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Alicia Morgans: Hi, I'm so excited to be here with colleagues, Dr. Heather Jacene and Dr. Oliver Sartor, to talk about the SNMMI consensus statement on patient selection and appropriate use of Lutetium PSMA 617 radionuclide therapy. Thank you so much, both of you, for being here with me today.

Oliver Sartor: Delighted to be here, Alicia. Always a pleasure.

Heather Jacene: Yes, thank you so much for inviting me.

Alicia Morgans: Well, of course. Well, you guys are wonderful colleagues and really such wonderful people to think through this particular issue, the use of this novel agent in our advanced prostate cancer setting. So, Heather, I'd love to start with you and just think through the people who came together to put together this consensus statement. How did SNMMI really put together the group that ended up collaborating here?

Heather Jacene: Yeah, so I think that was something that SNMMI did extremely well. When you look at the group who came together to write the document, it is composed of nuclear medicine physicians who are seeing and treating these patients, as well as medical oncology colleagues who are referring the patients. So, it is really a multidisciplinary document that gives both the perspective that's not only limited to the Lutetium PSMA 617 treatment itself, but also how does it fit in with the other agents and treatments that are available for patients with advanced prostate cancer?

Alicia Morgans: Well, and to that end, Dr. Sartor, can you tell me, it was interesting in this document, other therapies were incorporated as being potential options for treatment in advanced prostate cancer. What are your thoughts there, and anything that we should acknowledge and comment on?

Oliver Sartor: Well, I think we all know, Alicia, that the metastatic CRPC space is a complex one, and if you're going to be looking at the PSMA Lutetium in the post-chemotherapy space, post-RP space, there are other alternatives. And one might be cabazitaxel, which is FDA-approved for those who've progressed in a post-docetaxel space. And by the way, there may be some precision therapies. If you have an MSI-high, then thinking about a PD-1 inhibitor. If you were to have a BRCA2 mutation, then it may be a PARP inhibitor, and then of course, radium might also be able to play a role as well as the usual steroids, external beam, et cetera. So, I'll simply say that a medical oncologist or whoever might be managing the patient has to be cognizant of the multiple opportunities for therapeutic benefit. It's not just about PSMA 617. It's about the best option for the patient at the particular time they're being evaluated.

Alicia Morgans: I think that's a wonderful way to think through it, especially as we really do need to acknowledge that there are other therapies available for these patients, and though we are so excited to have this novel agent, we have to think through the best one for the patient at that particular time, so it's really important to include all of those.

Now, one of the things that I thought was so interesting and important is that there was actually a system used to really describe the appropriateness, and each of these settings was given a score for appropriateness of use of Lutetium PSMA 617 in these different clinical settings, including mCRPC after chemo and an AR pathway inhibitor, treatment of mCRPC after just an AR pathway inhibitor but before chemotherapy, and then treatment of patients with metastatic castration-sensitive prostate cancer. So three different scenarios and we had this ranking of appropriateness. Now, Heather, I wonder, can you talk to us a little bit about that ranking and let us know which were the appropriate categories for use as of this document?


Heather Jacene: Certainly. The appropriate use criteria are something that are very commonly applied to radiology testing, and it's generally based on the data and a clinical scenario is given a score rating from one to nine. And we rate scores as seven to nine as usually typically appropriate, scores four, five, and six may be appropriate in certain clinical settings, and then scores one to three are generally not appropriate to use that test. So in this document, we try to apply what's typically used in radiology to these clinical settings.

Alicia Morgans: Perfect. And as we could see in the document, really, mCRPC after chemotherapy, NNA or pathway inhibitor was given that top rating of a nine, whereas the other two scenarios were a three and a two, really suggesting at this point at least, according to the data that we have, that these are not the appropriate settings.

So Oliver, I'd love to hear your thoughts. There were two studies used to really inform the use of Lutetium PSMA 617 in this document. These are the two published studies with this agent, the VISION trial, and the TheraP trial. Any thoughts there, especially as we think forward and realize that there are more studies in the pipeline that will inform future use of Lutetium PSMA 617?

Oliver Sartor: Yeah. Alicia, I'll try to be efficient. The VISION trial was a pivotal phase three leading to the regulatory approval, and all the patients had previously been exposed to a novel hormone - abiraterone, enzalutamide, apalutamide, darolutamide - and then progressed and also been on a docetaxel or at least taxane-based chemo. So VISION sort of set the stage as a phase three, but the TheraP is also very important because of the different control group. In the TheraP, all the patients had to be chemo-eligible and they went on to be randomized to either the PSMA 617 Lutetium or cabazitaxel.

Now, it turned out in the TheraP trial that there are a variety of endpoints including PSA, quality of life, etc., that were favorable as compared to the cabazitaxel, but the overall survival for cabazitaxel and the PSMA Lutetium were essentially the same. Now, for the VISION, the control group would be standard of care, but excluding chemotherapy, and in that setting, it turns out that there's a survival benefit for the VISION trial.


Now, very briefly, there's a pre-chemo trial that'll be reported at ESMO. There's going to be additional trials that'll be presented further down the line, and I simply say it's too early to make conclusions about trials that have not been presented. So right now, we're in the post Abi, post Enza, post novel hormone space, post taxane, and then we have the option of going to the PSMA Lutetium, provided the PSMA PET shows eligibility and you believe it's the most appropriate therapy for your patient, but considering the alternatives.

Alicia Morgans: And that makes a lot of sense. And then I think just to dig in a little bit. In terms of patient selection, Heather, this document does comment on the use of PSMA PET as a way to identify potentially appropriate patients, really similar to the VISION trial. The TheraP trial also used an FDG PET to identify patients. Any thoughts or any guidance that we have from this document related to patient selection in terms of the PET scan that we should use?

Heather Jacene: Yes. So as you alluded to, the criteria between the VISION trial and TheraP for accepting patients were a little bit different. In the VISION trial, patients had to have all tumors that were greater than the liver uptake of the PSMA, and they couldn't have any PSMA negative disease. The TheraP trial used a slightly stricter criterion for eligibility where patients had to have at least one tumor with an SUV more than 20, all the lesions had to have an SUV more than 10, and you couldn't have a lesion that was PSMA negative and FDG positive. That led to a slightly larger number of patients becoming ineligible for the treatment based on the TheraP criteria.


Overall, the committee on this document felt that the VISION criteria would allow the agent to reach a larger number of patients, and at least in the United States, it's a bit more challenging to get the dual tracers for an individual patient. So I think there will, in the next couple of years, we'll probably see a lot more work about using the images as biomarkers for prognosticating and for prediction, but right now, most places and the document is recommending using the VISION criteria for selecting patients based on the PSMA PET scan.


Alicia Morgans: Great. Very helpful, and certainly very clear in an area that sometimes can be challenging to think through. So as we start to wind down, Oliver, I'd love to hear your thoughts on part of this document that's very, very helpful for clinicians in terms of how do we choose patients and keep them safe, thinking about renal function that needs to be at a particular level? The recommendation here was a GFR greater than or equal to 30, and then also thinking of course about bone marrow dysfunction with a hemoglobin greater than eight, white cell count greater than two, ANC greater than one, and platelets greater than 75 being the recommendations in this document, again, for baseline laboratory cutoffs. Any thoughts, any insight from the discussions that took place within the panel to define these values?

Oliver Sartor: And Alicia, really good point. There are some areas of controversy here, and it's a bit hard to be dogmatic, simply because we don't really have great cutoffs that we're going to use. In the SNMMI document, we have a consensus statement, and people were thinking that it's okay, so long as your hemoglobin is greater than eight, your white count's greater than two, platelets greater than 75, and creatinine clearance is greater than 30, and ANC greater than one. So these are the parameters that we kind of agreed upon.


Now, how strong is that evidence? Because consensus is one thing, evidence is another, and it turns out that we have a consensus but we don't have strong evidence. I'm simply going to say that a lot of the dosing for this type of agent in part depends on the circumstances. Imagine, for instance, if the patient had docetaxel, Cabazitaxel, multiple hormones, then what other alternatives might be present if you tested them for genetic alterations and found none? This might be your only shot. And there, you might have a slightly more liberal approach toward the hematopoietic counts and take a bit more of a risk because the patient needs to have more of a risk taken.


As it turns out, I think as we go forward, we're going to have some better cut points in terms of safety, a bit more data-driven, but right now, I think there's some latitude being given to the clinicians in saying it's okay to treat, even if the counts are not ideal, particularly considering that this could be the best alternative for the patient.


Alicia Morgans: Really, I think this is so useful in practice when we are struggling with some of these decisions. Now, Heather, there definitely are some unanswered questions, some current clinical struggles, and one of those is how we think about imaging during treatment and even when we think about stopping treatment. So any thoughts, any guidance from the document here?

Heather Jacene: I think this is also an area of controversy, or maybe not so much controversy as uncertainty. In the studies, they used RESIST and the prostate cancer working group 3 criteria for following patients every 12 weeks during their treatment. There are certainly some places who are continuing to do that based on the clinical course of the patient, following them also with PSA levels. Some places, I think, aren't yet following patients during the course of the treatment or have a specific timeline when they're getting it, basing it a bit more on how the patients are clinically doing and using both the clinical and the PSA levels to drive when they are also doing routine scanning like CT or bone scan.

One area to pay particular attention to is patients who have liver disease or who may develop liver disease during the course and making sure that there's a contrast CT to look at that disease. I think that using PSMA scans, PET CT scans to follow these patients is an area that we'll see grow in the future, and also using post-treatment. So you can image the Lutetium PSMA 167 as well during the course of treatment, and there is evidence showing that that could potentially provide some information about if after three or four cycles, you don't see anything else on that post-treatment scan, do you need to continue therapy? And I think those are data that are hopefully going to be emerging in the upcoming years.


Alicia Morgans: Absolutely. I think we're all eager to hear that data. And then, Oliver, one of the final comments from you. In VISION, a fair number of patients, at least half of the patients, actually received simultaneous AR pathway inhibitor treatment with their Lutetium PSMA 617. This is an area that we continue to think about. Should we be using these treatments in combination with our Lutetium when we are applying this therapy? The document does comment on this. What are your thoughts here and the thoughts of the consensus panel?


Oliver Sartor: Yeah, really good point, Alicia. The VISION was designed with a standard of care in mind, and that typically was going to be the hormonal type agents, steroids, external beam radiation. And when I embark on therapy with these patients, I'm thinking about the standard of care plus Lutetium. First of all, I get questions about external beam radiation. If you think a patient needs palliative radiation, well then, do it. They ought to do it. If they need steroids, then give steroids. If you think that there's potential benefit to be derived from an androgen receptor pathway inhibitor, then do it.


And by the way, within VISION, if you look at the forest plot as part of the manuscript very carefully, you'll see there was a tendency, not in a statistically significant way, but for benefit for those who had an androgen receptor pathway inhibitor plus Lutetium as opposed to Lutetium alone. Now, I'm going to maybe give a little plug for Louise Emmett and I won't use her full talk, but I simply think it'll be interesting to look at a prospective trial evaluating hormones and Lutetium versus the hormones alone, Lutetium alone type approach.


Alicia Morgans: I could not agree more. Certainly looking forward to that presentation as well. So as we do wrap up now, I would love to hear from both of you, any kind of final comments and thoughts on this document? Anything else you wanted to mention in this really valuable consensus piece? And we'll start with Heather.


Heather Jacene: No, I think that just to wrap together all of the things that we were talking about, just as the document is multidisciplinary, I hope that it will really encourage everybody who's out there practicing to think multidisciplinarily about these patients and some of the areas where, as a nuclear medicine physician, you may feel uncomfortable treating the patients and the medical oncologist might not. But by working together, I think we can really bring these agents to the right patient at the right time when they need it most and get them through the treatments together. And I think that's, at least in our practice, been really important and helpful.

Alicia Morgans: As a member and a part of your practice, I could not agree more on that comment, of course. And Oliver, your thoughts?

Oliver Sartor: You know, Alicia, any document today I think should be viewed in the context of the changing data that we encounter virtually every day. The document was a really good document when it was written, but you know what? There's going to be new data that are going to provide new insights, and I really think it's important that clinicians not be bound to guidelines as much as they are to the evolution of data and what they believe will help their patients going forward. So I look forward not only to the document having an influence in the near-term future but also the new data that will influence the next steps. So let's stay tuned and look forward to learning more about this disease and treatment.


Alicia Morgans: Wonderful. Well, just to summarize, this document gives a high level of appropriateness to the treatment of mCRPC after chemotherapy and an AR pathway inhibitor, and lower levels of appropriateness to other stages of metastatic disease. This is an area that may change over time. There, I hope, will be updates to this document, particularly as we see new data coming out in the very near future related to PSMAfore and PSMAddition a bit later on.


We also review that there are safety data in here that I think are really helpful parameters to help us guide our clinical practice and help keep our patients safe, and to think about what we need to monitor especially things like cytopenias, kidney function, as we are treating these patients, and of course their day-to-day, how they're doing, and deal with any complications that arise from their perspective, including things like nausea as we heard from Dr. Sartor.


Thinking about things like combinations with AR pathway inhibitors might be a good idea, certainly is something to consider, and more data is going to come on that as well as data on how we follow these patients with PSMA PETs over time, thinking about CTs with contrast for liver disease in particular. And as everything evolves, continue to refer back to your Today for the updates as they come. So thank you both so much for your time and your expertise. I really appreciate you.


Heather Jacene: Thanks, Alicia.

Oliver Sartor: Thank you, Alicia.