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Phillip Koo: Hi, my name is Phillip Koo and welcome to UroToday. We're continuing our series discussing PSMA PET and radioligand therapies, and we're very fortunate to have with us Dr. Ephraim Parent, who's a consultant at the Mayo Clinic in Jacksonville. Welcome, Ephraim.

Ephraim Parent: Thank you very much for the invitation to speak with you today.

Phillip Koo: One of the hot topics and one of the biggest challenges right now is figuring out how to select patients using PSMA PET to undergo RLT. We have the VISION criteria, and other different sources out there that talk about this, but really help us break it down to the basics. Give us the 101-level teaching for the use of PSMA PET in that setting.

Ephraim Parent: I think it has become clear, hopefully, to not just radiologists but everybody in the field, how important the PET is for the correct identification of patients prior to getting Pluvicto or the radioligand therapy with PSMA. We know, as you identified, that appropriate identification of patients that would benefit from this is key to have a successful outcome, and the last thing we want to do is do something that's futile or not going to be helping anybody and potentially could be causing problems.

I believe it is now standard practice, at least in the United States, and probably the world, where before patients are being put on therapy, they're going to be undergoing a standard of care of PSMA PET imaging. A lot of times, again, these patients, we're assuming, have already met some of the criteria such as failing hormonal therapy, failing chemotherapy, and we're now looking for this group. So once we have that cohort in place, we do PSMA PET, and what we want to do is identify that there is local or PSMA-avid disease that would then, in theory, respond to the radioligand. When we identify this, there are some guidelines around this that are not necessarily hard and fast, but I think most people follow them. The PROMISE criteria are commonly used. As newer PSMA PET agents are coming on board with Posluma. We'll see how those criteria apply to successful treatment results.

But looking at, I would say, the more commonly used PSMA agents, PSMA-11, which is the Locametz or Illuccix or Pylarify, the DCFPyL, a lot of times we're comparing to normal organs of uptake that have well-established criteria to identify marked or PSMA-avid disease. These target organs that we compare to, a lot of times the patients would look in the report to see these numbers and wonder why we are talking about this? It's providing a framework for our justification for saying, "Yes, this would be an appropriate therapy."

And so, typical organs that we evaluate are the parotid glands as well as the liver. Those kinds of provide a framework for moderate or marked uptake. And ideally when we are identifying patients with disease that we would hope to respond to Pluvicto therapy, which is, again, the only FDA-approved therapy right now with PSMA, is that they're going to have lesions that have uptake greater than liver. If they have lesions less than liver or lesions that don't really have uptake that looks suspicious like in an enlarged lymph node or a sclerotic osseous lesion that we think might be actually metabolic disease, then we start having a discussion about doing other imaging and the appropriateness of PSMA therapy.

Phillip Koo: Great. In your reports, do you actually report out an SUVmax or do you just always just compare to the liver or parotid glands?

Ephraim Parent: Our practice always reports SUVmax. And I think that while, yes, this is predominantly a visual comparison, if you want, that you can do a qualitative assessment, I think using the SUV is a very good method to improve your confidence, if you will. It provides a backup to say, "Yes, my eyes are seeing this correctly. I am seeing this." Especially when you have small lymph nodes or other things like that, I think it provides a framework to be able to verify what you are seeing visually and is actually the quantitative assessment. And frankly, with PET, we have this ability to provide semi-quantitative metrics. It seems to me that this is something that is kind of tailor-made to be able to provide, not just a guess, but a true estimate of how successful the therapy will be for these patients.

Phillip Koo: I agree with you a hundred percent. Sometimes I pause a little because sometimes the referring physicians just focus on that number and forget about everything else. I think the take-home message here is use that number in the context of the qualitative assessment as well, and the whole picture, just don't focus on that single number. In your experience, those patients who have heterogeneous disease and maybe there's uptake in some lesions below liver or no uptake, what patients of those do you tend to still move forward with RLT? What patients do you maybe lean towards other options?

Ephraim Parent: I think that's a very good question. Actually, I think there's still some range in how this is approached in the community. In our practice, we're pretty rigorous, because we try to do our best due diligence to identify patients according to the criteria, not just VISION, but I would say also things like the therapy which incorporated FDG PET. So we know, based on several small series of papers, and they're kind of consistent, that there's a minority of patients that have this, it's termed discordant hypermetabolic disease, meaning that they have metastatic prostate cancer, but one or more lesions don't really have as much PSMA expression, but they have a fair level of FDG uptake. And so they've kind of changed their metabolic machinery to kind of move away from PSMA as part of their genetic profile, and we know that if these patients are not appropriately identified and they're put on therapy, they will not do well. This has been established in both patients that have been covered with standard of care as well as getting Pluvicto therapy.

So we do this pretty rigorously. We really try to identify patients that have soft tissue or bony disease that looks like it's prostate cancer, and if we're not certain, we will absolutely get an FDG PET. We do that. Again, probably about 20-30% of our patients will end up getting an FDG PET, and of those, I would say there's actually a fair amount that have discordant disease and we end up not treating with Pluvicto. Typically, if there's a question, like say it's a pulmonary nodule, there's a case I can think of when we first started doing this, there was only a single pulmonary nodule. It was about a centimeter, didn't really have PSMA uptake. FDG was mild, but we stuck a needle in it. It was prostate cancer. Again, that's that kind of confirmation that... I don't know if it's so much important that the FDG is positive, but if the lesion itself is PSMA negative and you know it's prostate cancer, we can assume that. It's very frustrating for, a lot of times, these patients, where they're on their last line of treatment, but we know they're just not going to do as well.

It's a conversation at the tumor boards or just with the patient themselves where you're talking with oncologists, radiation oncologists, and other care team members to identify, is there something we can do to make them qualify for therapy or is this just kind of where we're at? So there's, I think, some art to this, but I think ignoring the data will ultimately just lead to a disappointing outcome for the patients and providers.

Phillip Koo: I think that's great advice and agree. It's a complex topic, complex question, and a multidisciplinary approach makes a lot of sense. So, going back to selecting patients, do you require PSMA PET within 3 months of starting treatment, 6 months, a year? I know there's a lot of variability in that answer.

Ephraim Parent: Typically, I would say within 3 months. I think once in a blue moon, we'll have an outside PSMA PET that was within 6 months. But things haven't really been changing, PSA is not moving, but I'd say that's the exception. Most of the time, I would say the vast majority of our patients, we are within 3 months, and realistically, probably within a month or two of getting the last PSMA PET study. Ultimately, it is because the longer you go, why at this point as Pluvicto has now been on the market, why are we waiting? Because what you don't want to have is something change and you just want to be up-to-date, and in my opinion, have the most concrete information before starting this therapy. Because once you've started the therapy, we will do post-SPECT imaging based on the Pluvicto that can help guide us, but ultimately, you've committed yourselves to these six rounds of treatment and you want to make sure that you're not just wasting everybody's time, but also the substantial cost of this therapy.

Phillip Koo: Is it safe to say, then, you're not getting a PSMA mid-cycle or post-treatment?

Ephraim Parent: That would be the exception. Again, you can always probably find the one-off or something that changes, but we attempt to do 24 to 48 hours after getting the Pluvicto cycle, the dose, we will do a SPECT-CT, where we're not injecting new tracer, but we're just imaging the tracer we injected. And we will do that routinely. That's pretty much the only imaging we will do. Now, granted, there are patients, as we know, not everybody's going to have a successful outcome on this and sometimes PSMA is rapidly going up, other things are changing. Are we doing MR? A lot of different imaging can take place, but that's kind of the exception that is unfortunate. But for most patients, we don't do any dedicated imaging, MR or otherwise, until after therapy is completed outside of this post-treatment SPECT-CT.

Phillip Koo: That's great. The final question is, where's the next step? I think PSMA PET, we're still looking at it in a relatively binary fashion, positive, negative. What's the future hold with being a little bit more advanced and using more advanced imaging analysis tools to select patients better?

Ephraim Parent: This is a great question. I think that it kind of depends on where therapy is going, if you will. We know there are a lot of trials. When I think of the things that are most imminent on the horizon that would have the biggest outcomes for patient care, it is, can we move the therapy that we're already doing upfront? Can we move this earlier on? So the PSMAddition trial that, again, this is sponsored by Novartis, but they're looking at this as an upfront therapy where patients have not gotten hormonal therapy or chemotherapy, but do they have metastatic disease that would then respond. So we're participating in this trial, and this is a large trial. But these are the type of things that would dramatically change the timing of the PSMA PET imaging, where this becomes a, you're diagnosed, and while instead of it having just a small percentage of patients that would be getting PSMA PET upfront, I would imagine you'd have a large percentage of patients that would be getting this to see if they would qualify for therapy early on.

In terms of the different types of imaging, the nuances of imaging, I think there's a lot of possibilities out there that are not yet explored outside of a few case examples. For example, we know there were other metabolic agents that were pretty good for prostate cancer, choline 11, fluciclovine. These were kind of pre-PSMA standard of care images that probably a lot of patients remember getting these studies. Is their utility, in comparing this to PSMA, to identify better than FDG or as a way to better predict patients' outcomes to therapy? Because that's ultimately what I feel with imaging, what we want to do is not just say, "Okay, look, here's a bright spot, here's disease." But we want to be able to predict with a high level of confidence if patients will be successful on therapy. Because ultimately, while time in a way is money, it's also patients' lives, right? So if you say, "Okay, look, we have a year or two," I would rather get somebody on the appropriate therapy because they're going to have a greater chance of having a good quality of life.

So I think as things progress, we will have a better understanding of how these different metabolic markers could affect the outcomes for therapy. But again, these are kind of conjecture at this time. We don't have large studies to really identify patients outside of say, FDG, because I think still to this day, that's the most commonly used agent outside of PSMA for identifying patients as they should respond to Pluvicto therapy.

Phillip Koo: Yeah, I think that's really exciting to think of PSMA PET as a predictive marker, and hopefully, other tools like metabolic tumor volumes and other things that we can look at with the data that we've already acquired I think will really unlock some even more information. Well, thank you so much, everyone, for joining us. We appreciate the insights and we look forward to having you back here at UroToday.

Ephraim Parent: Thank you very much.