Ann: SECuRE trial update, page-138

@Coit- Thanks for your great questions!

1/ False Positives Lead to Unnecessary and toxic treatment:Does this presume that a patient, on receipt of a positive scan, would commence chemotherapy (toxic treatment)?

The short answer is NO!

False positives can definitely lead to patients getting unnecessary and sometimes toxic treatments - in real life. In the clinical trial, that’s not going to happen as the trial protocol is protective: treatment decisions are made based on standard of care (SOC) scans only, not on the experimental Cu6 scan results. So, during the trial, even if there’s a false positive on a Cu6 scan, it won’t affect what treatment the patient gets.Neither will a true positive that gets missed by SOC!

But in real life, outside of a trial, every scan result, including false positives, gets shared with the treating doctor and the patient. So if a future Cu6 scan shows a false positive, it’s very likely that the doctor might act on it, thinking the cancer is worse than it really is. That could mean the patient gets put on treatments that they didn’t actually need, and that comes with side effects and risks, for no real benefit. That's why it’s super important to keep false positives as low as possible — ideally none, but we know that's not fully achievable.

In the COBRA trial, the SOC scans were read by local doctors, and treatment decisions were based on those. But both SOC and Cu6 scans also went to blinded trial radiologists for review. That is how we get to find out how the Cu6 scans were better than SOC. Treatment was according to SOC: It was afterwards that about 50% of the treating doctors said that what the Cu6 scan results showed was significant enough to have them treat their patients differently.
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2/ Only 9 out of 50 had biopsies: assuming all have been shown a red flag, why wouldn't you progress to have the biopsy rather than think you have cancer? I have been stabbed like a voodoo doll (some 16 biopsy needles in one session) - not pleasant but at least I know my status.

Great question! There is soem context that I hadnt even considered before which I think is crucial!

First, these patients in the COBRA study were men who already had prostate cancer, and had already gone through treatments like prostatectomy, hormone therapy (chemical castration), chemo, and/or radiation. Now, their PSA is rising again, so doctors are trying to figure out if and where the cancer might be coming back! That's the setting! Its hard.
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Situation 1: SOC finds a LESION! Congrats to SOC.
Doctors might then offer a biopsy to confirm.No issues there and that's what your question refers to. So, what might the patient do? Its actually tougher than deciding to have a blood test: reason - some of the lymph nodes and other suspicious lumps that need to be biopsied are deep inside the body (nodes next to the biggest artery coming straight from the heart (aorta), in the bones, in the liver, in the lungs, or even in the brain)! Its a risky undertaking trying to get to them! You can end up with major damage, but no cancer, or both cancer and major damage to your organs - and die from the damage, not the cancer! The patient then has to choose between;
1) Doing nothing and just accepting a diagnosis - pray and wait to see if it grows, then decide, or,
2) Going straight to additional treatment without confirming (imagine if offered a SECURE trial spot for some 67Cu-Sar-bisPSMA), or,
3) Having the biopsy - confirmation and hope to avoid complications!

So, these are the decisions that those testing positive had to make. I think they were 20 positive SOC scans vs 26 in same day 64Cu-Sar-bisPSMA (happy to be corrected - I will need to check again on this). Either way - if 20 had positive SOC scans, then its only in those 20 that biopsies would have been a consideration - of which 9 proceeded! Thats actually not as bad as I first thought when looking at 9 out of 50 (or 52).
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Situation 2: SOC finds ZERO LESIONS! No see - No biopsy - Simple!
The real bummer here is the frequency of FALSE NEGATIVES from Illuccix and Pylarify scans (the SOC imaging agents)! They miss lesions that are actually there! So, since all management is guided by them, a negative scan means there’s nothing to biopsy! That will account for some of the men trialled that didn’t go for a biopsy (in addition to the group that chose not to). How many in this group? No idea!

And guess what: Even 6 months later, the SOC scans were seeing smoke! (Per Annual Report 2024, Page 24): "... Twenty participants in the COBRA study (40%) underwent follow-up SOC PSMA PET, performed up to 6 months after the 64Cu-SAR-bisPSMA scans. Both the number of patients with a positive scan and the number of lesions identified by 64Cu-SAR-bisPSMA were higher than those detected by SOC PSMA agents, even when those follow-up scans were performed several months after the 64Cu-SAR-bisPSMA PET ..." The struggle continues!

So, the number that may have needed biopsies, never even got the chance! You cant biopsy what you cant see!
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Situation 3: The ones that did not complete: Out of the 52 recruited into COBRA, some did not complete the trial (for different reasons). Per 2024 Annual Report, "42 were included in the calculation of the efficacy endpoints."
Why not complete? These are sick people, and experiments that don't add value to your now may be a tough ask. So, the number reaching the stage of being advised to have a biopsy will reduce - and that of those who agree and proceed will tumble as well.
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IN CONCLUSION: 9 biopsies out of 52 enrolled might not be as bad an achievement as first assumed: its effectively, 9 out of 20 if we assume that all SOC positive participants were offered a biopsy - a very good result.

NOTE that COBRA is not a good setup for biopsies: these patients already had cancer, and had been treated before (as argued above). The trial that has a biopsy as part of standard care is CLARIFY! (on the other hand) recruits patients who are actually going to have biopsy