Ann: SABRE topline results, page-38

Is there SOC for this group? Yes - CT, bone scan, MRI, and PSMA PET/CT are still SOC for staging and restaging prostate cancer.

Interestingly, the so called PSMA negative label is itself not a simple matter of the cancer not expressing PSMA! Its the scan result, not a biological classification. Its tracer dependent!

We have seen it before in PROPELLER and COBRA, where we had negative Illuccix and Pylarify results - 6 months after they tested positive on 64Cu-SAR-bisPSMA! Officially, those men would have been classiffied as PSMA negative, and on those grounds, would have been denied Pluvicto as a therapy!

In SABRE, these patients (at least some of them) were once PSMA PET-positive (e.g. during initial diagnosis or prior recurrence) and received treatment (surgery, ADT, radiotherapy), but some may later appear PSMA PET-negative on follow-up scans - simply meaning that their current scan does not show detectable PSMA-expressing lesions.

• SABRE Eligibility criteria:" ... Patients with PSMA-negative BCR of prostate cancer following definitive therapy. To be considered for inclusion in the study, candidates were required to demonstrate negative or equivocal findings for prostate cancer on approved PSMA PET (68Ga-PSMA-11 or 18F-DCFPyL), anatomical imaging (CT and/or magnetic resonance imaging [MRI]) and any other SOC imaging, if available..."

The distinction is yet another complicating matter for Clarity (a job for the Clinical/Scientific Advisors): Even COBRA included some of these same men, who were negative SOC - meaning that, if 64Cu-SAR-bisPSMA had been used instead, perhaps it would have detected cancer lesions in some of the same men that ended up included in SABRE (on accould of negative SOC, including 18F-DCFPyL or 68Ga-PSMA-11 scans).

All roads seem to lead to: 64Cu-SAR-bisPSMA PET/CT first, and if Negative, do a 64Cu-SAR-Bombesin PET/CT! Doing this in reverse is currently limited by the need to qualify for targeted therapy with Pluvicto. In future, 67Cu-SAR-Bombesin may well change that!