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Emmanuel Antonarakis: I'll be talking about PSMA-PET utilization by guidelines. The relevant disclosures. Here are the Curium and the Novartis disclosures. So I'm getting paid by both of them, and they are also paying my institution for clinical trials.

So this is an American meeting. I apologize to my European and Australian colleagues. I'll be reviewing mainly these three American-centric guidelines. So first of all, the most recent NCCN 2025 guideline. So here we're talking about imaging. We're not talking about the therapeutic agent. So here the NCCN recommends all three of the FDA-approved imaging agents, DCFPyL, POSLUMA, and Gallium PSMA-11.

And there's a statement in there that these are superior to choline C-11 and F-18 fluciclovine exams as well as CT and bone scan. So there's a suggestion that these scans can be used instead of, as opposed to waiting until you have a negative or unequivocal result, and then using these agents. The third bullet point has to do with the companion diagnostic for Pluvicto use.

So these are the three or four indications according to NCCN for a PSMA-PET. First of all, high-risk, unfavorable intermediate-risk, localized prostate cancer to exclude metastatic disease. Secondly, patients with biochemical recurrence after prostatectomy or radiotherapy, looking for, again, a micrometastatic hormone-sensitive disease. And then third, workup for progression, which I think what they mean by that is, if you're looking for metastatic disease in the M0 CRPC space, or you're looking for eligibility for Pluvicto.

There's this interesting comment on the right that the NCCN panel no longer feels, as they did in previous years, that conventional imaging is a necessary prerequisite. I think after this statement was put into the guidelines, a lot of payers stopped requiring negative or equivocal CT and bone scans before approving PSMA-PET.

Now, when you look at this famous flow diagram—I was reviewing this earlier this week when I was making my slides—this is the high-risk, very-high-risk localized scenario. It's very interesting to me that there is nothing in that green circle there that specifically calls out any imaging agents. We know that we are doing imaging in these patients to rule out metastatic disease, but that, to me, seems like a missed opportunity. And I would encourage anyone who is on the panel, because I am no longer on it after having left Hopkins, that would be an ideal place where I think it does belong, and it's not currently there.

In the BCR flow diagram, it is there, but it's buried in that green circle. And if you look at the green arrow, it says that in a patient with BCR, you should do bone imaging and soft tissue imaging. But there, again, that statement is so vague. And then there's that little superscript f. Then if you go to the end of the document, you read what f means, and it says CT, bone scan, and PSMA-PET. So I think, again, there's an opportunity to clarify these flow diagrams because very few people read the 70-page discussion at the end. Most people just look at the flow diagrams. At least that's what my fellows do in clinic, and it would be good to have it there.

There's also a table of prognostic and predictive biomarkers, which is kind of buried in the back. At the bottom, I noticed that PSMA SUV_mean is considered by the NCCN panel as both predictive and prognostic for appropriate use of Pluvicto. And of course, there it's the SUV_mean below or above 10 based on the substudy from VISION. So again, perhaps a predictive biomarker, at least as far as NCCN is concerned.

Now the Society of Nuclear Medicine, SNMMI, 2023 criteria were actually developed in 2022, published in 2023. So these might actually need an update too. Several people in the audience were part of these. The blue ones are the ones that had the highest score, meaning the greatest amount of consensus.

So if you start by looking at the nines—bullet point 6, 7, and 11 had the strongest evidence. So bullet point 6, PSA persistence or recurrence after radical prostatectomy, so BCR. Bullet point 7, a BCR after radiotherapy, again, very high evidence to use it there. And then number 11 as eligibility for PSMA RLT, such as Pluvicto.

There's then these sort of lesser levels of consensus, the sevens and the sixes. And then the ones that are not shaded are the ones where there was no consensus or a consensus that they should not be used.

The American Urological Association and SUO Guidelines, also 2023, probably require an update as well. Here, they endorse PSMA imaging for biochemical recurrence. They also state in that middle paragraph that you don't necessarily need a negative or equivocal conventional scan to order it. They also have a section for nonmetastatic M0 CRPC, where they endorse or recommend that you should be getting a PSMA imaging agent every 6 to 12 months to look for occult metastatic disease where you would be redefining your patient as M0 CRPC going to M1 CRPC.

Also, of course, they endorse the indication for radioligand therapy at the top. And then at the bottom, I think this is the only guideline that specifically calls out the indication for metastasis-directed therapy. They specifically mentioned the ORIOLE study, although they could have also mentioned STOMP or other trials. So in the hormone-sensitive, biochemically recurrent setting, there is a lower level of recommendation by the AUA to do a PSMA-PET in those patients to offer them MDT, either with or without ADT.

Now, what is missing from all of those guidelines? This is what Tom asked me to think about. And these are the things that are not covered by any of the three. Using PSMA to quantify tumor burden—that's not in there. Using PSMA to determine progression of disease—that's not in there. And then assessing disease response as a response characteristic—that's not in there. And perhaps the reason for those is we don't have the evidence generated yet to support any of those guidelines.

But there's two groups that are working on these things from various angles. The first is the Prostate Cancer Working Group 4, and there's an emerging subgroup that Michael Morris is very involved in. And the goal of that group—and by the way, this is not published yet, so it's in progress—is how to use PSMA for clinical trial design framework and in the context of designing and approving drugs and also biomarkers.

The second is the SPARC, which I must admit I had not heard of until recently, and I don't believe they have a peer-reviewed publication yet. That, as was mentioned by one of the previous speakers, stands for the Standardized PSMA Analysis and Reporting Consensus. There's some overlapping experts in both groups, but the second one, the SPARC, is more focused on how PSMA should be used for reporting, standardizing the reporting, also using it for staging and response assessment as well, which I think is an unmet medical need.

So I think by this time next year, we should have a lot more information from Working Group 4 as well as SPARC about the unmet needs for PSMA imaging. Thanks very much.