Ephraim Parent: Hello, welcome. My name is Ephraim Parent. I am presenting the third case in the joint collaboration with SNMMI and UroToday in presenting cases highlighting the power and utility of PSMA PET. I'm just going to go ahead and get started.

The patient that we have today, he has known metastatic castrate resistant prostate cancer. He has a Gleason 9, so high-grade prostate cancer, and he's been on several rounds of therapy, including several anti-androgens as well as taxane therapy with docetaxel. At the time of imaging, he's presenting with increasing prostate serum antigen or PSA scores. At the time of imaging, his most recent PSA was 24.2 nanograms and he had a doubling time of 2.7 months. He underwent both FDG PET and PSMA-11, or Locametz or Illuccix are the trade names PET scans, to determine his eligibility for the PSMA-617, or Pluvicto, therapy.

I'm showing the maximum intensity projection, or MIP, images of both scans. The FDG PET is on the left side of the screen and the PSMA-11 scan is on the right side of the screen. Once you look at this, there's a few things that kind of jump out really quickly. If we start just looking, because it's on the left side of the screen, we'll start looking at the FDG PET. We see that there's a lot of these dark dots which are lymph nodes that we are seeing here that I've highlighted in red several of them and they do not have a clear correlate for the PSMA scan. I will be showing the transactional slices to further elucidate that on the next slides.

But in addition to the lymph nodes that we're seeing on the FDG PET, we also see many osseous lesions, and that's pretty much everything else that you're seeing here with the black dot. And some of them, such as this lesion here that I've highlighted with the green arrow, have a good correlate on the PSMA, whereas others, such as, if you now turn your eyes to the PSMA scan, have uptake on the PSMA PET but don't really have a good correlate for the FDG.

So, without going into a lot of detail, we can pretty quickly assess that there's kind of a discordant nature to the disease, both that the lymph nodes appear to have more FDG uptake and the osseous disease is either kind of matching or has more PSMA uptake than FDG. Again, looking at some transactional slices to further delineate this. This is a right obturator node that we're seeing here, and we see this intense FDG uptake here on the right. This same lymph node on the PSMA PET scan has mild uptake, but less than liver. So it would really be not PSMA-avid disease. These are just the fused and then the PET and then CT images all showing the same image on different projections.

This is another lesion, a kind of aortocaval node, that has intense FDG uptake here. And then there is some PSMA uptake here, but really, when we equate it to the reference organs such as the blood pool of liver or the parotid gland, you see it has uptake somewhat less, but comparable to liver. Again, with these lymph node disease, there's a clear discordance between the FDG uptake and the PSMA uptake.

When we turn to looking at the osseous disease, again, we see areas of increased FDG uptake, but that is not as well represented as on the PSMA PET scan, where we see more uptake involving that lesion in the right hemisacrum of the S1 level. But there's more uptake on the PSMA PET scan than we see on the FDG. There is some disease there in this evident of FDG, but much more obvious on the PSMA PET scan. Similarly, there's a lesion here in the right iliac crest with moderate to markedly increased PSMA uptake, but very little to no FDG uptake. This is a different picture than what we see with the lymph nodes, and again, I'm kind of highlighting a couple other lymph nodes in the right retroperitoneal fossa here that have intense FDG uptake, but very little to no PSMA uptake.

The conclusion is, when we look at this, is that there is discordant disease, that the soft tissue is predominantly FDG-avid and the osseous disease is either matching hypermetabolic and PSMA-avid lesions or predominantly PSMA. And when you look at this, it was determined that this patient was not appropriate for undergoing Pluvicto therapy, as these patients are known to have a worse outcome when compared to patients that have either matching or only PSMA-avid disease.

To highlight this, these are a few cases or papers that are coming from the literature. For example, from the literature, we have a patient here on the left that has a hypermetabolic left inguinal lymph node and very little to no PSMA uptake. In that same lymph node, this would be a discordant hypermetabolic lesion. This is a different patient here, also from the literature, that had an external iliac lymph node with relatively little FDG uptake, but rather intense PSMA uptake. And this would be an example of a patient that did not have discordant disease or just PSMA-avid disease. Again, when they look at this, they find, in this group, there is about 23% of patients had this discordant disease and they had had a higher grade of disease and progression.

When they look at how these patients responded to treatment, there is a marked difference in how the patients with discordant hypermetabolic disease responded to therapy compared to those with PSMA-avid disease. In those patients with discordant disease, they had overall survivability of 2.6 months versus 13.5 months, which is pretty remarkable.

The question could be asked, well, what if these patients, the reason they didn't do as well is because they did not receive the PSMA therapy, which is, in case, what happened with this group of patients. This study here that came out in 2021 kind of answered that same question. They similarly identified a minority of their patients that were being evaluated for PSMA therapy having discordant disease, in this case it was about 33%. And all patients, both those with discordant hypermetabolic disease and those with just PSMA-avid disease, underwent lutetium-177 PSMA therapy. The only difference is that those with the discordant hypermetabolic disease underwent fewer cycles.

When we look at the Kaplan-Meier plot, we can see that there's a clear difference in outcomes. They've all received PSMA therapy, but there's a clear difference in those that had PSMA concordant disease and those that had discordant disease. We can see that the overall survivability of the patients with discordant disease was 6 months versus 11 months.

So there is clear evidence that is kind of borne up by several small studies that patients with discordant hypermetabolic disease will have a worse outcome on the PSMA therapy. And even if it's only a single lesion, they will have worse outcomes. That's why the package insert and the consensus is that patients with discordant disease or evidence of PSA-negative disease should probably not be treated with the Pluvicto therapy, similar to our patients that I presented today. That concludes this case. I'd like to thank the SNMMI group for helping put this together and thank you very much for your attention.