Future-gazing radioligand therapy in prostate cancer | With Oliver Sartor and Michael Hofman

(upbeat music) - Hey Renew. - Hello, Declan. How are you today? - I'm very well. I was to be back in studio with some studio guests. - Back in studio and spit crowded, but in a good way, we've got some fantastic guests today. - We really do, so welcome to this episode of G.U. Cast. This one is supported by our silver partners, Novartis, which is very appropriate for today's topic of future gazing in radio ligand therapy for prostate cancer. - And I have a feeling we're gonna get a little bit of a history lesson too. - We are, so that's the idea today. We've got a couple of very eminent experts in the field of radio ligand therapy and prostate cancer with Professor Michael Hoffman, Professor Oliver Sartor, we'll get to in a moment. But the idea is to, well, let's reflect a little bit, but we want to pick their brains and see, what is the future? Where are we going with this extremely exciting area of radio ligand therapy? - It's just such a rapidly evolving field, isn't it? From the days of therapy and vision, we've just come such a long way. So it's fun to feature gaze a little bit and see what's possible. And maybe look back on this podcast in a few years time and go, we predicted it then. - And look, we know a lot of our audience know a bit about things like therapy and vision, these trials. And these are the P.I.s of both of these trials. We have sitting here in the G.U. Cast studio. So Michael Hoffman, friend of the podcast, our new tier medicine colleague at Peter Magg, chair of our PSMA Imaging Terror Nostec Center. Welcome back into the studio. Good to see you, Michael. - Thank you, Reverend Declan. - And Professor Oliver Sartor, visiting from the U.S., Oliver MNGU, medical oncologist, prostate cancer, expert extraordinaire from Tulane and New Orleans. And in Mayo Clinic, more recently, welcome. And thanks so much for dropping in. - Well, thank you. A lot warmer here than it was in Rochester, Minnesota. (laughing) - It is at this time of the year, but yeah, so you're down here in Australia for a couple of weeks, I think. Oliver, enjoying some time down here. And you popped into Peter Magg, this morning into our MDT, our tumor board meeting and delivered a grand round lecture and had a tour of the PET Imaging and Theranostec facilities. And they allowed to GU cast and we'll have some entertainment later in the day. - Absolutely, beautiful facility and great people, great work. - Great, fantastic. So that's the idea, Renew, but we thought we would go back, didn't we? And it's kind of 10 years into PSMA Theranostec. So in our experience here in Melbourne, so we're gonna ask Michael a little bit to take a break. - Yeah, 'cause a lot of people just know about Letitian PSMA, but there's a lot of other things that came before it that were very good at treatment of prostate cancer and palliation of symptoms. So it'd be nice to get a little snapshot. - Well, maybe before we go back and ask Michael about, take us back to the start of Letitian PSMA, which is 10 years in our experience this year. And Oliver, you were telling us before in your grand rounds lecture at Peter Magg, this morning that you have a very, very long history of radio ligand experience in prostate cancer. What are you to take us back a little bit? - Well, yeah, actually you remember rather precisely, 1993, okay, 1994. - Wow. - And I was sitting down at a meeting and ended up with a guy named Bill Geckler. And Bill Geckler may not be recognizable here, but Bill Geckler was one of the patent holders for Sumerium 153 ETA TMP. And I was struggling at the National Cancer Institute trying to do something innovative in prostate cancer. And I must admit, it was not doing particularly well. We're working hard, but not having much to show for it. And Bill was saying, I can take that isotope and I can put it right on the bony metastatic lesion and radiated. And I just sort of looked at him and I said, "Well, how the, can you possibly do that?" And he explained that it would actually bond sort of this phospholic acid. It's like a bone scan, but therapy. I said, "Wow, that's gonna work." And that was my beginning in 1993. - Wow. - Wow. - What were you doing in 1993, Renew? - I didn't know. (laughing) - School? (laughing) - Exactly. - Well, I was a little bit further on, but university for me, my school for you. So that's the history of it. I recall, in urology learning, there was no role for barely and molecular imaging in nuclear medicine, when we were coming through urology, bone scan was about it and so on. But take us back to the start of prostate cancer for you with PSMA imaging, but especially the perinostic side of things are supposed. - Yeah, it's been an incredible journey in the last decade, but it started a little bit before, a little bit after all of it. - Yeah, I've probably been doing nuclear medicine for 20 years now and 10 years in prostate cancer, but really transitioned from a lot of neuroendocrin tumor aeronostics and just amazed with gallium 68-dota-tate PET and lutecium-dota-tate PET and the impact that had on patients' lives, improving their quality of lives with neuroendocrin tumors. And did that in really high volumes. There's a huge neuroendocrin tumor service at Peter Mack. I think in one year I saw 550 patients with neuroendocrin tumors, these are rare tumors, but when you see them in high volumes, you kind of get good at them pretty quickly. And then it was at an EAMM meeting in Birmingham in 2010 that I first saw PSMA, I think in one of the translational sessions, a very sciency and it just looked to me very much like Dota-tate. Back then I was a little bit geeky and I took notes from the meeting and I wrote 'cause I've still got my notes, I can pull them back and I wrote, this is the kind of, this is a game-changing molecule, I can just see it. So I went back and I was like, I'm gonna do PSMA imaging and therapy and it took a few years. I think we did our first PSMA PETs a few years after that in lutecium. And yeah, there were lots of skeptics 'cause we had a calling program and calling produced a little bit blurry images, they weren't fantastic. They were hard to read and Declan, what was it like when we doing calling images and I came to tell you that we've got this new test, it's better than calling. It's called PSMA PET, what did you say? - Well, I remember that, I came to Peter Mack in 2010. So around the time you were in Birmingham, 15 years ago, a small cancer center, we're growing a big prostate cancer program and the NukeMed people, Rod Hicks and Michael, tormenting me a bit saying, you know, we've got a co-lean PET program running us. I don't think that's much good in prostate cancer and we can do it every second Tuesday. It's got a half-life of 20 minutes. It comes out of the cyclotron. Sometimes it works, sometimes it doesn't. And so we recruited patients, I can't remember the trial, but it was very underwhelming. And then renew their turn up and say, we've got this new one now. The new pet, I said the pet goes are coming back and knowing me at lunchtime again. And I remember sitting with you too and opening a laptop and you said, we've just done a PSMA PET CT. It was 2014, here are the images. That was jaw-dropping, go, oh, well, that was the primary and there's lymph nodes and there's a bone mesh and I think patient lined up for a prostate to me. Incredible images, incredible tumour. And that was the start of it and I said, I presume it's very difficult, you'll do it every second week in the afternoons out of the cyclotron. It'll be very unreliable and impractical, listen, no, no, this is gallium labeled. It's very straightforward. And I think you had colleagues from Heidelberg from Germany visiting or unsavaticable, which kind of helped drive that very fast from when they published the initial experience. And like was onto the Lutitium, which, you know, regular listeners will know, renew, we talk a lot about this. We're not going to delve into every trial. We want to go future gazing, but I suppose, if you remind us then about how you went from PSMA imaging in 2014 to PSMA Theranostics in 2015, 10 years ago, maybe that'll kickstart us before we ask about it. I guess all these molecules, we make them in our radio pharmacies. We have that capability on site at P2MAC, which is fantastic. And the platform's very similar to what you need for neuroendocrine tumors. So we could give these peptides to our chemists and pharmacists and off they go and make it. And it's very easy. This is kind of click chemistry for both Lutitium and gallium. So it's not overly challenging to make colines, actually, much, much harder to make. So we made couple clever decisions. One was we dumped the coline program overnight. We said, we're just going to switch across. This is obviously better. Other places persisted with the coline for some period of time. And the other clever thing we did was I decided, we're going to do this all as part of prospective trials. We don't want too much just, let's just treat patients. So every patient that we treated was done as a phase 1/2 protocol, which was subsequently published. And an easier pathway would have just been to follow on your neuroendocrine strategy, which was compassionate access, essentially. Yes, your failed treatments. We've got this treatment for you. That was being done in Germany already. We could see the data. It was compelling. So we did everything on prospective protocols. We did the ProPSMA trial together, which was a lot of fun. We just generated some incredible data. And now I think contributed to the global science to really take commercial interest out. I think I presented a lotitian PSMA at ESMO in 2017. I don't know if you were there. I was a bit of a, I was a little bit of a unknown at that time, just this nuclear medicines and our physician in this audience of over 2,000 people, predominantly medical oncologists. So I was quite nervous. And I gave this talk of the first 30 patients that we treated. And I would say most of the audience had never heard of a lotitian PSMA. And maybe I don't know if you remember that talk or how-- I was in the room. Yes. And to say the two word unknown is a little bit of an understatement. Nobody had a clue. Now, all of a sudden, it was like, we're looking at a pet image that we're looking at, pissed me, pets like the therapy. It's a lotitian. What is a lotitian? A lotitian, what is that? No, I mean, I mean, the room was totally unprepared, but I was prepared. I was listening. And I was very much influenced. It was that dose that we took forward into the vision trial. So I was in the room when it happened. Isn't that amazing what you're saying? Those moments, then, that lead to, yeah, OK. But then he sits there, sets up the vision trial. We're not going to go into that today. But obviously, what we can clearly state is there's a very clear standard of care for men with progressive MCOR PC now based on vision and therapy, which you would copy on both published and new and journal. And I think it's worth saying that, as a I remember, as a nuclear medicine trainee reading, the asymptotrial of radium 223. And just seeing that that high quality data will-- it's the only way to change global practice and make these things available. And that really inspired me. I did a PET CT Fellowship at Garzance and Thomasus, where Declan you have also worked. And they were producing New England Journal manuscripts on PET and lymphoma. And I was somewhat inspired, let's just try and produce high quality data so that we can really change global practice. And it's a really great example of trials learning from one another and kind of taking it forward and seeing where the next kind of walking the road is and figuring out which pathway to go down. And Oliver, what about your story? I mean, in a vision kind of maybe started from there, but how did you really get into thermonostics trials? 1993. OK, I call it. Then fall that up with radium. And let's explain thermonostics in a little bit of a different way, because we're imaging trading. But now the imaging is bone scans. And the therapies were either somerium or radium. But with somerium, we got a variation with radium. We got survival. And that's a big deal. That was a really big deal. And then that morphed in to the P.S. made targeted therapies with rotation inspired by the Hoffman experience and being able to figure out the doses here, the first prospective problem. And we tagged along on the dose, but we kind of knew how to do the phase three. And I was part of the insight team at that point, which had the P.S. made 617 from the commercial purposes, prior to the virus. And we developed that trial. And of course, that turned positive as well. So it's a history that goes back a long ways. But the real, to me, insight was you can target radiation to the right spot and benefit of patient. And do it without a lot of side effects. And that has been such a huge insight that it's, to me, not just in our endocrine story, not just the prostate cancer story. But in the future, we're going to future gaze is about all of oncology. We're going to do this across the board. And it's going to be all sorts of cancers, and all sorts of targets. And we're going to change the way oncology is practiced. But it's going to take high quality trials. Thank you, Michael. So with those approvals, Renew, so you have the MCRPC progress of its now in every guideline. And it's becoming increasingly funded around the world based on vision and therapy. But because there's so many ongoing trials in earlier disease settings, and your paper on lutech to me that myself and Michael were involved with read out in European urology, that's a big leap forward. And that's not clearly standard of care. It's just a sign that maybe these therapies can come forward. But I suppose we're wondering where will we see the next kind of approvals? Where will we be able to say in a place like this, Petition PSMA is now a standard of care option for this stage of disease? And Oliver's got his hand on his head. No, the answer to that. Patients ask this all the time, don't they? They want to know, well, look, I've got this type of read about this, but this is my type of prostate cancer. So yeah, we're a start of 2025, so that we want to ask that question. Where do you see, let's talk to Lutition PSMA. We'll talk later in the podcast about other traits. But where do you think you might see tick? This is now OK, it's actually very simple, because in order to change practice, it takes the phase three trial. And the phase three trials are as follows. We have the vision trial, which is post-AIRPI and post-taxane. And now we have to delete the taxane. You just go post-AIRPI with no part of taxane. That trial is called Petition PSMA 4. Published in Lancet in the last year. I presented it as mode 2023 for the first time. And that's now in front of the FDA right now. That's the next opportunity for approval. Now, Curium has another trial called Eclipse. The PSMA IN team, we haven't seen the data yet. It probably presented it to ASCO. They'll probably be submitting as well, but we don't know. But the first one is going to be PSMA 4. And it's in the meta-sector PC pre chemotherapy space post-RP. Next one is going to be Hormel's Sensitive Prostate Cancer, completed a cruel in January of 2024, 1140 patients, Metastatic Castrate Sensitive Prostate Cancer, PSMA PET positive, everybody ATARPI, and then they get post-traumatic slutitium. And we're going to have to wait and see. We don't know how this way. - PSMA addition. - PSMA addition trial. And when the PSMA DC trial and PSMA DC trial is PSMA PET positive conventional imaging negative, SPRT plus or minus the utilitation with an MFS endpoint. So the next one is going to be PSMA 4. The next is a report on PSMA addition. And the next one is phase three is going to be the PSMA DC, PSMA DC sensor delay castration. But I am going to predict that within two months, we're going to know about PSMA 4 at the FDA within two months. - Fantastic. Let me ask you a question. Because they are the practice changing studies. There's no question. And we need those without those. It means it's just not available. But then we have our small studies, like therapy or insipi or upfront PSMA, our little phase two cooperative group, or our physician sponsored trials, which kind of we've specialized in a little bit. And I like to think that they're, although they're not practice changing on their own, they're very complimentary to these phase three studies. It optimizes, how do you sequence it? Or it even provides the FDA some confidence that, yes, I can make this decision for the vision trial. But if I didn't have therapy, maybe they might ask her another trial if that doesn't exist. True, do we need these other little trials? Are they valuable? Or do we just need the industry phase three trial? - No, no. We absolutely require export three trials. And one thing you've done, Michael, is to leave far ahead of the game. I mentioned very specifically the vision trial, who's your prospective trial that led to the medicine schedule, okay, without a doubt. If we get a look at the upfront, we have the first experience for you with the castrate sensitive trial, it doesn't change practice, but it informs us very valuably. And then as we move forward with the whole variety of trials, and I'm gonna pick on the Luparps study for a second with combination, that paves the way forward for the largest studies. We must have compliments. We cannot just do the giant phase threes, because we don't even know what to do. We know what dose to use, what combination to use, and how to pick the patients. So to me, this is all part of a larger ecosystem, and we stirred together, and we come out with good things. We have a mix of trials, a mix of investigators, a mix of priorities, a mix of isotopes, a mix of combinations. It's all good because it works together. - Yeah, it makes perfect sense, doesn't it? And hats off to Michael and Shanine, who is there this morning, and other investigators who've done these paragraph. Luis Ahmed, who you're spending time with in Sydney as well this month. But I think I really like that. Renew I like the idea that our audience wanna know, when are we gonna see approvals? And I think Oliver just said to us, right? This is in front of FDA, so that's already one step earlier. - Yeah. - I suppose, what about the timing of the step into hormone sensitive? So I run, and Michael, I run as ad who has led the. - From PSMA trial, presented it as more recently, Lancet oncology is hormone sensitive, but again, smaller phase two trial, and it gives people a little insight into maybe what PSMA edition might show, but what's the time scale for a PSMA edition? - Okay, so as we completely cruel with 1140 patients, January 2024, it's reasonable to think that by January 2026, we'll have some pretty good information because that'll be a meeting of two years followup. Now, we know that the medians with an ADTRP, when it comes to RPFS, are probably gonna be out in the 28 to 36 months, and maybe even a little bit longer, depends on patient selection, but we're gonna be having some reasonable information within, I'll say, a year and a half from now, something like that? - RPFS. - RPFS, RPFS primary endpoint. It's a crossover. - That's serious. - Now, one of the things that's problematic, and I just wanna emphasize this for a moment, when you have high rates of crossover, it obviously is gonna be treating patients before they hit the OSN point, and you're gonna be confounding the OSN point, and that happened in PSMA for, because of those were eligible, 84% crossover. - Yeah. - And so, it's really hard to hit an OSN point when you have such a high rate of crossover. - But of course, we think that's a good thing for a trial, isn't it, to have a crossover, you know, ethically, and super exciting. I think earlier use is coming, it's only a matter of when, I'm confident we're gonna move pre-chemo pretty quickly. Enzope's got some follow-up, just about to read out. And even the upfront PSMA results are, they're actually way better than I expected. If anything, therapy results were, maybe not as good as I expected. Now, when we look at OS versus KabaziTaxel, but you look at upfront and Enzope, and they're both significantly better than I expected. I'm gonna give a little bit of a shout out on Enzope, which is reported initially in a combination with insolidamine, and I think that the impact of the overall survival endpoint, which will be potentially presented fairly soon, is gonna be high. And the overall survival attracts attention like no other endpoint can. And I'm just saying, I look forward to EscoGU, but the reason is could be presenting that data. So it could be a big impact. - Really exciting. And I think the other advantage of these, the smaller phase one to trials, Michael, is it gives a lot of information about tolerability, safe doses. But the other thing we do is we're really tight with patient selection. And that's one key thing that we see in trials. But Oliver, how does that translate into the real life setting? Especially when it comes to mutation, PSMA treatment, how is patient selection kind of regulated? - Oh, tightly, unbelievably tightly. And let me explain if you don't understand how, because if you don't have insurance coverage in the United States, you don't get the drug unless you're on a clinical trial. On a clinical trial, you can do whatever the eligibility criteria is. While the insurance coverage is set in accordance with the FDA label. And the FDA label is set in accordance with the inclusion exclusion criteria that are established by the pivotal study stunned that the FDA used this to approve the drug. That'd be vision. So take the vision criteria and take that into the FDA approval and put that in the label. And that's what the insurance companies will do. And they will not do anything else because you can't get reimbursed. And at $42,000 a dose, I don't know anybody who's paying for it themselves. So bottom line is the insurance companies rule the roost, governed by the FDA label, governed in turn by the trials that are pivotal for the approval. Just that simple. - And as we bring, you know, mutation appears to me forward in the treatment spectrum, I think patient selection then becomes even more important. And I think the great thing about all these smaller trials is that there's this translational component and embedded into a lot of these that inform us about how do we better select patients? And it's particularly important when we're using it earlier and earlier in the treatment setting and comparing it towards where we did diabet on a case in the MDT today on a patient who had been treated with Turbium 161 on our clinical trial. And Oliver looked at the picture in a microsecond. He was like, "What's the SUV mean of that patient?" And he was surprised that the patient had a good response when he saw that it was a very high SUV mean. Yeah. So we do have these prognostic predictive biomarkers. And I think that's going to be a little bit of the art of medicine who's you've got the patient in front of you. There's five treatment options, pap inhibitor, dosataxal, at lutecium, awesome combinations. What are you going to choose? And if you've got a very high SUV mean, I'm going to be choosing lutecium. But guess what, if your SUV means really low, I might say, you know what, you're going to need lutecium, but actually think you're going to do better with dosataxal first. And that's what we already kind of do in our practice if you come to our lutecium thermonostics MDT. Some of it's all about sequencing. We're not saying you're not going to get this. We're just saying, why don't you use what's likely to have a better response? And everyone wants lutecium. That's the truth, because it's so well tolerated. It's the new drug. But when the patients come to me and I say, look, you're probably going to respond better to chemo. Like I'm back to their oncologists, and they ask for chemotherapy. It's quite remarkable. Well, one of the things that's a little bit interesting is that I'm going to quote Michael in a way that he may not have anticipated. So translational studies, less good at con. And he presented last year at ASCO, an immensely important funding on circling tumor DNA. And simply looking at the circling tumor DNA fraction could have a predictive effect on the lutecium efficacy. And I didn't think that was going to be true. So while we're looking at molecular imaging, we're probably also going to have to look at circling tumor DNA in addition to the fitness of the patient and other parameters. But when it comes to best decision making, it's going to be multidisciplinary. And genetics is going to play a role, too. So we're, I told Michael a bit earlier in the conference, I said, you know, their infants and their children and their adolescents and their adults. And you know what, the truth is, we're really in our infancy. We know so little. We've learned a lot, but we're so much more to learn. And we are going to change the world, but we can have to learn a lot more in the process. And that learning is how we're going to change the world in the end. So lovely to be here. Michael, since we're future gazing, surely AI algorithms and AI tools will help us select patients and predict who's going to respond better. Surely. Surely. Yeah, it's a challenging one. But you know, AI is coming. We all probably use it a little bit in our day-to-day practice. I'm all for getting AI to help me do what I do on multiple levels. SUV mean is probably a pretty good one for a single-click solution for AI to do. That's coming. We're going to need some AI assistance. Some of this needs individual face-to-face patient consultation. There's no way around it. There's a nuance there that humans just do better than AI. And patient preference is very important. What does the patient want? Do they want to live longer? Or are they focused on quality of life? Some patients will tell you, I don't care how toxic the treatment is. If I'm going to live longer, give it to me. Other patients will tell you quality of life is my number one. I know what side effects. This is really important. And before we move away from latissian psimae, I'm interested about treatment combinations. Because so far, we've been really disappointed by prostate cancer in the immune system. And we've seen a lot of this in our lutectomy translational work as well. Where do you think the future is? If we could combine latissian psimae with the ideal thing that would change the immune system, whether it's a vaccine or a CAR-T, where do you think the future could lead us? Wrong question. Sorry. No, it's a good question because it leads me to, I think, a more interesting place. So you're focused on the immune system. And I'm focused a little bit larger. So let's talk about combinations for a brief second. Well, what do you think intopias? That's combination therapy. That's combination therapy with hormones. And guess what? I think it's going to be a lot better than just the monotherapy. So let's consider hormonal therapy. Let's consider immunotherapy. It doesn't always have to be the PD-1, PD-01 axis. It doesn't have to be C2-A4. There's going to be other ways to do it. And I'll come back to that in a second. Let's consider isotopes and isotopes. Michael is in a trial with Wardium-2-3 target in the bone in combination with quotation. We guess where a lot of the paleoures occur. They occur in bone. Maybe we need to treat bone better. OK, and then I'm not going to mention the liver, but the liver is a problem. Let's imagine we have DNA repair inhibitors. Let's go to Peter Mack, and we're going to talk about partitioning, sandu-percent of the data with a luparpe, which is a really great idea to be able to inhibit the damage repair genes, all damaging the DNA. So we're going to damage DNA and inhibit those that repair the damage. And maybe get one plus one is equal to 2.5 or three. So combinations with hormones and isotopes. And by the way, chemotherapy and radiation sensitizers and DNA repair inhibitors and immunotherapies, I'm not sticking with just immunotherapy. There's more of the story. Now, let me-- one more brief statement. So the immune system can be engaged a lot broader than in the context of PD-1 and PD-L-1 and C-2-L-4. Right now, we have active T-cell engages. And now we're talking about biospecifics. These are non-radiative compounds. But we're going to be the steep one-targeted biospecific T-cell engage, and you know what, it's active. And now we have the masking of things like the genetics where we're going to be masking to diminish the side effects and targeting a T-cell engages. So we can engage the immune system in new and different ways. And that's going to be complementary with the nutrition. It doesn't always have to be exactly at the same time. And it doesn't always have to be on the same target. Anyway, so let's expand our immune system discussion to a bigger platform. And renew the final area we want to go into while we have these two folk here in the audiences about moving away from Lutishium and wondering where we're going to be in five or 10 years with other radio tracers, other targets. You mentioned steep one already. So, you know, we believe that we're still just at the kind of start of radio ligand therapy in prostate cancer with maybe kidney cancer today, as we talked about, but again-- Infancy, remember your answer. Infancy. You're not even a child yet. Just an infancy. So, you know, you try lists and pioneers in this area. Can you give us a snapshot of where you think we might be? Or you'd love to be in five or 10 years? But little things you're already using maybe, or little snippets of it, all over first, and where we might be in five years in our podcasting studio. This is an infancy. We'll still be going in five or 10 years. Yeah, so what are we going to be excited about? OK, so combination therapy. Absolutely. I'm excited. I don't think we understand. Dostin schedule yet. I think we can optimize Dostin schedule. I think we may be using different isotopes. We present presentations on terbium coming up. Well, terbium may be just the ideal catch me out for a low volume cancer, or maybe it's going to be an alpha. And remember, there's more than one alpha. There's actinium, and there's lead to 12, and maybe acetate. I mean, of course, radium is the old one. So, we have different isotopes, different combinations, different targets, which we've begun to talk about, but just touching on. Different doses and schedules come back in five years, and all this is going to be different. Come back in 10 years. It's going to be totally different. It's going to be so much fun. That's so good. And on targets, just before we go to Michael on his end, so PSMA is what we've been talking about. It's been amazing. And so can you explain just for the layer of members of the audience, what sort of targets you have in mind? So PSMA is expressing-- Let's talk about what I'm going to now call validated targets, because I can-- if I talk today, I give a big, long-listed targets. But, steep one. Steep one is a real target. Some of these patients have any beautiful responses with a T-cell-engager from Amgen. Let's talk about HK2. HK2 has got real responses. Have a patient spend almost complete remission for three years after targeting with an actinium-based HK2 antibody, unbelievable response, PSA 400, and beautiful. So HK2, steep one, PSMA are all validated. Then we get into all these other things that might emerge among certain differentiated subsets or undifferentient subsets. Maybe it's going to be a stroke, too. Maybe it's going to be a DRL3. Maybe it's going to be a B7H3. I don't really know if that's what we need to explore. But targets today, PSMA, absolutely positively. HK2, I believe it's real, steep one, it's real. And that's the beginning, not the end. Amazing. Michael is going to throw it to you, tracers, targets. What gets you excited about? What trials would you love to do? And what tracers are you excited about? Well, I've given a little thesis on this. In a few talks at nuclear medicine meetings, where I'm asked to do a longer talk on this. Maybe we can link to one of those. But it reminds me of a editorial I wrote for J&M about a year ago, which we titled "The Hierarchy of SUVs." And I very much believe that we need to get dose to tumor. And if we can do that, we'll have successful thermonostics. And we can image and see it and quantify it. It's not that useful when you're in a big phase three trial. You don't need all of that. But to start with, you know, is this going to work or not? That's very useful. And we're still in the era of palliative thermonostics with rotation PSMA. And I think the future is going to be hopefully curative thermonostics, where we give big dose of radiation. And we actually cure patients, eradicate them. No more cancer. And this is not pie in the sky because the best thermonostic we have to date is radioactive iodine for thyroid cancer being used for over 80 years. You take a patient with metastatic thyroid cancer, lung bone metastases. And with a single dose of radioactive iodine, they can be cured. And we've been doing this for over 80 years. And it's truly remarkable. And we can image iodine. And when we do that, we see SUVs. So SUVs being standardized uptake value. When we now image with a pet version of iodine, I-124, we can see SUVs over 2000, which is incredible. And you know, that's not new. That's 80-year-old thermonostics. PSMA, you know, a high SUV max we're talking would be 100 or 150, maybe 300 is a maximum. And you get radioactive iodine often over 2000. That's not even unusual. It's frequent. So it's not surprising that radioactive iodine is a curative thermonostic. So I think with the advances that we have now in radiochemistry, there's been incredible paradigm change in our ability to make peptides of all different descriptions, mini bodies, even antibodies. I'm less excited about antibodies, but small fragments. I think we need slightly smaller molecules for thermonostics. But the radiochemistry is unbelievable now. And we've got a whole new library of traces to play with from actinium to lead to one, two, to turbium to astatine. There are so many. So when we combine these new traces with new targets, I think we're going to have curative thermonostics. Maybe early phase prostate cancer, we can cure. Maybe we're going to put it up here. I'm just going to put the urologists out of business. Bye-bye. I do actually have the podcast, sorry. I do actually believe that you could cure patients with a lutectomy type approach, but it's going to be a minority of patients. They're the patients. When you image them with PSMA, you see a super high SUV. We saw this in pro PSMA. There was an edge of the bell curve. There were some patients that had SUVs over 80 in their prostate primary. Now I would love to treat those patients with an e-age of an lutecium approach. And maybe with the right isotope, you could cure those patients with a single dose of radiopeptide. Hey, that's very inspirational stuff. But soul hurts would have been proud. Michael delivered the soul hurts lecture at the SNMMI last year, their keynote lecture, and the godfather of thermonostics. And you have this pen. And it's very interesting, isn't it, to hear that all over? Yeah, so it's cured. You can cure cancers really like in therapy. It's tracers and targets and bang. When you find something that has an SUV max of 2000 in the prostate, there you go. You're going to have focal therapy with them. Pretty amazing. But you know, we might be able to do it with some of these combinations as well. Because I'll give the classic example with an oncology. So Hodgkin's disease was considered to be incurable. And then we give one chemotherapy. And it would work. And another chemotherapy might work. But everybody always came back. And then this crazy guy named Vince DeVita said, I'm going to give one. I'm going to give two. I'm going to give three. I'm going to give four all at the same time. And he had mop chemotherapy. And all of a sudden the previously uncurable became curable. And patients widely disseminated disease when a complete mission stayed there forever. So I believe not only in the thermonostic approach, but also the combination approach. And using these molecules, which work differently from a mechanistic perspective, to be able to intervene on a tumor, which may have several vulnerabilities that wouldn't combine, become lethal. Hey, it could be pretty cool. There you go. What a great way to finish an inspirational podcast about the future gazing and radioligant therapy. And patients are-- Very exciting field. You're using the word cure in patients who we don't talk about, or minimizing morbidity, compared to traditional treatments. It is an exciting idea as a head end. Absolutely. That went a lot. Grace, I'm very much in joy. That's so great to have had Oliver-- The gurus of thermosics. Absolutely. The gurus here in the audience with us picking their brains. And I hope that you all enjoy that. Thanks very much again to Novartis, our silver partners for supporting GUCAS so we can put on this sort of thing. And then we're going to go and enjoy a bit of lunch with these two now. Pick their brains a bit more, and then see where we can go. That's good. And see you next time. Thanks very much. Take care. [MUSIC PLAYING]