COBRA: Assessment of safety and efficacy of 64Cu-SAR-bisPSMA in patients with biochemical recurrence of prostate cancer following definitive therapy

Introduction: Early diagnosis of recurrent prostate cancer (PC) and accurate staging are essential to inform the best treatment strategy. Prostate-specific membrane antigen (PSMA) is strongly upregulated in PC, making it an excellent target for both imaging and therapy of PSMA-expressing PC. ⁶⁴Cu-SAR-bisPSMA may offer a number of advantages over the currently approved PSMA PET agents for PC due to the bivalent structure of SAR-bisPSMA and longer half-life (t_1/2) of ⁶⁴Cu (t_1/2 = 12.7 hours), compared to the approved monovalent PSMA agents utilizing ¹⁸F and ⁶⁸Ga (both with t_1/2 < 2 hours). Pre-clinical and clinical evidence has demonstrated a higher tumor uptake (2-3 times) and detection of additional PC lesions using ⁶⁴Cu-SAR-bisPSMA compared to approved PSMA PET agents.

Methods: This was a phase I/II multi-center, single arm, non-randomized, open-label study of ⁶⁴Cu-SAR-bisPSMA administered to patients with biochemical recurrence (BCR) of PC following definitive therapy (NCT05249127). Key eligibility criteria included adenocarcinoma of the prostate, recurrence (rising prostate specific antigen [PSA]) and negative or equivocal findings for PC on standard of care (SOC) imaging (e.g. PSMA PET, CT, bone scan). The primary objectives were to assess the safety of ⁶⁴Cu-SAR-bisPSMA (200 MBq), and its ability to detect recurrent PC. Patients underwent PET/CT on the same day (Day 0, 1-4 hours) and the next day (Day 1, 24±6 hours) post-dose. Efficacy endpoints included patient level detection rate (DR), correct detection rate (CDR: number of patients with a true positive scan / all scanned patients) and true negative rate (TNR). ⁶⁴Cu-SAR-bisPSMA uptake was assessed by standardized uptake values (SUV) in lesions and tumor-to-background ratio (TBR). The ⁶⁴Cu-SAR-bisPSMA PET/CT scans were assessed centrally by 3 independent, blinded, readers. The ⁶⁴Cu-SAR-bisPSMA PET/CT results were assessed against a Reference Standard (histopathology, conventional imaging and/or PSA levels) that was determined by an independent, blinded, central expert panel.

Results: Fifty-two patients were imaged in the study (32 completed the study). No clinically significant changes in laboratory values were observed, and only one treatment emergent adverse event was related to ⁶⁴Cu-SAR-bisPSMA (Grade 2 worsening of type II diabetes, resolved). In patients with negative or equivocal SOC scans, the DR with ⁶⁴Cu-SAR-bisPSMA on Day 0 ranged from 44 to 58% depending on the reader (95% CI range 30.0 to 71.8%), increasing on Day 1 to 58 to 80% (95% CI range 43.2 to 90%). CDR also increased from same day to next day imaging. Additional lesions were identified on Day 1 in all anatomical regions (total number of lesions ranging from 53 to 80 on Day 0 increasing to 82 to 153 on Day 1, depending on the reader). TNR rates (reported as a range with 95% CI in %) were high across all readers and similar for both days of imaging: Day 0 – pelvic region 93.8 to 96.9% (79.2 to 99.9), extra-pelvic region 93.9 to 97% (79.8 to 99.9), bone region 91.9 to 94.6% (78.1 to 99.3); Day 1 – pelvic region 81.3 to 87.9% (63.6 to 96.6), extra-pelvic region 90.9 to 97% (75.7 to 99.9), bone region 78.4 to 97.3% (61.8 to 99.9). Overall, the SUVmean, SUVmax and TBR were higher on Day 1 compared to Day 0.

Conclusions: The COBRA study confirms previous reports that ⁶⁴Cu-SAR-bisPSMA is safe and effective in detecting PSMA-expressing PC. It also shows for the first time that more patients had a positive PSMA PET/CT using ⁶⁴Cu-SAR-bisPSMA on delayed (next day) imaging compared to same day imaging in patients with BCR of PC, who had a negative or equivocal SOC scan, with high specificity on both days. Additional lesions were identified on next day imaging in all anatomical regions. Furthermore, lesions identified on delayed imaging had higher SUVs and TBR compared to same day imaging. These findings have important clinical implications as identification of additional lesions can inform different treatment pathways for these patients.