Oliver Sartor: Hi, I'm Dr. Oliver Sartor with UroToday, and having a special guest, Dr. Michael Morris, Head of Prostate Cancer at Memorial Sloan Kettering, I think everybody knows Mike. Mike, we're going to be talking about some interesting things today about the utilization of lutetium and other possibilities within the metastatic CRPC space, and we're going to focus a little bit on what we call the PSMAfore space, a trial that you helped lead. Let's start off by talking about what is this space, and then move on to the options and sequences that might be possible so you take it, right?

Michael Morris: Sure thing. First, thanks for having me, Oliver. It's always a pleasure to be on UroToday, and always a pleasure to talk to you. What we're referring to a little bit in lingo with PSMAfore space is really referring to that first metastatic CRPC place in a patient's history after the patient has progressed, generally speaking on an ARPI for castration-sensitive disease. Most patients should be on ADT and either abiraterone, enzalutamide, apalutamide, or darolutamide for initial therapy. Then when they progress, we know from a considerable amount of data that a second-line ARPI is generally not going to have profound or durable anti-cancer effects. And in today's day and age, one could get either chemotherapy, or lutetium, or if they have a susceptible mutation, they could get either a PARP inhibitor or immunotherapy if they're MSI-high. There are really four standard choices that one could get now in that space, and the question is how do we decide who gets what? What's best for which patient? And are there specific sequences even that lend themselves to the optimized care?

Oliver Sartor: Mike, this is a wonderful topic because it truly bedevils our field. And so within the FDA label on the lutetium within this "PSMAfore space," it very specifically noted that the lutetium was appropriate for those in whom chemotherapy might be delayed. So help us from your perspective understand which patient might be more appropriate for chemotherapy, which for lutetium. Just for a brief moment, let's not worry about the MSI-high or the HRR mutated type patient because that's going to be a different discussion.

Michael Morris: Remember that lutetium is only appropriate if you express PSMA, because otherwise you're not going to deliver radiation to the tumor. So certainly, a patient who has a low PSMA PET scan should not get lutetium and they should get chemotherapy. Now, that is only around 10% of the population in that space so that's not going to apply, it's not going to relieve you of the burden of the decision for that many patients, but certainly if they don't have a positive PSMA PET, then they should get chemotherapy. The harder question is what features lend themselves in somebody who is PSMA avid? What features lend themselves to chemotherapy versus lutetium? A lot of people feel very concerned about visceral metastasis, in particular liver metastasis. Those patients do poorly with all therapy. But I think that many would say that you need to go in with chemotherapy for those patients, especially if it's unclear what the tumor dosimetry would be. It's not to say that I don't think that patients with liver metastasis if they're PSMA avid would never get lutetium, but in terms of the sequence, I think many of us would give chemotherapy first, especially if their PSA values were low relative to their distribution of disease, if they had really unfavorable genetics like p53, RB, and PTEN. There are some things that, some biomarkers that we might use to bring, they have rapidly progressive disease as well that would lead us to chemotherapy before lutetium, but there aren't good randomized data to really inform these decisions.

Oliver Sartor: Mike, I'm going to go a little bit complicated here, but it's a question I would like to ask you. When we begin to look at the PSMA PET scans, assuming positivity, we see a wide spectrum of disease. We may see patients with one to two lesions, we may see patients with 59 or even 100 lesions, so it's a broad spectrum of volume. How does that volume influence your decision? And if you will, consider the possibility of SBRT in the mix of things, which is not a systemic therapy, but as a therapy we sometimes use. Thinking about this volume, how does that influence you in your patient selection?

Michael Morris: Sure. I think that's a really important question. It speaks to the other side of the spectrum. We were just talking about the patient who is really in trouble and you think they need upfront chemotherapy to render them into a safer space. Then you have the other side of the spectrum in which patient may have responded to their initial ARPI for castration-sensitive disease and now they just have one or two new lesions as the manifestation of their CRPC. For those patients, I generally do give them SBRT to address their individual new lesions. If they are long-term responders, I might even switch their ARPI and RT in that circumstance. I think that those very slow progressors who have just a small amount of disease, I would hold off on their total marrow exposure to systemic radiation therapy with lutetium and probably just deliver metastasis-directed therapy. I think that's an excellent point that you make though is we're dealing with a full spectrum of disease here for which there is not one size that fits all.

Oliver Sartor: Mike, that's completely in agreement with my own thinking. And when I see these patients in the clinic, I see the heterogeneity, and some of the patients are rapidly progressive, high volume, plus or minus of visceral mass. Some of the patients are low volume, slowly progressing, and that heterogeneity is I think a challenge for the clinicians everywhere because we don't have good guidelines of who to separate. I'm going to switch topics just a little bit because I'm very interested in the way that you are using lutetium, and the manner in which you monitor the responsiveness or progressiveness of the disease after lutetium is given. What do you do with scans? What do you do with PSA? What do you do with clinical parameters? What do you do with conventional imaging? Love to hear your thoughts on how to follow these patients from the perspective of ascertaining response and progression.

Michael Morris: Sure. About every two cycles, so just shy of their third cycle, we will get a PSMA PET to assess either response or progression, but it's not a single point of data for decision making. We look at the PSA, we look at the scans, we look at the patient's counts, and we look at how the patient is feeling. Now what we will do is if all things are pointing towards progression, even after only two cycles, if we see a proliferation of new lesions on their scans and the counts, and/or the counts are plummeting, or the patient has new pain and the PSA is rising, we will stop therapy and move on. We don't want to treat a patient with a full six cycles if things look like they are going in the wrong direction. This isn't like radium, for example, where we can image and we don't know what an image looks like. We have now in today's day and age, tumor-directed imaging, and we can use that and I find getting a PSMA PET very informative and very, very useful. We also do at MSK post-injection imaging to ensure that the drug is going to the tumor, especially if we are going to consider discontinuing therapy, if we see that the drug's no longer localizing to the cancer because what's emerging is just not PSMA avid will also discontinue treatment. The dilemma is of course, let's say that you get mixed signals, the PSA is going down, scans are doing a different thing. I generally err on the side of keeping the patient on treatment if I really am unsure if the patient is benefiting or not. But when I'm sure that he's not, I like having those early looks to know that.

Oliver Sartor: Mike, I'm so glad that you covered that, and it's a really important point, so it's a really important issue. Sequential therapy, your approach, how do you think about it today?

Michael Morris: It's interesting that you raise this question now because just a couple of weeks ago, Kim Chi presented at ESMO a trial in which, this was a Canadian study, in which patients either received chemotherapy or they received a dosing and then of course they could receive as subsequent therapy what they didn't receive in going into this study. There would be nothing to prevent a patient who got chemotherapy from ultimately getting Pluvicto and vice versa. And when they looked at the data, although radiographic progression-free survival was pretty much overlapping of the two treatment sequences: chemo and then Pluvicto, or Pluvicto and then chemo. Patients who seemed to have an overall survival advantage were those who received chemotherapy first. I think that does raise an interesting question. First, we should have more definitive data and expand that into a phase three concept. I guess in the absence of that, it raises a question of should we be looking at some real-world data to try and confirm or refute that recognizing that's not randomized. There's a fair amount of selection bias in terms of real-world data, but I think that it does bring to the fore of where should Pluvicto be placed optimally for the patient's best survival likelihood. We have approval now across the entire spectrum of metastatic castration-resistant disease, and we really don't know how we should be sequencing.

Oliver Sartor: Mike. One of the things when I looked at the data from that Canadian study, it bothered me. We looked at survival in the PSMAfore space, it came out with about 24 months and that's pretty solid. It's in both arms, crossover everything, so that was pretty commensurate with I think my expectations, a couple of years. If you go from the ADT, ARPI progression, got a couple of years in CRPC and then survival. In the Canadian study, the findings, particularly the lutetium arm first were very distinct. And in fact, it almost looked like what I call the VISION population with about a 15-month survival instead of a 24-month survival. And I was wondering, were those Canadian patients analogous to those we treated in PSMAfore or were they really a very different maybe chemotherapy-suitable subset? And if I were a patient considering randomization on that type of trial, I would not be volunteering for the trial unless I was truly a chemotherapy candidate. I'm just wondering about the patient selection, that's the bottom line.

Michael Morris: I totally agree with you. I think that that trial is a trial of patients who the patients and their clinicians would agree that upfront chemotherapy is appropriate, but they just don't know. And so those patients, I think do represent this specific subset that was excluded from PSMAfore, that is it's set in the eligibility criteria. If you think your patient needs chemotherapy, don't put this patient on study. Now, on the Canadian trial, it would've really been a perfectly appropriate trial because they had a chance of either getting chemotherapy or lutetium, so that intrinsically seems to me, and I think I'm hearing the same from you, to be a higher risk patient population.

Oliver Sartor: All right, so Mike, we've talked a little bit about the heterogeneity of the patient population. We've talked about lutetium, we've talked about monitoring, we've talked about some sequencing. Let's talk a little bit about safety. There are concerns about giving an isotope earlier in the treatment paradigm because of the longer-term follow-up may give predisposition or more likelihood of marrow suppression, clonal hematopoiesis, maybe even renal problems. How do you view this safety issue, particularly as we move the lutetium a little bit earlier into the CRPC space?

Michael Morris: I think it's a real issue, a real concern. You and your colleagues at Mayo did a very nice study of the hematologic potential toxicity risk by looking at both clonal hematopoiesis and at MDS and other alterations, and there is some signal there. I think if you look at all of those together, it's around one and a half percent. At the same time, I think that as we move into the alphas, marrow tox, that could be presented downstream with early therapy, and also nephrotoxicity. Even with lutetium, our German colleagues had a very nice analysis. Following patients' creatinine after lutetium for a long time, and there's about 40% of renal insufficiency after enough years and enough doses are administered. I think it's something that we need to look at very closely as we move these therapies early. I don't think that that's a reason not to do the trials of early therapy, but it is a reason to look carefully at the toxicities from kidney, marrow, and blood to ensure that the degree of benefit from early therapy is commensurate and justifies the early toxicity that we might see. I don't think we have the answer yet, but I think that it is something to be cautious about and to proceed carefully.

Oliver Sartor: Thank you, Mike. The next question, I'm going to warn you, is not really fair because we don't have a lot of time to discuss it. We could talk about it for hours and hours, but within prostate cancer, we seem to be stuck with giving one therapy at a time. And the combinations which we were so critical to, I mean going all the way back to testicular cancer, to Hodgkin's disease, it was the combinations that led to the most traumatic effects. Why can't we get to the combination therapies in prostate? And if you could move forward with a combination today, which one would you choose? That's a 45-minute answer, but we only have a couple of minutes, so I'm going to ask you to be succinct if you don't mind.

Michael Morris: When we think of combinations, there are two benefits that we should consider. The first is the additive combination that is just killing more populations of cells than we would've ordinarily kill. For example, if you had a targeted therapy that was not strictly PSMA-directed, and so you are basically culling more cells. For example, PSMA and KLK2-directed therapy, PSMA and STEAP1-directed therapy. Those may yield a greater reduction in tumor burden in increase in quality of life, and greater longevity. Then you have the potential interacting mechanisms where one is really helping the other. For example, the combination with agents that promote PSMA expression and thereby increase the amount of dosimetry delivered to the tumor. That could be AR-directed therapy. That could be the new AR degraders. That could be even other means of regulating PSMA expression, or immunotherapeutic combinations in which you are basically exposing epitopes that otherwise might not be exposed and increasing the immunologic activity to make the tumor more amenable to a combination. I think like combinations with the T-cell engagers are provocative and some of the newer immunotherapeutics. I think that I don't have necessarily a favorite regimen, but if I had a favorite mechanism, obviously two drugs that are amplifying the antitumor effects mutually, not just additive combinations of killing more cancer with two different mechanisms, have their appeal in order to really change the game of how we're treating the disease as opposed to one drug just stacked up on another.

Oliver Sartor: Mike, we're going to need to wrap it up. We actually ran a little bit longer than expected, but I enjoy the conversation. Always enjoy hearing your insights and perspectives, your experiences, and you've contributed so much to the field, so Michael, let me say thank you for your many, many, many contributions over the years, and for those to come, you're not done yet. With that, I'll wrap it up here at UroToday. Again, thanks to Michael Morris for joining us on this special session.

Michael Morris: Thank you so much for hosting, and for having me on today's episode. Thank you.