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

44 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. 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). 64 Cu-SAR-bisPSMA has demonstrated higher tumor uptake (2-3x), prolonged retention and detection of additional PC lesions compared to approved PSMA agents. Methods: This was a Phase 1/2 study assessing the safety and efficacy of 64 Cu-SAR-bisPSMA (200 MBq) in PC patients with biochemical recurrence (BCR) and negative or 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 Reference Standard (histopathology, SOC imaging, prostate-specific antigen response). Efficacy endpoints included detection rate (DR) and correct detection rate (CDR). The number of lesions detected, their size and the intended change in PC treatment due to the 64 Cu-SAR-bisPSMA results were recorded. Results: Fifty-two patients were enrolled (50 had 64 Cu-SAR-bisPSMA PET results). The 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). The CDR as assessed against the 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 the gold standard of histopathology as the Reference Standard (44.4–55.6% and 55.6–77.8% for Day 0 and Day 1, respectively; N=9). This highlights the limitations of using less sensitive methods (e.g. current SOC imaging) to verify the 64 Cu-SAR-bisPSMA PET findings. More lesions were identified on Day 1 than on Day 0 (82–153 vs. 53–80). The 64 Cu-SAR-bisPSMA imaging led to clinicians changing their intended treatment plans in 24/50 (48%) of participants. Conclusions: This study showed that 64 Cu-SAR-bisPSMA is effective in detecting PC lesions. 64 Cu-SAR-bisPSMA identified lesions in up to 80% of participants with BCR of PC and negative or equivocal SOC scan. Histopathology confirmed the presence of PC in lesions identified by 64 Cu-SAR-bisPSMA in up to 78% of cases in which biopsies were performed. More lesions and patients with a positive scan were identified on next-day imaging. PET results led to clinicians changing the intended treatment plan in approximately half of the patients. These findings have important clinical implications as the identification of lesions in BCR patients can inform different treatment pathways. Clinical trial information: NCT05249127 .