in this setting. Prostate-specific membrane antigen (PSMA) is expressed in benign and malignant prostate tissues and luminal surface of salivary/lacrimal glands, small intestine and renal tubules. The double PSMA binding moiety of SAR-bisPSMA in ⁶⁴Cu-SAR-bisPSMA (imaging) and ⁶⁷Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of ⁶⁴Cu-SAR-bisPSMA compared to the single-target PSMA agent, ⁶⁸Ga-PSMA-11. Pre-clinical efficacy data of ⁶⁷Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition compared to the control group as well as a dose-dependent delay in eventual tumor regression in a PC xenograft study. These results led to the development of this clinical study, which aims to assess safety and anti-tumor efficacy of ⁶⁷Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of ⁶⁴Cu-SAR-bisPSMA and ⁶⁷Cu-SAR-bisPSMA. mCRPC patients with progression, prior exposure to at least one androgen receptor pathway inhibitor, and positive ⁶⁴Cu-SAR-bisPSMA PET may be treated with ⁶⁷Cu-SAR-bisPSMA. This study is being conducted in 3 phases: a ⁶⁴Cu-SAR-bisPSMA Dosimetry Phase (n=6), a ⁶⁷Cu-SAR-bisPSMA Dose Escalation Phase (n=up to 24), and a ⁶⁷Cu-SAR-bisPSMA Cohort Expansion Phase (n=14). The primary and key secondary objectives include assessment of ⁶⁴Cu- and ⁶⁷Cu-SAR-bisPSMA safety and dosimetry, determining the maximum tolerated dose (MTD) or maximum feasible dose (MFD) and anti-tumor efficacy of ⁶⁷Cu-SAR-bisPSMA. The ⁶⁷Cu-SAR-bisPSMA dose levels investigated in the escalation phase include: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and up to 24 GBq across two doses (cohort 4, two doses at MTD or MFD). The Dose Expansion Phase of the study will allow the administration of up to 4 doses of ⁶⁷Cu-SAR-bisPSMA at the MTD/MFD. Response measurements include reduction in PSA levels, radiological progression-free survival, duration of response and overall survival. Radiological response will be assessed by RECIST 1 V1.1 and PCWG3. At the time of submission of this abstract, cohort 3 is open for recruitment and no dose limiting toxicities have been observed to date. Clinical trial information: NCT04868604.