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Phillip Koo: Hi, welcome to UroToday. Today we're very fortunate to have with us Dr. Tom Hope from UCSF, who's very familiar to all of us. Thank you very much for joining.

Thomas Hope: Thank you for having me again.

Phillip Koo: We're almost a year since the FDA approval of Pluvicto, Lutetium-177 PSMA, and now that we have a little bit of experience, there have been some challenges, I imagine, in real world types of situations that weren't necessarily addressed in VISION. Can you enlighten us with regards to some of those challenges and how you deal with them, especially from the perspective of a high volume center?

Thomas Hope: Yeah, so there's a ton of challenges and it's a learning curve for sure, especially for nuclear medicine physicians who aren't really used to treating patients who are so sick. So I'd break them up into three categories.

The first main category I would go with is patient selection. How do you determine who to treat? And the issues with that are a couple fold. So A, low expressing patients, patients who have a PSMA PET where you have an SUV of eight. It's slightly higher in the liver. They meet the criteria. You're pretty sure they're not going to do very well. Maybe they have higher volume disease. How do you prioritize PSMA radioligand therapy over second line chemotherapy or other treatments? And I think we don't really understand how to handle these. I call it the VISION gap. The people who don't meet criteria for therapy but do meet criteria for VISION, particularly on the lower end of that in terms of expression. How do you handle those patients.

I think the second struggle is patients who have laboratory abnormalities. I get lots of emails, "Do you use the VISION cutoffs for hemoglobins or platelets? What about patients with renal failure, et cetera?" And I think it's really important, particularly in the VISION patient population where patients are sick and there's no other treatments available. You can't not treat a patient because their hemoglobin is 7.8. You transfuse them just like you would with chemotherapy, and I think we're not used to that obviously in nuclear medicine, all the supportive care that you need for patients with marrow disease, et cetera.

And it's also I think one of the lessons I learned early on. You'll stop chemotherapy, you'll let the counts recover, but if they have a lot of marrow disease, their counts may never recover, and you got to be really careful pausing, waiting for people to recover and actually be more aggressive than you think you would need to be in these patients who have significant marrow disease.

And same with kidney failure. VISION, if I remember, the cutoff was EGFR of 50, and that's a pretty high cutoff. A lot of patients have an EGFR less than 50, and we don't really see any kidney toxicity from lutetium PSMA radioligand therapy. We obviously treat patients with lower GFRs, and even if it's under 30, we'll have a tumor board discussion about whether or not we should treat those patients. The main issue if you do have kidney toxicity baseline is actually marrow exposure because you have prolonged blood pool activity. So selecting patients, how you do that is actually quite difficult.

I think the other aspect that I struggle with is on the other end, when do you stop therapy? What is treatment failure? You don't have much to go to after this. So when patients PSA starts to rise, you keep treating. How much progression is too much progression? Once you see a new lesion and you'll see a lot of patients whose bone disease shrinks, but their liver disease grows slightly or their nodal disease changes differently, or maybe their quality of life's improving, but they're actually progressing in some areas. How do you handle that and when do you determine that it's end of line for these patients and you should stop therapy? So I think that's something I really struggle with in, and how to define ending of therapy in patients who aren't doing as well.

And then also in the same vein, patients who do well, do you spread out doses? Your PSA goes down by 90% after two cycles, what do you do? Maybe you have a little bit of uptake. We do a lot of post-treatment SPECT imaging, and I find that incredibly valuable to track your patients over time. How do you use that information with a PSA response to delay a dose? Do you wait for the PSA to rise? There's a lot of patients, your PSA after cycle one, it does weird things because you're treating the disease, but then it'll start to come down.

Once it comes down, then it will sort of nadir and some patients will just keep going down for months. Other patients will come right back up. But how do you use that treatment, holidays, et cetera, to actually spread out the doses and use it as effectively as possible while minimizing toxicity.

And then I think the third one is just workflow. A couple fold. So A, can't get doses. It's very hard to get this. There's production issues obviously, and so we don't have availability of doses, so it's very hard to prioritize your patients. There's a lot of these patients coming through nursing resources, scheduling resources, nuc med technologists, all of that to help set this up, is actually quite a herculean effort to get programs up and running. I think all of us around the country are sort of learning a lot of lessons this time through about how to actually get these treatments to the right patients effectively and as quickly as we can.

Phillip Koo: Great. So you know, talked about the VISION gap with patient selection. We have lab abnormalities, we have when to start, when to stop, and then we have those operational issues. So it's actually really comforting to know that someone like yourself in a high volume center with experience is still running through these challenges and finding ways to overcome them. So what type of advice would you have for those in the community or those centers that are just starting, how to manage and deal with a lot of these situations that you necessarily can't always plan for?

Thomas Hope: So I think the most important aspect of this is having a really close relationship with your medical oncologist. And I think that's the relationship that's really key because your medical oncologists that you're working with to manage that patient will have seen this patient over a long period of time, will know them, will know their goals of care, will know their marrow history, will help you with the transfusions. Obviously if we don't do much transfusions, we work with our team in medical oncology to manage all that. So I think that relationship is absolutely key. The multidisciplinary discussions, tumor boards, all of that, you have to work together as a team. So I think with iodine therapy historically, you get sent a patient, you give them the pill, patients get treated, everyone does well because it's such an effective therapy, they go away. This is very different. It's not just they come in the door, you give them the drug. You have to really work with the team and really help manage the patients, have a little more ownership than maybe we're used to historically in nuclear medicine.

Phillip Koo: Great. So we're going to shift gears a little, and we know now that PSMA-4 is positive. We anticipate hopefully the results being released in May and then maybe a label expansion soon following that. What are the nuances or things that we should be thinking about once this hopefully gets approved in that pre-chemo therapy space?

Thomas Hope: Yeah, I think as you move earlier, toxicities mean more. So when I was describing the struggles we have with patients with marrow injury, et cetera, that's very different when you're in a VISION setting and there's likely not other treatments afterwards. So I'm much more willing to take a risk and treat patients who have low counts or kidney failure or something like that earlier on. There's more available options. They have longer lifespans that toxicities are more cumulative. So if you go in the castration sensitive, I'm more worried about dry mouth than I would be in a VISION setting. So having five years of dry mouth is very different than having eight months of dry mouth, et cetera. So I think, and as a general thing, when you're moving earlier on, you need to be more and more cognizant and concerned about the patients and the toxicity because they have a longer lifespan after the treatment.

So I think that has a couple rules. So a, do we need six cycles? We need to start to be a little more judicious about how many treatments we give when we give them, how do we spread out the doses and how do we use this most effectively in our patients rather than just pounding patients with our treatments. I actually personally think the pre-chemo post Abi, Enza RC environment is actually the sweet spot for PSMA radioligand therapy upfront. When you're treating patients, ADT and receptor inhibitors, those are going to increase your expression. And when you progress in the CRPC setting, that's actually probably the place where these drugs are going to have the best effects.

I like this space and I think it's where the drugs will end up, majority being used in the long run, but we have to start to learn about that. As I'm learning right now about the post-chemotherapy sort of end of this train, the patient populace are able to learn as well about pre-chemo. These will be lower volume patients. A lot of these patients that we enroll in these trials we're enrolling in the eclipse trial, which is the same thing as PSMA-4 with lutetium PSMA, they're much lower volume than we're seeing in our standard of care lutetium PSMA-617 patient populace. So how we think about that's different.

Phillip Koo: That's really great insight. I think oftentimes we hear about PSMA-4 and all these different trials that are bringing it earlier and we think, "Oh, it'll be better tolerated. Not a big deal. We don't have to worry about side effects." But you're right, the side effects when they do happen are going to mean more, and I think it's something that we all have to be prepared for. One question that comes up oftentimes is the safety of radium and lutetium, whether one's goes first versus another. What are your thoughts on that now that we have some data?

Thomas Hope: Well, data was a very, very generous term to use. There's data that obviously patients who went on VISION had, some of them had radium beforehand. No evidence of increased bone marrow toxicity from that. I think the community in general, I don't think really appreciates how well radium's tolerated. It's actually an incredibly well-tolerated drug, doesn't actually cause very much marrow toxicity. And I'm personally concerned that the use of radium is going to go down. It's already not high enough and it's going to go down with the introduction of lutetium PSMA. Now, how should it be used? I think as a different question, right? ALSYMPCA, the trial that led to the approval of radium is an interesting inclusion criteria from an imaging standpoint, right? Because it's supposed to be we're treating only bone disease, but it allowed patients who had three centimeter nodal beds in it, which is sort of crazy, right?

Three centimeters is a big, big lymph node. Obviously you couldn't have a liver or lung metastasis, but pretty large lymphadenopathy. And that might be why you didn't see patients who had PSA responses in that trial. But at the same time, there was nearly a four month overall survival benefit in a poorly selected patient population. So you got to remember that. So now we have PSMA PET, we know who's bone dominant, right? Or not bone dominant, but bone only. And probably about 40% of patients have bone only disease. So then the question comes, "Okay, I have a patient on a PSMA PET, bone only disease. How do we determine between radium and lutetium?" I mean, obviously there's no right answer. We don't have any data to tell us about that. But generally speaking, right? If you have a bone scan that matches the PSMA PET, good uptake on the bone scan, that's something that would push you towards radium.

And then if you have on the PSMA PET SUVs of 80, and that's going to push you to lutetium, right? And then also to me in general, the lower the volume you are, the more likely I think I would use radium. I think radium's a little better tolerated. And so maybe I would use that as a window of opportunity to use radium, and then you would go on to lutetium. I mean, clearly there's clinical data out there that there's no evidence of additive marrow toxicity when you sequence radium before lutetium. So there's no right answer there, but I think it's something our community has to figure out how to deal with instead of just forgetting about radium, which I think is a big concern for me.

Phillip Koo: Those are wonderful comments. I agree a hundred percent. The radium is underutilized and it is very safe. And I love how you talk about PSMA PET allowing us to select patients better. And I have no doubt that if we could identify those bone only patients, yes, they probably might have a PSA response and they will respond better. And also looking forward to the PEACE-3 data with Enzalutamide, hopefully that shows some good results there as well. Well, thank you very much, very insightful. Learned a lot and appreciate you taking the time to be with us.

Thomas Hope: Great. Absolutely good seeing you again.