COBRA: Assessment of the efficacy of ⁶⁴ Cu-SAR-bisPSMA using histopathology and standard of care imaging as reference standard in patients with biochemical recurrence of prostate cancer following definitive therapy.

5102 Background: Accurate staging of recurrent prostate cancer (PC) is essential to inform the best treatment strategy. 64 Cu-SAR-bisPSMA may offer several advantages over the currently approved PSMA positron emission tomography (PET) agents due to its bivalent structure (SAR-bisPSMA) and longer half-life of 64 Cu (12.7h vs. <2h for 18 F and 68 Ga), as previously reported (2-3x higher tumor uptake and detection of additional PC lesions vs. approved PSMA PET agents). Methods: This was a Phase 1/2 study assessing the safety/efficacy of 64 Cu-SAR-bisPSMA (200 MBq) in PC patients with biochemical recurrence (BCR) and negative/equivocal standard of care (SOC) imaging (NCT05249127). PET/computed tomography (CT) imaging was performed on Day 0 and Day 1 (1-4h and 24±6h post-dose, respectively) and interpreted by 3 blinded central readers. PET/CT results were assessed against a composite Reference Standard (histopathology, SOC imaging [interpreted by 2 readers], prostate specific antigen response post-focal therapy). Efficacy endpoints included detection rate (DR; % participants with a positive scan out of all scanned participants) and correct detection rate (CDR; % participants with a true positive scan out of all scanned participants with at least one evaluable Reference Standard). Results: Fifty-two participants were enrolled (50 had 64 Cu-SAR-bisPSMA PET results); 39 and 30 had follow-up SOC imaging by Day 90 and by Day 180, respectively, and 9 had histopathology. 64 Cu-SAR-bisPSMA DR range across readers on Day 0 was 44–58% (95% confidence interval [CI]: 30–71.8), increasing on Day 1 to 58–80% (95% CI: 43.2–90). DR on follow-up SOC imaging by Day 90 ranged from 15-31% and 7-10% by Day 180. CDR as assessed against the composite Reference Standard on Day 0 was 19.0–26.2% (95% CI: 8.6; 42.0), increasing to 26.2–33.3% (95% CI: 13.9; 49.5) on Day 1. CDR was considerably higher when using histopathology as the Reference Standard (44.4–55.6% and 55.6–77.8% for Day 0 and Day 1, respectively), than SOC imaging (10.3–20.5% and 23.1%–25.6% for Day 0 and Day 1, respectively). Conclusions: 64 Cu-SAR-bisPSMA is effective in detecting PC in BCR of PC, with lesions identified in up to 80% of participants with negative/equivocal baseline SOC imaging. CDR was considerably higher when using the gold standard of histopathology to verify 64 Cu-SAR-bisPSMA PET lesions vs SOC imaging, which highlights the limitations of using less sensitive methods to verify the 64 Cu-SAR-bisPSMA PET findings. These results have important clinical implications, as the identification of lesions in BCR patients can inform different treatment pathways. Clinical trial information: NCT05249127 .