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Phillip Koo: Hi, my name is Phillip Koo and welcome to UroToday. Today, we have with us Dr. Thomas Hope from UCSF to talk about the recently published consensus statement on patient selection and appropriate use of lutetium-177-PSMA-617 radionuclide therapy that was recently published in the Journal of Nuclear Medicine. First off, Tom, congratulations on getting this to the finish line so quickly with a very multidisciplinary group of physicians.

Thomas Hope: Thank you, and I'm glad to be here again and happy to talk about it.

Phillip Koo: Papers like this really provide a great resource for the community, especially when you're dealing with treatments that are new and there's a lot of questions. Can you walk us through the process and how you envision this being a resource for a lot of those practices out there looking to get into theranostics or RLT?

Thomas Hope: I think this document, it's primarily focused on appropriate use, which comes out of the PAMA legislation for PET radiopharmaceuticals. But in this setting, the actual indications aren't all that debatable. It's post chemotherapy mCRPC. That's the label and that's what we're going to use until new literature comes out and approval of PSMAfore. We'll see how that changes. But actually the real value in this document are the struggles. And actually, I think this is what I really enjoyed the process of writing this document, because there's so many issues about how we use this, what patients we should use it in terms of toxicity, patient selection, imaging, et cetera.

And so the document actually ended up being a lot more focused on trying to provide information to help clinicians who aren't used to treating patients with PSMA radioligand therapy and really, how to address these patients that aren't right down the middle, obvious patients who are candidates for PSMA radioligand therapy. I think that's really what was valuable to us, and I hope that other clinicians read this and learn from it, because it was really for us. I learned a ton just in the process of discussion with all the experts who were on the committee.


Phillip Koo: I agree with you 100%, and hearing the discussions about a lot of the topics really allowed me to learn about how this could be utilized across the country. One of the hot topics that came up was patients with renal failure or renal disease and how you adjust those or factor that into whether or not they should receive the drug. What are your thoughts and some of the conclusions about that?

Thomas Hope: I think the first thing to remember is oftentimes, people, when the drug first come to market, they look at the inclusion criteria of the trial and then they apply those inclusion criteria to the patients they see in clinic. It's really important to remember that the patients they treat on a trial are selected carefully so that you limit toxicity and it gets the drug approved. It shouldn't be used as the gatekeeper for the patients that you see in clinical practice. I think this is true for kidney injury. The trials, we referenced the TheraP and the VISION trial, which respectively had, I think a 50 and a 60 mLs/minute eGFR requirements to get on the study.

And in those trials, they didn't really see any difference in kidney toxicity within the treatment in the control arms, so we don't really expect there to be any significant kidney toxicity out of proportion compared to other drugs like lutetium dotatate. In the post chemotherapy setting, the expected lifespan of patients is not really long enough to even develop kidney toxicity. We talked about loosening that up, and the guidelines ended up recommending a GFR over 30, and then with the caveat that you can treat patients with a GFR less than 30, but probably should discuss that with a multidisciplinary team before moving forward.

But that doesn't mean that patients can't benefit from treatment if they have lower GFRs, and I think that's really important to realize. We haven't really seen much kidney toxicity in patients. And I would say when I say that, it's limited to patients who are treated with six cycles. There's a couple of case reports in the literature that when you go beyond six cycles, you can start to see some evidence of kidney toxicity from the cumulative radiation. But when you're talking about those first six cycles, we don't really have any evidence that there's actually kidney toxicity associated with it.


Phillip Koo: Great. So then, I love that approach of taking some of those patients that might have lower than what was in the trial and just talking about it as a group. Platelets came up as well. Your thoughts there? I think there's a recommendation to sometimes lean towards high volume centers in some of these tricky situations.

Thomas Hope: Yeah. There's hemoglobin, platelets and white blood cells, and this agent is marrow toxic. I don't think it's as marrow toxic as chemotherapy, but a lot of these patients, especially in the post chemotherapy setting, come in with pretty beat up marrow. They might be transfusion dependent. Their platelets are low from the prior chemo or because their marrow is replaced by tumor. They have so much tumor in their bones, their counts are going down. Those are the two reasons people come into this treatment with a lot of marrow toxicity. Now, those patients, it doesn't mean you shouldn't treat them. You just have to be aware of toxicity associated with the treatment.

If you have someone whose marrow's replaced with tumor, if you don't treat them, that tumor grows and replaces the marrow and the patient passes away. If you do treat them, there's going to be a lot of associated marrow toxicity. So you're sort of between a rock and a hard place, but in the end, a lot of these patients will benefit. Just be cautious about the fact that you're going to see a lot of marrow injuries in the short-term after the first or second cycles. There are many patients who you will treat, you'll debulk the disease, and the counts will slowly recover beyond and above what they were at at baseline. There are also patients who won't recover as well.


We recently went back and looked at the patients who didn't meet the VISION hemoglobin criteria and platelets criteria. What was interesting about it is they had a lower overall survival than the patients who did meet criteria. Not surprising because they're sicker, they have higher volume disease, they are more heavily pretreated, but they had the same PSA response. But the PSA50 rate, in those patients is the same as the patients who had higher counts, so you get the same efficacy. You're just treating a sicker group of patients, so you just have to be cautious about withholding what's an effective therapy in the setting of these lower counts.


Phillip Koo: I think that's a great point that I think is often misconstrued where you have patients with that marrow packing. This could actually help their marrow potentially in the long run. Another hot topic is patient selection, and we hear a lot about using FDG and whatnot. What are your thoughts on, and the group's thoughts on FDG to help select patients?


Thomas Hope: Not surprisingly, there was a lot of debate about the role of FDG and whether or not FDG should be used. In general, it was agreed that FDG should not routinely be used for patient selection for PSMA radioligand therapy. There's really just a lot of debate in the community as to what the role of FDG is for patient selection and radioligand therapy. When I talk about heterogeneous disease, which is what you're really looking for, where PSMA negative, FDG positive disease in the setting and someone who would otherwise qualify. In heterogeneous disease, I think of it in two groups. One is liver lesion, and you sort of know that. You have a four centimeter liver lesion, doesn't have PSMA uptake. I don't really need an FDG PET to show me that.

The extraosseous disease, you can just look at the images and you can feel fairly confident that you're characterizing that heterogeneity accurately. The bone disease is a different story. You've got a patient coming out of docetaxel chemotherapy. You have some bone disease. The SUVs are six. You don't know if that's this mean FDG positive, PSMA low expressing clone, or is that treated disease? It's really in the bones where you can't really tell well what's going on in terms of heterogeneity. Now, in some patients, and depending on the pace of the disease, it’s not really matching what’s going on the PSMA PET and the pace and what's going on. Maybe you get an FDG PET.


More of what I've come to, my style here, and it's not reflected as much in the document, is I think of the first two cycles as seeing if the patient responds. I am coming to the point where I try to make everyone get at least two cycles. If they can get it through two cycles, you'll see if their PSA is going down. You're going to see how they're responding. We use a lot of post-treatment imaging, post-treatment SPECT/CTs after each cycle to evaluate if it's progressing or responding. And I use those two cycles to say, "Hey, are we going in the right direction?" Because right now, when you're in the post-chemotherapy setting, there actually isn't another good place for the patient to go for therapy.


As we start moving earlier and earlier, that's a different story, because then you're going to start deciding between two more effective therapies. But right now, it's really last line. I really want to give the opportunity to the patients, so I don't use FDG as a gatekeeper per se. On therapy, there are patients whose PSA will start rising and you don't see any new lesions on the post-treatment imaging. And so are they developing some PSMA negative? We have used FDG PET in that setting, but it's really the minority of patients where FDG PET is really needed for patient selection.


Phillip Koo: Great. We talk a lot about and hear a lot about non-PSMA expressing disease. In the paper, I think we recommended using contrast enhanced CT or MRI oftentimes to identify that. That being said, are you routinely getting a contrast enhanced CT with a PSMA PET for patient selection?


Thomas Hope: Yeah, we use a contrast CT and we use it to follow patients. This merges into baseline and during treatment. We're trending away from getting a bone scan in general, so we're using the post-treatment imaging to look at the bones, the post-treatment SPECTs and the PSMA PET. The bone scans have sort of disappeared from my practice in managing patients here. But we use contrast enhanced CTs on treatment and at baseline, and that's actually incredibly valuable.

And the baseline is important, actually not so much to make sure that you see PSMA negative disease, but if they have a lesion two months later during treatment and you don't have a baseline CT scan to compare to, you have no idea if that's new, shrinking, growing, what the avidity is like. It's really important to get that both as a baseline and also to screen patients. Frankly, it's somewhat unusual to miss PSMA negative disease on baseline even without contrast, because the lesions are usually obvious enough in the liver. When you have PSMA negative disease in the liver, it's not subtle typically.

Phillip Koo: I presume you're not using PSMA PET to follow these patients. Are there certain instances in which you will get a PSMA PET for patients who are on treatment?

Thomas Hope: That's a good question. As I mentioned, we do a lot of post-treatment imaging, so you image a patient a day after with gamma cameras, SPECT/CT. We do that, and that's like getting, in essence, a poor man's PSMA PET after every cycle. And I find that surprisingly valuable. You can see disease shrinking and growing, heterogeneous response. It helps you really interpret what's going on with their PSA. If they're developing back pain, is there a lesion there? We just had a patient today who had back pain, who they got an MR of the spine and they saw a new lesion, and we looked on the post-treatment images and there was no uptake there. So, that's a PSMA negative clone that's confirmed by comparing to the post-treatment imaging.

Maybe it's probably 50 to 60% of our patients actually have a change in management throughout their treatment based on the post-treatment imaging. The only time we really use a PSMA PET during therapy is when we actually do stop treatment every now and then. And not as infrequent as you might think, maybe 20% of patients, because their PSAs go down 95%. Their post-treatment imaging shows near resolution. It is usually not a complete response, but significant decrease in the disease. And so let's say seven months later, the PSA starts rising. To make sure that their new progression that's occurring, given that you're so far out from the treatment, we'll repeat the PSMA PET to make sure that we're still treating PSMA avid disease.


Phillip Koo: Last question, we're eagerly awaiting the presentation of the data with PSMAfore, the use of Pluvicto, castration-resistant patients before chemotherapy. That's been reported out as positive. How do you predict this is going to change the landscape? And I imagine the consensus statement will have to be adjusted accordingly.

Thomas Hope: Yeah, the consensus statement was written with the expectation that it will change. It even says it in there, when a new indication gets approved by the FDA, that this document would reflect those changes. Until that's reported out, obviously it's not indicated pre-chemotherapy. My expectation, and you manage these patients, you want to move this pre-chemo. It's much better tolerated. It's less marrow toxic. Patients are going to want to go to this before chemo.

The only question here is going to be in patients with lower expressing, more liver dominant disease. Would those patients be better suited with chemotherapy? But in general, this will go pre-chemo pretty much. In my practice, 80, 90-plus percent of my patients would go pre-chemo. I would obviously not require docetaxel treatment prior to PSMA radioligand therapy, assuming the results of PSMAfore, SPLASH, ECLIPSE all come out nice and positive as we all expect.


Phillip Koo: Well, thank you very much, Tom, for your time. Always enlightening and always learn a lot every time. And just thank you for your contributions to this important topic soon.