COBRA: Assessment of safety and efficacy of 64Cu-SAR-bisPSMA in patients with biochemical recurrence of prostate cancer following definitive therapy.
Authors: Nordquist Luke , Lengyelova Eva , Saltzstein Daniel , Josephson David , Franklin Gregg E. , Morrish Glynn , Gervasio Othon , Parker Michelle , Miller Robert M. , Shore Neal D. 
Published: June 2024

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Background: Accurate staging of recurrent prostate cancer (PC) is essential to inform the best treatment strategy. Prostate-specific membrane antigen (PSMA) is used as an imaging target in PC. 64Cu-SAR-bisPSMA may offer several advantages over the currently approved PSMA PET agents due to the bivalent structure of SAR-bisPSMA and longer half-life (t1/2) of 64Cu (12.7h), compared to the monovalent agents utilizing 18F and 68Ga (t1/2<2h). Clinical/translational evidence has demonstrated higher tumor uptake (2-3x), prolonged retention and detection of additional PC lesions using 64Cu-SAR-bisPSMA compared to approved PSMA agents. Methods: This was a phase I/II study assessing the safety and efficacy of 64Cu-SAR-bisPSMA (200 MBq) in PC patients with biochemical recurrence (BCR) and negative or equivocal standard of care (SOC) imaging (NCT05249127). Patients underwent PET/CT on Day 0 and Day 1 (1-4h and 24±6h post-dose, respectively), interpreted by 3 blinded central readers. The PET/CT results were assessed against a Reference Standard (histopathology, SOC imaging, Prostate Specific Antigen response) that was determined by an independent, blinded, central expert panel. Efficacy endpoints included detection rate (DR) and positive predictive value (PPV). The intended change in PC treatment due to the 64Cu-SAR-bisPSMA results was recorded. Results: Fifty-two patients were enrolled and imaged (32 completed the study). Only one adverse event was related to 64Cu-SAR-bisPSMA (Grade 2 worsening of type II diabetes, resolved). The Day 0 DR range across the readers was 44–58% (95% CI 30.0–71.8), increasing on Day 1 to 58–80% (43.2–90.0). Pelvic lymph nodes, a common site of PC metastases, had a Day 0 PPV range of 71.4–87.5% (95% CI 29.0–99.7) and Day 1 of 50.0–61.5% (15.7–86.1). The relative decrease in Day 1 PPV was related to the challenges to obtain the reference standard for additional lesions identified on Day 1, where biopsy of all lesions was not feasible and due to the low sensitivity of current SOC imaging. Additional lesions were identified on Day 1 (82–153 vs. 53–80 on Day 0). The 64Cu-SAR-bisPSMA imaging led to clinicians changing their intended treatment plans in approximately half of the patients (48%). Conclusions: This study showed that 64Cu-SAR-bisPSMA is safe and effective in detecting PC lesions in patients with BCR. In patients with a negative or equivocal SOC scan, 64Cu-SAR-bisPSMA identified lesions in up to 80% of patients. More lesions and more patients with a positive scan were identified on next-day imaging, a feature that currently approved PSMA tracers cannot offer. PET results led to clinicians changing the intended treatment plan in approximately half of the patients. Taken altogether, these findings have important clinical implications as the identification of lesions in BCR patients can inform different treatment pathways. Clinical trial information: NCT05249127 .