Telix Pharmaceuticals Limited (TLX) Earnings Call Transcript & Summary

Thank you for standing by, and welcome to the Telix Pharmaceuticals Limited TLX591 ProstACT Expert Forum. [Operator Instructions] Today's format is a fireside chat hosted by Dr. Colin Hayward, Group Chief Medical Officer at Telix. Please go ahead.

Great. Thank you very much, and welcome to this interesting webinar PSMA Targeting Radiopharmaceuticals, the ProstACT therapy program with first-in-class our rADCs, TLX591 or Lu-rosopatamab tetraxetan. Now look, there's clearly growing interest in radiopharmaceuticals, in GU oncology as a whole, but especially in prostate cancer given recent data in PSMA 4, for example, the ongoing SPLASH study. But we, of course, have ongoing studies in a recent interim report of SELECT -- ProstACT SELECT, and you have seen the news about ProstACT GLOBAL recruiting the first patient in Australia. So that's a very exciting news for us here at Telix. And this gives us an opportunity to revisit and reeducate the extensive development program to date and the history and the data that it's gotten us here and maybe continue to discuss and identify a few interesting points or maybe some key differences of the potential antibody-based therapy versus small molecules. And if we can go to the next slide, please, just the standard disclaimer slide. And then what I'd like to do is introduce a distinguished panel, and there isn't really any more qualified people in the world to have a very good discussion on TLX591. And we have a panel from around the world who I'll let introduce themselves. So Dr. Tagawa, perhaps you could just start for me.

Thanks for introduction. My name is Scott Tagawa. I'm a medical oncologist at Weill Cornell in New York. Overall, globally, I've been -- I treat patients with gene malignancies and I'm involved in developmental therapeutics in GU malignancies with a focus in cell surface targeting and I'd say, especially in that realm in the last 15-plus years focused in PSMA targeting with radionucleotides.

Fantastic. Thanks, Scott. Dr. Lenzo.

Thanks, Colin. I'm Nat Lenzo. I'm a nuclear physician and internal medicine physician based in Perth, Western Australia. I've been involved with Theranostics for many years, but I've been involved with administering Lutetium PSMA-based therapies for prostate cancer for the last 8 years. I'm glad to be part of the ProstACT SELECT trial. We were the #1 recruiter for that trial in Perth and labeled sort of the PI on the ProstACT GLOBAL trial, and we're glad that we've enrolled our first patient just in the last few weeks on this trial. So glad to be here.

Thanks, Nat. And Dr. Sartor.

I'm Oliver Sartor. I'm a medical oncologist and currently at the Mayo Clinic and have appointments in the Department of Medical Oncology, Urology and Radiology. I've long been interested in Theranostics going all the way to the days of Samarium-153 and Radium-223, been quite involved with the use of PSMA lutetium small molecules. And I'm simply glad to be here and to be able to contribute tonight talking about the first antibody lutetium trial.

Wonderful. Thank you. Thank you all. So maybe I could just open up and just say a few words of our progress recently if we go to the next slide. So as I mentioned, there's increasing interest in radiopharmaceuticals not just in prostate cancer, but clearly prostate cancer is leading the way, particularly the interest is there because of that high U.S. incidents of metastatic castrate-resistant prostate cancer that's 42,000 and growing 5% a year, which clearly translates to a very high market potential. And that first PSMA-targeted therapeutic, that's reaching over [ $700 million ] in sales year-to-date September '23, so clearly, a very large opportunity and a large opportunity for men with prostate cancer to help them live longer and live better quality lives. Clearly, the small molecules have produced some fantastic data to date. But are there any differences or any other opportunities we can on improving therapy for men? We go to the next slide. The ProstACT GLOBAL, we'll go into in a little bit more detail. We can see that we've launched this with the first patient recruited in Australia. And there are some key learnings that we've done in terms of planning this study that we'll go into in a little bit more learning from the other PSMA studies in similar populations but how we designed this study. And if we go to the next slide. We recently announced some interim data from ProstACT SELECT. Just as a reminder, ProstACT SELECT is a dosimetry biodistribution study, no control arm really giving us an indication that Illuccix is highly effective as a companion diagnostic for TLX591 and showing that we can identify tumor and target tumor with the antibody. In addition, gives us promising insights into this patient population in terms of the safety data as well. And if we go to the next slide, we can see some of that hematological profile that we see and how that differs from the original development work with Scott, and maybe -- perhaps this is the population is a more resilient population and earlier treatment population and so not getting quite the same numbers in terms of thrombocytopenia and neutropenia in particular. And if we go to the next slide, some of the key areas we've met the objectives in terms of demonstrating the patient friendly, 2 doses and tumor targeting in that population, looking at the uptake in the dosimetry in different organs to show the safety, seeing that tumor retention is in that for at least 2 weeks and we've taken out those imaging to at least 2 weeks. The hematology, the lower rate of hematological events, which I've just shown. Now efficacy is very, very preliminary. There was a baseline drop in 64% of patients at some point of those patients who had a baseline PSA on full dose. But really, the PSA and most importantly, the longer-term outcomes of the rPFS are still ongoing, and we all hope to have -- be able to present that data next year as the data matures. Next slide. So my perspective, but I would say this coming from the company perspective, is that this is promising efficacy demonstrated. And I think it's important to realize that the development program to date has had over 200 patients, many of whom Scott has been involved in those initial studies. We've seen that patients with high PSMA tumor antigen expressed was SUV. And we have specificity in terms of antibody binding and an acceptable safety profile. And that simple 2-dose regimen administered over 14 days may offer significant advantages in terms of patient convenience but also in terms of the lutetium dose and the total lutetium dose that's needed for those patients. Next slide. So with that just quick introduction and quick overview to set the scene, I'd really like to hand over to Scott to talk through the development of TLX591 or Lutetium rosopatamab and give us his insights of that development to date. Thanks, Scott.

Thanks, Colin. Next slide. Disclosures. Okay. So I suspect many of you have heard something similar in the past in terms of what is on this slide. mAb stands for monoclonal antibody and ligand, generally speaking, for PSMA is going to be a small molecule. The main differences in how they act in the body is really based on their size. That's for the most part has -- and that size changes their kinetics and their biodistribution. So kinetics, how long they're circling around, and biodistribution, where they land. And you can kind of just read the data that's sitting in front of you. I think if you were to look up pictures of imaging of the antibody with PET pictures of the small molecule PET, you could see some differences in terms of where they land. So -- and I would say their advantages and their disadvantage are quite similar. It's a little bit of a spin. So antibody has advantage of circling for a long time. So I give an infusion today. There's more targeting of the cancer tomorrow, more targeting of the cancer the next day. And I think that is especially important for lower PSMA expressing sites whatever the target that's going to be, but then the downside of that longer circulation can be an effect on the bone marrow, and we can talk about that sort of toxicity. And then it's cleared through the reticuloendothelial system like any big protein, which is predominantly liver. And the small molecules, an advantage is they rapidly go to any target site, so PSMA in this first case. And then they're excreted and that's very nice imaging. An issue is that for areas that maybe have lower PSMA expression or that they're going to wash away, maybe there's less that are there for a longer period of time. And then there's the on target, but off-tumor uptake. Because of their size, they're able to get into the salivary and lacrimal glands being with -- for the dry mouth and dry eye side effects, the intestine in terms of nausea. And then could there be more kidney toxicity? We don't know. It's relatively early. And if that's going to happen, it would be a late effect. But anyway, at least there's a risk. So that's all theory. Next slide. So this is -- so another thing this is -- I mentioned this a little bit. So this is in different -- actually. Okay. These 2 pictures are one cell line, but we've done this in low PSMA, moderate PSMA and high PSMA expressing cell lines. And at the very beginning, there's good binding of PSMA with whatever it is, but there is superior internalization and more importantly, retention with the antibody. And that, I think, as a key in humans, is that it gets to where it's going to go, luckily, perfectly tumor in this case, and then stay there for longer, and that allows this radiation to continue to effect. In this particular case, the whole [ construct ] with lutetium-177 to 1 week half-life. So sitting in those tumors for weeks allows that radiation to persist over weeks. Okay. Slide. Okay? Another graphical representation of the retention that is there. And then I mentioned you could look at PET. This is probably a PET at around a week or tell about looking that's usually when this happens with J591 where we see clearly insights of tumor, it is there. And we've looked at images of lutetium 2 weeks out, and there's a lot that is there in the tumors. What you may not recognize, and I pointed out, is that the salivary glands if you look at any PSMA-PET. Otherwise, you generally see these dark spots in the salivary glands, in the cheeks and the same with the kidneys and the small intestines, it's a little bit more difficult for a nonradiologist, let's say. Okay. Next slide. So this is a long and what I would say, from a scientific point of view, kind of carefully done sequential Phase I and Phase II studies. As investors, maybe you say why you say, why you're doing Phase III earlier. But we did this academics. But what's nice is that we have all this available data going into the Phase III, so different beta emitters as well as gamma emitters and PET emitters have been labeled to this antibody. So we know the safety. We know the biodistribution of the antibody. And then to kind of break it down just fairly quickly in terms of 3 major points specific to lutetium, J591 and TLX591, you can see, I guess, mostly around -- I guess it's kind of going back and forth. So I was going to say [indiscernible]. So Phase I and Phase II studies are a single dose. This is in the pre PET era. So this is all comers. And actually, every single one of these studies is all comers, so you have to take that into account when you're looking at whatever endpoint you want to look at for efficacy. But we arrived at what we thought was a very good kind of maximally tolerated dose, recommended Phase II of a single dose that led to this fractionated split dose. So another way of talking about this, I would say, is dose dense. So if we're looking to cure a tumor with radiation, and we do that with prostate cancer, we shoot in over a period of time. But if we give it half in onetime and half 2 weeks later with the half-life of a week, we're essentially getting a pretty high dose to tumor in a continuous fashion for a month. And that's what we do nowadays when we're looking to cure prostate cancer in the prostate. So we did that Phase I/II study, where we arrived at we thought was a good regimen and a good dose. And it's been translated, slightly changed but to make it kind of easier to get a flat dose. But what that turned out to be was, looking at around 4 to 6 weeks, some decrease in the blood count, we know when it's coming. And they come back up and we support them if we need to. But that was associated with a very long overall survival. And that's what we can talk about PSA and other things, but a 42-month survival in heavily pretreated patients, that's something to keep in mind. And then the one that's on the bottom, which is people worry about what's going to happen to the blood counts. Well, with full dose docetaxel or Taxotere, we can give concurrent Lutetium-J591 with this fractionated patterns. So even with chemotherapy [indiscernible] blood counts, we could figure out a way to do those again. So anyway, long history of this development. Next slide. And this is that study that -- in the top left of the schema that we did skip or delay one cycle of chemotherapy, but we're able to give essentially full dose of each drug concurrently. Okay. Slide. Okay. And that's basically the summary. So in the era where we didn't have PET imaging, we kind of treated all comers. We could look at the SPECT scans, so that's looking at the lutetium itself and about 90% lit up, which is very similar to what we would think of in terms of what we might screen in or screen out of studies such as VISION or PSMA 4. We've seen some PSA decline. We've seen clearance of circling tumor cell. What I would think in noncontrolled study is fairly good survival. I did mention the one randomized trial that was presented earlier this year, nonmetastatic CRPC secondary hormonal therapy with Lutetium-J591 or [ Indium ] J591 to control and we were able to delay time until radiographically metastatic evident disease. So that is not exactly the same, but a little bit more analogous to this patient population of an earlier disease setting, whether it's efficacy in the first randomized trial with available data. So anyway, I've been talking for longer than intended to, so we can move on and maybe get to some questions.

That was great background. Thanks, Scott. I just want to maybe open up to the panel to ask a couple of questions, ask some questions of you. Development plan today, as you said, it's a very extensive development plan, way over 240 patients who've received 591 either with lutetium or other isotopes. Just a quick question for me. You mentioned as well the condition of those patients going into the original studies of the fractionated that you saw. Were these really sort of refractory to all comer therapies?

Yes. That's the way they're designed. They're Phase I and II trials, and the inclusion was they either were not fit or refused other therapies. So we do have, and it's been published that patients can get chemotherapy afterwards. So some patients didn't have chemotherapy or, let's say, they came in after docetaxel in the precabazitaxel era and then later could get cabazitaxel. So they were still fit for that. But not everyone had chemotherapy first, but many or most patients had multiple lines of hormonal therapy and some other experimental therapies. And most did have chemotherapy, but it wasn't all but heavily pretreated. And I do think that -- you mentioned this already, but I do think that speaks the fitness of the patient and the marrow speaks to the myelosuppression that might be seen and just take the approved agent, lutetium PSMA-617, same administrative activity, same schedule, less myelosuppression in PSMA 4 data that Oliver just presented recently versus VISION. And the difference, I think, is the patient population. Great. Oliver, any questions for Scott?

No. But I think one of the things that's interesting in this trial design. I don't like to comment on it now, perhaps we can discuss it more later, is that docetaxel is allowed. And it's allowed not only in the control arm, but it's also allowed within the isotopic arm. So we're trying to ensure that patients can get the best available therapies. And I think this trial design, which uses docetaxel and has the availability for docetaxel in both arms is an important contribution. And if it's positive, then I think it can help really change the standard of care.

Great. Thank you. Thank you, Oliver. Nat, any questions for Scott before I turn over to you.

No, I'd like to reiterate that, what Oliver said, when we are talking about trial design that's been comforting for patients and also made it a lot easier in our discussions with medical oncologists that there are -- there is the ability to have docetaxel as -- in different parts of the trial, both arms of the trial. So I think that was a very good move to put that in this trial.

Great. Thanks. Well, maybe I can then hand over formally to you, Nat, to maybe just delve into some of your own personal experience. As you mentioned, you are the lead recruiter in terms of patient at the SELECT study. You've been involved in an early study in combination with radiation, the ProstACT target study as well in very early [ PCL ] as well as recruiting that first patient to ProstACT GLOBAL. So you've got a lot of experience but also a lot of experience with small molecules in your years as a, you kind of mentioned, physician in treating patients from around the world. So I'll hand over to you, Nat.

Thanks, Colin. These are my disclosures. So I've been fortunate enough to be one of the PIs on the ProstACT SELECT trial. The ProstACT SELECT trial, which is now closed and as Colin said, was predominantly looking at and it's a Phase I biodistribution trial. But we were able to see in a number of patients very exquisite targeting by the antibody. And this is just some images performed with the TLX591 over a number of days. And you'll notice from the early 4-hour image, where it's mostly in the blood compartment, over time, we get deposition within the PSMA expressing metastases. This correlates very well with the Gallium-PSMA-11 images that we -- that you can see on the left as the baseline. And [ 312 ] hours exquisite targeting and retention within the tumor. So the hope is, as was said by Scott and also by Colin, we're going -- with this very good targeting and high retention of the antibody that we will hopefully see improvements in efficacy, and that's hopefully what GLOBAL -- the ProstACT GLOBAL will show us. Next slide, please. This is a patient who had predominant disease and is part of the SELECT trial. Once again, we see the targeting over time, clearance from the blood pool, clearance from the rest of the body. We do see retention in the liver. We don't actually see many changes to liver function, which is not uncommon. I've been using a number of agents, antibody agents for a number of years. And even though we see this quite a lot of retention in the liver. We just don't seem to see any issues either short or long term, which is encouraging. This patient here had previously been treated with enzalutamide and had novel disease. From our past experience using the peptides or the small molecules, novel disease is often very exquisitely radiosensitive much easier to get persistent responses. So hopefully, we'll see that as well. In this patient, we did see quite a significant drop in PSA. Next slide, please. We've been fortunate enough to have a Compassionate Access Program for the last few years, where we've been able to use TLX591. And this is a case in point, similar to some of the patients that Scott had in his trials, this is a heavily pretreated patient. There's a gentleman who developed Gleason 4 plus 3 prostate cancer in 2008, and he had locally advanced disease. So after his radical prostatectomy and salvage radiotherapy, he then relapsed in 2015 and 2017 and was actually diagnosed with pulmonary metastases in 2017. He then went on to docetaxel chemotherapy and then a number of different hormonal agents but then relapsed again and was lucky enough to get on to the therapy trial, which was a trial looking at Lutetium-PSMA-617 compared with cabazitaxel. He was on the lutetium arm rather than the cabazitaxel arm, which was a multisite Australian trial. He had a good response -- a moderately good response to therapy. And when I say a good response, he did have a PSA drop, but more importantly, by the time he started the therapy trial, he had quite significant bone symptoms. And he did get very good palliation, which is one of the things that was well demonstrated in the VISION trial, the quality of life benefits of Lutetium-PSMA-617. Unfortunately, he relapsed. He then went on to cabazitaxel, which sort of kept his disease stable, but unfortunately, he was getting recurrent symptoms and then quite severe symptoms. He had a trial of abiraterone even though he previously had enzalutamide and then came to us for compassionate access actinium, which stabilized the disease for a period of time but then progressed. And then he was fortunate enough to be able to get access to compassionate use TLX591. By the time we had put him on the TLX591, he was in severe pain. He was on a lot of narcotic analgesics. He had -- that was quite limited by his symptoms. And we saw really quite a dramatic response in symptoms. And I'd have to say that, anecdotally, I've been fairly impressed by the quick response I see with symptom control of patients with bone pain with the antibody. And hopefully, that will be borne out in data as it matures in SELECT and also what we're seeing in the GLOBAL trial -- ProstACT GLOBAL trial. He had a very good response, PSA response as well to the 591. He did have thrombocytopenia, which dropped. He never needed resuscitation initially. But he had quite significant anemia, which was a little bit unusual. And in fact, he then presented several months later with [ PI ] bleeding, colonoscopy revealed actually adenocarcinoma of the sigmoid. He was able to undergo a laparoscopic anterior resection. His platelet count never dropped to a level where it was dangerous at that time. But then he did progress clinically. He then developed some neurological symptoms, cerebral metastasis and then he passed away. But he did have a very good control of symptoms and his main symptom was bone pain. And that lasted almost up until the time of his death. So he was -- he and his family were actually very grateful at the quality of life that he was able to retain or get back after treatment with the antibody. Next slide, please. So the PSMA is actually -- scans are actually a very good marker of overall survival. There's a lot of debate about PSA responses, and I'm sure there'll be discussions with the others about what this means and whether PSA is the be all and end all. Certain drugs have not shown that greater PSA response but have shown improvements in overall survival. But suffice to say that a PSMA-PET is a very good independent predictor of disease. It actually is a predictor of aggressive disease. And it also seems to be getting favor and there were more trials coming out showing -- and data coming out showing that, it's quite useful also in evaluating treatment response. And I think we'll see more data coming out in the next year or so that proves that PSMA-PET is really a very good and independent biomarker for this disease. Next slide.

So maybe just -- thanks, Nat, for that summary. It's very interesting hearing that patient experience. Is there anything else you noticed in terms of -- you've treated many patients with small molecules over your time, many patients with antibody. Is there anything else you noticed in terms of the patient feedback?

Yes. Look, I think the small molecules are fantastic. I've used them for many years. They're a great addition to our treatment armamentarium. The -- and even though 6 weekly or 8 weekly cycles are good, it's better than the 3-weekly docetaxel. And we don't see a lot of side effects with the small molecules. I'd have to say, though, we see less side effects with the antibody. And as Scott said, the myelotoxicity we see, we know about it. We expect to and it's reversible. So we don't often have to intervene with that. We just need to monitor. We don't see any of the salivary gland toxicity at all. So in fact, I didn't mention with that last patient, the reason he didn't want any more actinium was his xerostomia. He developed quite severe dry mouth and dry eyes and really did not want anymore small molecule-based therapies. He had the 6 cycles of lutetium PSMA and then, of course, the 2 cycles of the actinium PSMA. So I think tolerability -- patient tolerability, the 2 weeks apart is actually really -- patients like that. I have a lot of elderly patients. They realize they've got a terminal illness. They don't necessarily want to be stuck around hospitals. And so we've been able to have a treatment and then be able to go away and do things as long as we're monitoring their blood counts is actually very, very well appreciated by patients. The lower dose is also useful. If you're running a busy Theranostic clinic, we're only giving 2.8 megabecquerels and with us 1 hour or 2. I can have multiple patients come through my clinic as an outpatient clinic. With the small molecules, they're very good, but at least in the Australian setting, they will be with us for several hours until they reach the safety status limit. So from a throughput point of view, from a radiation point of view also for my staff, there's less exposure to my staff with -- I'm only giving 2.8 gigabecquerels of the 591. So there were a number of benefits. But the small molecules are great, and they have good responses. They've got good data and the benefits we see for the antibodies they're marginal, but useful.

Got it. And thank you so much, Nat. That's great insights in particularly as well, just a reminder in terms of lutetium dose and the impact potentially in handling the patients and potential waste as well, I think, is important, right? Great. Look, Oliver, maybe you've been involved in study design for prostate cancer and other tumors extensively in the past. And maybe you could just give us a little bit more insights into the ProstACT GLOBAL study design and maybe some sort of similarities but also some differences perhaps to other studies that are ongoing at the moment.

Sure. Thank you very much, Colin. And I'll go ahead to the next slide, and I do have some disclosures and worked with a variety of the companies in the space. There are differences in the ProstACT GLOBAL than the VISION trial, the PSMA 4, the ECLIPSE and the SPLASH trial, which are other trials that have used in a randomized way the small molecules with lutetium. Now one of the things that is actually not shown here is the definition of PSMA PET-positive disease, and there's some distinction. And the cutoff in the VISION trials and in the other small molecule trials have basically been an uptake greater than liver. Here, it's 1.5x the liver uptake. That could be important because we have analyzed the small molecule trials. And to some extent, those with more PSMA PET-positive disease are those that manage to do a little bit better. So here on the ProstACT GLOBAL, you're actually cutting out some of the low PSMA PET positivity and including only those that have a higher probability of response in my mind. Now another critically important variable is the actual use of standard of care. So if we go to the VISION trial, it was a standard of care, plus or minus PSMA-617-lutetium 177. However, the standard of care excluded taxanes. If you look at the taxanes, they're known to be active, and I just finished another ad board, where there was significant discussion about the control group as well as the treatments that have been received in the PSA lutetium patients, and there is, I think, a growing pushback against the exclusion of docetaxel, which is a known effective therapy in these trials. So what we have here in the ProstACT GLOBAL is the standard of care that can include either an ARPI or a taxane. And it's going to be physician designated. It's going to be true in both arms. Now let's look to Group A, which is the one with lutetium for a moment, and if you're randomized to the standard of care, you could start at ARPI essentially at the same time that you would start the antibody. However, if you're going to receive the taxane, then you need to wait until the lutetium is already in and you make sure that the blood counts are such that they're eligible for taxane therapy. But nevertheless, it is a standard of care plus the lutetium in this particular study. Now in Group B, the physicians can choose either an ARPI or taxane, and they can start to taxane immediately if they so desire. But anyway, I think the bottom line is a little different in the selection, a little different in the standard of care and the inclusion of taxane is actually a big difference to me. Now next slide. We're going to be moving for a brief moment, into talking about TLX592, which is not the same as 591. TLX592 is an antibody that's been engineered for more rapid rate of elimination than the standard antibodies. And as Scott mentioned, you end up with a prolonged retention in the blood pool with the standard antibody. So this is going to be one that would have a little bit more rapid clearance. Now you could look at the 592 and look at the 591 in an animal model and be able to see that you end up with comparable tumor uptake with a more rapid clearance and the CUPID Study is going to be looking at 592. And I'll just jump ahead for a moment. You're seeing the copper data here with the imaging. But I think the plan is to move this into actinium. Next slide. So a couple of things that I think distinguish the TLX591. First of all, we have extensive data. Thank you, Scott Tagawa and colleagues in New York. And I think one of the things that is most promising is not necessarily the PSA decline, but rather the survival. And the survival in heavily pretreated patients has been much better than would have been anticipated with either a small molecule with lutetium or, in fact, almost any other agents. Some of the survival data in these early phase TLX591, J591 or [indiscernible] studies have been outstanding. Another thing is the dosing schedule. As Nat mentioned and Scott had alluded to, there is a potential advantage for being able to give a couple of doses and they allow the combination with these concurrent therapies, designed really as a standard of care plus the TLX591. And I think that's a good trial design and one that could have a benefit for patients. For the patient comfort, we don't get the same degree of on-target but off-tumor effects. You don't get the dry eye. You don't get to xerostomia. Nat had mentioned the PSMA I&T actinium-225 where the patient actually declined further treatment because of the dry eyes and xerostomia. There are implications, I think, for alpha therapy going forward, but that's not why we're here. I want to say that the 591 is not going to be associated with dry eyes and xerostomia we're seeing with the small molecules. I think the patient-centric comfort is something that has been mentioned several times before. It's a 2-week course of treatment instead of a 36-week course of treatment. There is going to be close collaboration with Medical Oncology. But in my opinion, that is an asset, you end up with a short treatment duration, significantly fewer clinic visits, but I think in cooperation with the medical oncologists for the inclusion of other standard of care therapies, as mentioned, is a significant positivity. There's also reduced cost, reduced radiation protection implications. And I think there are many advantages for reduced radioactivity. We demonstrate efficacy in this particular trial. It will change practice and what I think it would be welcome to the community. Colin, those are the issues that I wanted to cover. Now back to you.

Thank you. Thank you so much. Thank you to the whole panel for great insights to date. Now I wanted to just start a bit of a discussion. We also have received a few questions from the audience that I will go through in time. But I wanted to go back to this PSA as a prognostic marker. And Oliver, maybe you could sort of open and comment on that.

Sure. PSA is a valuable biomarker, but it's not the end all and the be all. One of the things that the VISION and the PSMA 4 trial did not include was any PSMA PET imaging. But in studies where we've looked at PSMA PET imaging, it turns out that that's likely a better prognostic finding as compared to the PSA itself. Now going to PSA just for a brief moment. Let's remember that it is produced within the cells that are most differentiated. As you move into the higher Gleason scores, the 8, 9, 10s, on a cellular basis, the production of PSA is lower for a PSA Gleason -- for a Gleason 10 tumor as compared to Gleason 7. So what you're measuring with PSA is a more differentiated function, and that may not be the best measure of a biomarker when it comes to survival. I'll take the survival that Scott has shown over the PSA declines. And I think that's where there could be some discrepancy. In the small molecules, we've seen the PSA declines. With this particular molecule, we've seen the survival. I think the trial needs to be done, no doubt about it. It would be silly not to do the trial. Here the trial is, we're going to give a shot on goal and see what happens.

Fantastic. Any thoughts on other prognostic markets that you've seen during your investigations with 591, Scott?

So in terms of prognostic markers, some of this -- there are known prognostic markers are prognostic, means independent of treatment. So things like LDH or overall tumor burden. Liver is not a great base for cancer. But in terms of other biomarkers that might be meaningful in terms of efficacy, in the more recent era. So this didn't really exist going back 20 -- 15 to 20 years ago, but we've been looking at circulating tumor cells, which are in the process -- a couple of different platforms in the process of being credentialed by the FDA as a potential approval for endpoint. And that -- and PSA has never been there. It's a major point. So starting off with a higher number or at least detectable and then coming down has been associated independently with overall survival across a number of different clinical trials, and we have demonstrated that with Lutetium-J591 across the more -- kind of more recent era. So that's something kind of in addition to just PSA for instance.

Great. Any further thoughts to add on that, Nat?

No, look, I think Scott is right. I think the circulating tumor markers, circulating DNA -- tumor DNA, I think is going to add a lot more. We're starting to use it in other tumor types now. It's a valuable addition, I feel, in other tumor types, so look forward to seeing that. And I think what Oliver said is completely correct. PSA can be actually very low in high-grade tumors. It's one of the problems with some PSA screening, where you can have a quite an aggressive tumor and your PSA is not very high. And even in some racial groups, we know that PSA is not often a good marker in certain races. So it is what we have. It's what we use. But I think in the era of PSMA-PET -- and we do a lot of PSMA-PET in Australia. In fact, in Perth, we do over 100 PSMA-PET in a week in a little town. So it's become a surrogate biomarker for us. We are doing follow-up scans and routine scans. So I think PSMA-PET has really changed the way we look at things. And I'm glad that PSMA-PET has been included in this trial on an ongoing basis because, unfortunately, in the earlier trials, there wasn't -- that we didn't have the serial data, which we really need.

Fantastic. Thank you so much. One of the questions we're asked often is are we able to recruit this study and is 2 doses an attractive regimen for patients? Will they be -- will we be able to recruit for the study? Oliver, what's your thoughts on that?

I don't think you'll have any trouble with recruitment. First of all, the taxane naive population has no radioisotopic therapy approved today. So PSMA 4 is not approved. There's no reporting yet for SPLASH or ECLIPSE. And I think patients are anxious to get this type of therapy. And if you look at the accrual in a whole variety of the PSMA-lutetium studies, they've been very rapid. I think accrual will not be a problem.

Great. Any further thoughts on that, Scott?

I completely agree. It's -- patients are clearly interested in, in a way, any nonchemotherapy regimen, especially some that have some data behind them. That's a -- if it's radioactive, if it's PSMA target or whatever it is, I think patients are interested. And then in terms of -- on the practical basis, just the 2-dose administration, it makes it easier to them. Of course, we're still going to monitor them on an ongoing basis, both for safety as well as efficacy in terms of scans and survival. But in terms of overall treatment, it makes it easier to them. And actually one interesting thing, so segue, we look at CTCAE that's the way -- the technical term, how we look at adverse events, but we created a patient report outcome specifically for radionuclides because dry mouth is not very accurate on this. But one thing that came out was a feeling of isolation. And part of that came out from some questions about, well, worried about meeting up my family, grandkids, et cetera. So there's less in terms of total amount of radioactivity that's injected. But it's also just twice rather than multiple times. So I don't know if that is going to equal less feeling of isolation, but I know that did come out in this tool that we create for other reasons that just happen to kind of come out. So that's another interesting fact that this is patient-friendly.

Very good. Look, Nat, maybe just something to put to you. You mentioned about the taxane therapy opening up recruitment and in particular, in Australia, where we know that's probably standard of care in that setting. Is that right?

Yes. No, look, I think the nice thing about this design is you've got 2 arms. You can go on to a novel antiandrogen, which is good. And in Australia, the fact that Telix will cover a second novel antiandrogen because of our restrictive PDS criteria. It's often hard to go into a second novel antiandrogen. So that's been welcomed. And also, the crossover desire, I think, is also welcome. It basically allows other therapies. It's other standards of therapy -- which is really standard of care to be introduced. That's been one of the issues in the past. So patients who have spoken about the trial, even if they know that they get randomized to the nonradioligand or the radio-antibody therapy know that there is the possibility to get that down the line. And that's actually very encouraging. In fact, I had a patient just very recently, who has been randomized to the nonradioligand. But he knows that, that is in the background if he needs it, which is really very useful.

Yes. And there's -- obviously, there's slight nuances there because Australia can offer compassionate use perhaps more easily than in other countries, in fact, perhaps on the biggest scale that -- looking at that crossover arm and taking that out might allow us to observe overall survival as an example. And moving forwards, was that -- that was seen as a critique of PSMA 4 but there was huge crossover there, Oliver, right?

Yes. 84% of the patients on the hormonal arm crossover. I think that many people are aware that the intent-to-treat analysis had -- has a ratio of 1.16. But confidence intervals were big and clearly overlapped 1. In the prespecified crossover-adjusted overall survival analysis, there was, in fact, a trend, 0.8 for the hazard ratio favorable for lutetium. However, again, the confidence intervals were large. The fact that the confidence intervals were so large, I think will be one of the reasons why there will be a little more scrutiny on that trial. And I'll simply say that nothing is approved in the space right now, and it will require regulatory action before any of the other agents might be introduced.

Got it. Yes. And obviously, regulators would like to see overall survival as the primary endpoint in a lot of studies in oncology, of course, but PFS has been an accepted measure. But particularly overall survival will come in as we go forward and particularly in terms of the reimbursement setting as well. I just received an interesting question. ESMO, I couldn't go to ESMO, but I know there's a lot of talk about quality of life and patient felt quality of life factors. But this is one about synergy between PSMA-targeted agents and enzalutamide. But is there any data to suggest any synergies between 591 and taxanes at all? And Scott, maybe your study gives us some thoughts on that.

That's why we -- I mean, some people would say oncologists have 2 drugs that are always going to combine them in some sort of trial. But there was a scientific rationale for the regimen, one, because at least at the time we thought because we were coming from early studies where we use [ Yttrium ], which is a much longer path link than lutetium and the big bulky disease was better with [ Yttrium ]. I said, okay, let's give a couple of cycles to may cytoreduce. That was why we started with cycle 3. But the main reason that we wanted to combine them was because we know that taxanes preclinically and clinically can radiosensitize. So it can happen with hormonal therapy as well, but that was the idea that can we safely deliver the 2 of them together and get more bang for our buck. That was the idea behind why we did that combination.

Got it. Thank you for that. Any other thoughts on that, Oliver, you want to comment?

Yes, I think that there's not only synergy potentially between the taxanes but also with hormonal agents. Within the VISION analysis, we looked at those who had the PSMA-lutetium with or without a hormonal therapy. And the truth is that those who are on the hormonal therapy stood a little better. Now in the PSM 4 trial, there was no hormonal therapy allowed in the -- excuse me, I should say, no novel hormones, so abiraterone and enzalutamide were allowed in the lutetium arm, and the FDA required the separation. I like the opportunity to use a combination. I think if we had [indiscernible] here, she would agree with that. And she presented [indiscernible] data at ESMO as well, and that was ending -- very interesting to me, showing interactions in a positive way for the hormones as well as the isotope.

Great. Thank you for that. There's a lot of interest in terms of the clinical position. I guess if this study is positive, how would the potential indications be different with 591? Would it end up in a combination with a taxane indication?

I think your Phase III trial will determine your indication and here, by overtly including the taxanes and RPs in both arms, I think you could end up with a quite distinct label which fits a little better with the way medical oncologists are treating patients. We do think about a single line of therapy, don't get me wrong. But we also think about combinations and sequences, and in the end, we want our patients to get as many of these life prolonging therapies as possible. I think this trial design does have some advantages. And I think that's a little bit distinct from the PSMA 4, the ECLIPSE and the SPLASH trials.

And can I just ask because it's a follow-on real question? It's like, historically -- and one of the reasons for this is a control arm going for abiraterone and then an enzalutamide type control has been widely adopted because that has historically being a real-world practice in the U.S. But is the practice changing in the U.S. that taxanes are used in that second-line setting more often?

Well, I think there's an overall recognition of the limitations of the hormonal therapy in the second line. It's still quite commonly used, but everyone understands that the second line hormone is going to be less effective than the first -- dramatically less effective than the first. And I think that there's a little more of a push these days to get in the docetaxel when you can as opposed to pushing it to the rear. Docetaxel is acknowledged to be an active agent and people want to use as many active agents as feasible for these patients. We're not curing them. We're trying to prolong their survival and fit in as many active agencies we possibly can. That's sort of a predominant philosophy, I'd say, today in the U.S.

Great. Scott, maybe you could comment on that using taxanes in your daily practice.

Yes. I mean I'm an oncologist. We give chemotherapy, not only. I think it depends. So part of it I think you used the term era but you might not have -- I think it's a little bit as the era. So in the setting where someone has had one AR pathway inhibitor and then what do we have that really has proven overall survival that is applicable to most patients, it really is chemotherapy because [ single cell T ] maybe for a small subset, radium for a small subset, PARP inhibitors for a small subset, but taxane chemotherapy is more or less universally there, even though data will show only 50%, 60% will ever get it. But I think that certainly, in my practice, I take the time to explain what's going on there. Most of my patients, virtually all, not just most, like 51%, the vast majority, I would say, are taxane eligible. I may adjust the dosing schedule for them. But I think most can receive it. And when docetaxel [indiscernible] it improved survival as well as patient comfort outcomes versus mitoxantrone which is based upon patient [indiscernible]. So for symptomatic patients, I think it's great to have, but not everyone needs that as the absolute next line, and that's why people have used AR pathway inhibitors kind of back to back. I think that changes, as I've mentioned, [indiscernible]0:45:48.4 that changes in the new era where we start to have more options. And even if, let's say, someone did a head to head docetaxel, there was no major difference because for that minimally symptomatic patient population and you still have the chemotoxicity, I think people might choose a chemo -- non-chemo containing regimen or one that's more delayed, let's say, with Lutetium-617 and J591 followed by docetaxel. And then in the real world, even if that was approved like that. Patient doesn't necessarily get that second part right away. So we'd have to see what happens. You don't have the problem. You have to see what happens, and maybe that's a future issue to kind of bring that.

A nice problem to have, that's what you're saying. Right. Look, we've come to the end of the hour, and I want to thank speakers for excellent input and feedback. We've tried to cover a lot of those advanced questions in the discussion, in the presentations. Thank you for those who've just submitted questions, and I'm sorry if yours hasn't been answered. Then, of course, we'll come back to you. But I think my excitement about 591 is the differences in terms of the dosing, the total lutetium dose, the side effect profile of the antibody. And also, those 2 doses, which I think is patient-friendly. So I want to thank you all. We're excited to press ahead with ProstACT GLOBAL and really find out and get the data that we can use to take this asset forward. So Oliver, Nat, Scott, thank you ever so much for your participation today. Thank you for those of you who've been able to join in whatever time of day it is for you. So thanks, everybody. I look forward to meeting again very soon in discussing further data from this and other studies. So thank you.

Thank you, Colin.