Telix Pharmaceuticals Limited ($TLX)

Good morning, everybody. My name is Kyahn Williamson, SVP of Investor Relations and Corporate Communications at Telix. And we're very pleased to welcome you today to our investor call and webcast to present the results of the ProstACT Global Phase III study, Part 1 safety and dosimetry lead-in. I'm just looking to the next slide, just ask you to take a moment to have a look at our disclaimer. In terms of -- and then moving to the next slide. Very pleased to introduce today's speakers. Dr. Christian Behrenbruch, our Managing Director and Group CEO, will make some brief introductory remarks. Our Chief Medical Officer, Dr. David Cade, will present the data. And then I'm very pleased to welcome our guest speaker, Dr. Pedro Barata, Medical Oncologist with the University Hospitals Seidman Cancer Center and Associate Professor of Medicine at Case Western Reserve University School of Medicine in Cleveland, U.S.A. and also a ProstACT Global Steering Committee member and investigator on the trial to also share some case studies and his perspectives. Following the presentation of the data, we will open the call up to questions from analysts. These -- through the conference call line, these will be focused on the clinical data. For the questions that we don't get to or questions on the webcast, we will respond to you at the conclusion of the call if we can't get to your question. With that, I'd like to hand over to Chris.

Thanks very much, Ky. I'm going to actually hand over to my clinical colleagues in relatively short order, but I would like to make a few brief introductory comments. We are delighted to present the results of the ProstACT Global Phase III study Part 1, and we thank for your patience as we closed out the study and completed the data and dosimetric analysis in preparation for engagement with the FDA. As a reminder, this Part 1 study is a specific requirement of the FDA in order to proceed to Part 2 in the United States. ProstACT Global is a highly innovative trial that is designed to integrate with current standard of care in the castration-resistant metastatic prostate cancer setting, including in combination with androgen deprivation or ARPI switch. ARPI switch is the preferred standard of care in this patient setting in the United States. However, the study design also reflects the fact that in many parts of the world, patients still receive chemotherapy following treatment with an initial ARPI, largely due to its cost effectiveness. As such, both approaches are permitted in the study. The data that is presented today confirms the safety profile of TLX591-Tx in the combination therapy setting. And while an important milestone for investors is not an entirely unexpected outcome given that we had an independent data safety review committee grant clearance last year to progress to Part 2 randomization in the ex-U.S. jurisdictions where we already have regulatory approval to proceed. Having now formally closed and read out the study, this enables us to go back to the FDA to obtain an IND amendment to include American patients in Part 2, subject, of course, to agency approval. As a reminder, the purpose of this gating study from the FDA perspective, the agency is looking for us to demonstrate safety, dosimetry and feasibility of the combination therapy and particularly the comparison between the different ARPI combos. As you will see, the data indicates that TLX591-Tx can be integrated with standard of care, both ARPI and taxane with no observed drug-drug interactions and no new or unexpected safety signals. Drug is well tolerated on top of standard of care in all 3 treatment arms additionally, and this is very important, based on the adverse event profile and specifically recovery from treatment-related AEs, there would be no impediment to patients receiving further treatment upon progression, including, if required, taxanes. We're now focused on enrolling Part 2 of the study globally as quickly as possible. Part 2 has quite a different recruitment cadence in Part 1 due to the more streamlined nature of the second part of the study. It is our belief that in the not-too-distant future, combining TLX591-Tx with standard of care in the first- and second-line metastatic setting, will give physicians new options to treat patients and potentially better outcomes after failing first-line therapy. Finally, before we move to the specific study outcomes, I want to acknowledge with gratitude the patients, their families and our clinical collaborators that continue to support this important trial. I'd like to especially acknowledge one of our key investigators, Dr. Barata, who joins us today as a speaker alongside Dr. David Cade, our Chief Medical Officer. And with that, I will hand over to the clinical team to go into the detail of the study outcomes. David, over to you.

Thank you, Chris. If we go to the next slide, today, together with Dr. Barata, I'm going to take you through the outcomes from Part 1 of our Phase III ProstACT Global study, in which we set out to evaluate the safety and the dosimetry of our lead prostate cancer therapy agent, TLX591 in combination with the androgen receptor pathway inhibitor agents, either abiraterone or enzalutamide or the chemotherapy agent docetaxel, which we evaluated in 3 separate cohorts of patients. In essence, really all of the Part 1 study objectives comprising the safety of the 3 combinations, very clear pharmacokinetics and a favorable dosimetry were achieved. Specifically, I'm delighted to see that there are no new safety signals that were identified, and the hematologic or the blood events were both transient and manageable as we'll go through a little bit more detail later in the discussion. The tolerability of TLX591 plus ARPI or docetaxel given sequentially following TLX591 was supported by the dosimetry and the low grade of non-hematologic events. The lesion dosimetry demonstrated very meaningful uptake in the lesions, and there were no significant differences in the absorbed dose profiles across the 3 cohorts of patients that we studied. And then finally, there were no adverse drug interactions observed in any of the TLX591 combinations. So if you put this together, fundamentally, these Part 1 results demonstrate the feasibility of integrating TLX591 with contemporary backbone standards of care globally is a feasible approach to undertake. So if we go to the next slide, as a brief recap of Telix's therapeutic candidate, TLX591, is a highly differentiated PSMA-targeted radiopharmaceutical that employs a monoclonal antibody to very selectively target prostate cancer-expressed PSMA while avoiding the PSMA that is natively expressed on some of the normal tissues. And what this does is it enables a very precise delivery to the cancer tissue, which is where we wanted to go of that radioactive payload. Now this approach really addresses a number of clinical needs that we need to address, particularly a 2-dose 15-day schedule that enables a much more feasible integration with standard of care, either ARPI or chemotherapy agents that we otherwise want to continue to offer patients. A very low radiation dose is imparted to the salivary glands and the kidneys, which are the 2 main organs that may be injured when we use small molecule agents as well as a very transient and manageable hematologic profile that we'll get into a bit more detail later on. There's very specific internalization and thus a prolonged retention within the prostate cancer cell, which is clearly evident on some of the post-treatment imaging, which Dr. Barata will show a number of case studies on. And then finally, there are some really potential real-world advantages from the lower administered activity at lower radiation doses being directed at the normal tissues, particularly in the kidneys, which may, in future, enable the patient to have additional forms of radiation therapy if necessary. So if we go to the next slide, this slide really nicely illustrates the fundamental differences between TLX591, which is a radio antibody drug conjugate, and a first-generation small molecule radioligand therapy, for example, Pluvicto. And I think the key takeaway here is that the dosing schedule is markedly different with TLX591 being dosed as 2 fractions 2 weeks apart compared to up to 6 fractions every 6 weeks with the small molecule. And so what this means is that the total amount of radioactivity that has to be delivered to a patient is much less with TLX591. And this is because the antibody delivery vector is specifically immunoreactive with the tumor-expressed PSMA type following, which it internalizes into the tumor cell and maintains a prolonged retention, which the imaging shows. I always love pictures. So on the right, you can clearly see the biodistribution and the clearance of the 2 different approaches and the advantage of the radio antibody approach where the liver, which is a relatively radio-tolerant organ, is the primary clearance organ followed by the large bowel and ultimately fecal elimination. The other image obviously shows the small molecule, on the other hand, which is primarily cleared from the blood circulation by the kidneys, which really does so welcoming the radiation, followed by the bladder, which you can see very clearly and ultimately, urinary elimination. You can also see significant off-target uptake in the salivary glands, which leads to dry mouth, which can be quite problematic, leading to a reduction in quality of life in quite a significant proportion of patients. So if we go to the next slide, let's move on to the study design, and I'll summarize the patient population. Go to the next slide, please. Now here, you can see why we designed ProstACT Global, the study the way we did. It's a very pragmatic study design that aims to evaluate whether adding TLX591 on top of standard of care can improve progression-free survival and overall survival. And what it does, as Chris mentioned at the outset, was that it aims to accommodate the different backbones of standard of care that are most commonly used by and are familiar to oncologists either within or with outside of the United States. So specifically, this chart of the world indicates that in the United States, when a patient experiences prostate cancer progression while receiving their first ARPI drug, the predominant clinical practice is then to switch the patient on to a second ARPI drug, very, very established practice in the United States. Whereas outside of the U.S., the more common practice, and this is reflected in the clinical practice guidelines, both in Europe, such as ESMO and the EAU guidelines but also those guidelines in China and Korea and Japan and elsewhere, the prevailing practice is to switch the patients on to a chemotherapy agent. The most common one of those that's used is docetaxel. If we go to the next slide, this is the overall design of ProstACT Global, the Phase III study and its current status, which is very nicely summarized on the top right. And as you can see, Part 1 -- sorry, Part 2, which is the randomized treatment expansion is enrolling 490 patients, and that enrollment is occurring currently in Australia and New Zealand and Canada following the independent data monitoring committee review in October of last year, but the study also now has the regulatory approvals, enabling Part 2 to commence randomization of patients in China and Japan, Korea, Singapore, Turkey and the United Kingdom. So that's underway at the moment. Part 1, back to Part 1. So Part 1, which is now complete, was a prerequisite of the FDA that was required by the FDA before we were given permission to commence Part 2 in American patients. So we're really encouraged by the data from Part 1, and we look forward to engaging with the FDA with these data at the earliest opportunity while continuing to obviously enroll into Part 2 in those regions where the study has been approved to do that. Now if we go to the next slide, this is a brief consult -- what we call a CONSORT diagram that really outlines what has occurred so far in Part 1 as we've completed Part 1. And you can see that there were 57 -- starting at the top, you can see that there were 57 patients screened. 36 patients who each progressed while receiving a prior ARPI agent were deemed eligible, and all 36 of those eligible patients received 2 doses of TLX591 as planned according to the study protocol. Then you can see the breakout below that. 11 patients were allocated into the abiraterone cohort, 11 to the enzalutamide cohort and 14 to the docetaxel cohort. I think it's a very positive sign that there were no treatment-related deaths on study, and 32 of those 36 patients enrolled remain alive as well as 26 patients that continue on the study as of the time of the data cut back on the 12th of January. So let's move on to what these patients look like. Next slide. These are the demographics and prior treatments of those 36 patients that we enrolled for Part 1 at baseline. And I think in summary, really nothing is especially remarkable about the demographics or baseline characteristics of the patients that were enrolled to Part 1 of the study. As you can see, the majority of patients in Part 1, almost 3/4 were receiving second-line therapy in this study, and the median age was 77 years which is somewhat older compared to other studies where the age is typically around 70. For example, in VISION, it was 71. So this is a relatively advanced group of patients. In terms of prior treatment, most patients, just under half of them, had enzalutamide as their prior ARPI agent. And most patients, almost 3/4, have not had a prior taxane chemotherapy agent in the earlier metastatic castrate-sensitive setting. So when we look at some of the prognostic factors, a subset of which are on the right, the median PSA was similar to other studies and the ECOG performance status was good. So in Part 2, as we proceed to enroll and ramp up enrollment to Part 2, maybe we'd expect the age to come down slightly, but otherwise, it will be a very similar set of demographics in the second part of the study. Next slide. So let's now look at the safety. Next slide. So the primary objective of Part 1 of ProstACT Global was obviously to assess the safety of TLX591 when either administered concurrently with standard of care, abiraterone or enzalutamide, or followed by standard of care docetaxel chemotherapy. Overall, the 3 cohorts demonstrated an acceptable safety profile with no new safety signals when compared to the prior studies, including the most recent ProstACT SELECT study. You can see in the table on the right, the most common treatment-emergent adverse events comprised fatigue and nausea and dry mouth, and almost all of these non-hematological adverse events were Grade 1 or Grade 2. In other words, they were mild with the exception of one patient who had a Grade 3 dizziness event. The hematological adverse events, as we would expect, comprise Grade 3 and Grade 4 thrombocytopenia, which is a reduction in the platelet counts on the lab test, which occurred in 14% and 31% of patients, respectively, as well as Grade 3 and Grade 4 neutropenia, which is a reduction in the neutrophil count, which occurred in 22% and 25% of patients, respectively. I think it's important to say that these hematologic events were certainly in line with the profile that we would expect for this class of radio-antibody drug conjugate, and they were transient and manageable as we'll discuss in a bit more detail on the next slide. So next slide, please. So the question that comes up, of course, is when you have a hematological event, what happens. And as I mentioned in the prior discussion, the hematological events are the main adverse events of interest for this radio antibody drug class of therapy. Now in terms of thrombocytopenia, which is the most important of these events, as you can see here, the platelet counts were very consistent across the 3 cohorts with the near or the bottom point in the platelet count occurring very consistently at an average of 43 days, which is about 6 weeks after the first dose of TLX591. But what's most important is what happens from here. So from the nadir, you can see that the platelet counts recovered to Grade 1 or better than an average of about 15 days after the lowest point. And from there, they continued to revert back to the normal range in the majority of patients. Importantly, no patients experienced any febrile neutropenia related to TLX591, which is a relatively common adverse event that patients may characteristically experience from conventional chemotherapy. So in summary, the hematologic adverse events, which are very well characterized and understood from prior clinical studies with this agent were self-limiting and they resolved spontaneously without intervention in the majority of patients in Part 1. So this is very encouraging. Let's move on to, next slide, please, the dosimetry. Next slide. So while safety was the primary objective of Part 1 of ProstACT Global, the main secondary endpoint was to assess the pharmacokinetics, biodistribution and the radiation dosimetry of 591 when administered concurrently with those standards of care. Overall, the 3 cohorts demonstrated a very predictable pharmacokinetic profile. And if you think about where you want the radioactivity to be, you either want it circulating in the blood pool so that it's available to be taken up by the tumors or you want it in the tumor lesions themselves or you want it in the liver as the drug is cleared from the body as we saw in those earlier images. Now the importance of these 2 graphs, and I'll explain them to you, is that the graph on the left demonstrates the blood radioactivity concentration, which, as you can see from the curves, is sustained but declining over time. In the right-hand graph, what we see is essentially the reciprocal of that, which I think very nicely demonstrates the tumor radioactivity concentration, which increases early and then is sustained over time through the antibody-specific binding, its internalization and its prolonged retention on site within the tumor. These exposure and washout kinetics were very clearly consistent across the 3 cohorts, as you can see by the oversitting of the lines, which indicates that there was no evidence of TLX591 interacting with any of the ARPI drugs when we co-administered those agents with TLX591. Next slide. Now let's move on to the normal organ dosimetry. This is very important. So this is those organs that we want to keep the radiation away from. And as you can see very clearly, this part of the study confirmed that the radiation exposure to those normal organs was very low and certainly well below safety limits that have been determined from the external beam radiation and the radioligand therapy literature. And a particular note, you can see that with TLX591, there's a very low radiation dosing imparted to the kidneys and the salivary glands, which are the 2 normal tissues that small molecule radioligands tend to hit the hardest. And this reduces the risk of developing kidney impairment or dry mouth, each of which may very significantly impact patient quality of life, both during treatment and in the out years to come. You can see on the right-hand side of this chart, the liver, as I highlighted earlier with the images. The liver is a very -- it's a relatively radio-tolerant organ. So it makes sense that this is the primary clearance organ and therefore, it receives the highest dose, which it is capable of doing. And then from there, the activity is cleared from the body via the right colon, the left colon, the rectum, which is sort of downstream of the liver and ultimately via fecal elimination. Next slide. And then finally, Part 1 studied the lesion dosimetry, which, again, was highly consistent across the 3 cohorts of patients and it showed that following the administration of 2 doses of TLX591, 14 days apart, there were consistent and meaningful physical radiation doses imparted to the tumor target lesions across all of the main anatomical sites of disease, the 3 main ones being the skeleton, which is where prostate cancer goes, the lymph nodes and the soft tissues. I do think it's important to note that while these radiation doses are meaningful, radioantibody drugs possess a different mechanism of action compared to small molecule ligands. And as a recent dosimetry think tank at the ASCO meeting concluded, it's important to be mindful that tumor dosimetry is measured differently from trial to trial. And while it's available for go/no-go decisions in radiopharma development, we ultimately still rely on objective clinical measures of efficacy, such as PFS and OS, which, of course, what ProstACT Global Part 2 is already underway to evaluate. Now we are -- I would like to hand over to Dr. Barata. We're very fortunate to work with investigators of the caliber of Dr. Barata. And Dr. Barata is going to take us through a couple of typical patient cases from Part 1 of this study. So Dr. Barata, over to you.

I appreciate it very much, David. I hope you and everybody can hear me okay. Pleasure to be here with you all. Can you show me next slide, please? So we have a couple of cases here, part of this component of the study for you today. And what we're looking at is actually our first patient case. So this case in brief kind of illustrates a 64-year-old patient known to have metastatic prostate cancer involving the lymph nodes who got treated with TLX591 in combination with abiraterone. So just for context, this patient had evidence of mCRPC, so castration-resistant disease, previously got treated with enzalutamide and ADT, and the investigator decided to choose abiraterone as standard of care along with TLX591 and end up enrolling in that cohort. So baseline gallium PSMA PET did show disease in the lymph nodes, as you can see here on the left, including subcarinal, pera tracheal, abdominal, pelvic lymph nodes. So extensive nodal disease, if you will. He did receive a single dose 177 lutetium TLX591 at approximately 2780 MBq and then was followed by a serial SPECT to evaluate biodistribution. I think what we can see is here early images at 4 and 24 hours show kind of an expected distribution of the rather label antibody within the vascular compartment and also the liver, which does reflect what David presented before, that systemic circulation and hepatic clearance. Importantly, by 96 to 168 hours, we do see a clear uptick and which I think demonstrates effective targeting of those PSMA expression lesions. I think it's relevant to note the persistence in the signal even at 360, highlighting, I think, to me, the prolonged tumor retention of these antibody-based radiopharmaceutical. So I think this prolonged residence time, I guess, supports this radiation delivery to tumor sites. And I think it can reflect the potential advantage of this approach compared to small molecule, for example. I should note that this patient remains on study at 279 days at the time of data cutoff, and this was last January 12, 2026. Thank you. Can we move on to next slide? So I'm going to show you a little different case. This is an older patient, 83-year-old patient, also known with mCRPC, predominantly bone disease as shown in the baseline gallium PSMA PET that includes the disease in the vertebra as well as in the ribs. This patient was also previously treated with ADT and enzalutamide. And the investigator determined that the patient should receive docetaxel at standard of care following TLX591. So patient did receive TLX591, approximately 2890 MBq, and again, got serial SPECT imaging in that context. So as with the previous case, we see early images there demonstrating the same type of distribution, which is, again, consistent with the pharmacokinetics and of the monoclonal antibody base radiopharmaceutical. And by 96 hours and beyond, we do see a clear localization of the radio tracer in the skeletal mets, which I think confirms the uptake of the sites of the PSMA-expressing tumor in the bone. It's also relevant one more time to note that we do see activity detected through the 360 hours, which again demonstrates this prolonged tumor retention and sustained radiation exposure. This patient also remained on study at 160 days at the time of the data cutoff, same day, January 12, 2026. And in this context, I think it's important to highlight the feasibility of sequencing TLX591 with docetaxel while maintaining effective tumor targeting and favorable biodistribution. So 2 cases, one standard of care, abiraterone, the second standard of care docetaxel received sequentially. Both cases, patients were -- remain on study at the time of data cutoff. Thank you. And please show me the next slide. I'll give it back to you, David, thanks so much. Happy to take questions.

All right. Thanks, Dr. Barata. Next slide, please. So let's summarize and then we'll move on to -- we're very happy to take questions. So to summarize, Part 1 of ProstACT Global really has confirmed for us that TLX591 plus the most common standards of care has an acceptable safety profile. It's got favorable normal organ and meaningful tumor dosimetry. In particular, I think these findings were consistent across the 3 cohorts. That's a very important finding across those 3 cohorts that we studied. As expected, there were no new safety signals identified. There were no drug adverse interactions and that was shown very clearly in the behavior of the agent when it was combined with the ARPI agents. And a low radiation exposure to the salivary glands and to the kidneys are very important and I think attractive features of this agent, which really support and explain its tolerability amongst the patients that have received the agent, the 36 patients in Part 1 of the study. So really, we're very encouraged by these data from Part 1. I think they're sound, and we do look forward to engaging with the FDA at the earliest opportunity, while, of course, at the same time, ramping up enrollment into Part 2, which is the exciting part of the trial, the randomized treatment expansion in all of those regions where the study has already been approved. So I'd like to thank you for dialing in. Thanks for your attention. I hope that's been informative. And we are very happy to take any questions.

Your first question comes from Andy Hsieh from William Blair.

So maybe a couple of just quick ones for Dr. Barata, if you don't mind. Just from a patient baseline characteristics, I noticed that the visceral metastasis rate is about 36%. Can you comment on that, whether that's kind of high compared to other prostate cancer studies like a PSMA-4 or VISION study? And also before the CONSORT diagram, it seems like the screened failure rate is also a little bit high, about 37%. So I'm curious about what the most common reason for not meeting eligibility. And I have a quick follow-up in terms of maybe absorbed dose.

David, I'll defer to you if you want me to address the VISION question first or vice versa, I'll defer to you.

Yes, Dr. Barata, you go ahead, and I can add a little bit of color to it as well.

Of course. So thank you for your question, really relevant. And I think you're quoting several data sets, trial and real-world data regarding the prevalence of visual disease, right, which usually lands in up to 20%. So you are right, when we compare things, the number needs to be higher. But my interpretation is twofold. Number one, I think it's an advantage of this design is the ability to offer chemotherapy as part of the cohort here, which is different from other studies. What that means is this tells me that the investigators around the world were very comfortable offering this protocol because they have the option of going with chemotherapy, which is a standard of care in many parts of the world, particularly for patients with aggressive disease such as visual disease. And the other piece is definitely the sense from investigators that if you have a positive PSMA as a tracer, even though you have visual disease, you do believe that radiopharmaceuticals play a role. So in my opinion, the higher rate than expected, it's a good thing for this particular study design because it reinforces the opportunity to run this study in the context of more or less aggressive disease. But to your point, in the context of more aggressive disease as well. So it does play relevance in both scenarios, in a scenario of a crossover to a different RPI or the scenario of going with the chemotherapy. So a fantastic point that you raised.

Yes. Maybe, Andy, look, you've got a very sharp eye. So I'll answer the second part of your question. Just to repeat it, you asked in the CONSORT diagram why was a significant number of patients excluded, 57 screened and 36 enrolled. It's an excellent question. So primarily, that's because of the 21 patients excluded, 18 of them didn't meet the eligibility criteria. And within that 18, the vast majority were because there's a baseline independent radiology review that looks at the PSMA positivity of these patients. And so obviously, you want to have a high PSMA positivity, in other words, a high expression of the target because they are the patients that ultimately stand to benefit from therapy, whereas those patients with a low PSMA expression are very likely to respond. So we select patients quite heavily on that basis, and that's why patients that don't have high PSMA expression are weeded out and thus excluded. Does that answer the question, Andy?

Apologies. Andy has dropped off the line. Your next question comes from Laura Sutcliffe from Citi.

Since Andy just dropped off, I might follow up to his question first. Do you envisage that initial baseline screen in any way becoming part of who is eligible for this in the future? So would you be cutting down your eligible patient population by means of a required PSMA expression level? And then I'll come back with another question.

Yes, Laura, look, that's a great question. And the answer is yes. So in the entry criteria into the study, patients have to have lesions or at least 1 lesion that has PSMA positivity that is twice the liver. So that is a requirement to enter the study. And that's for sensible reasons because PSMA positivity is sort of -- is an indicator of how much the radioligand therapy, the radioantibody drug conjugate, will go to those lesions. So if the patient has a very low PSMA positivity, there'll be much more off-target uptake and that won't hit the tumor target. So that's why that is set. That was used in the VISION trial. We've increased the requirement for PSMA positivity in the study. And typically, the eligibility criteria guide, the ultimate label discussion with FDA. But that's a matter for that discussion in the future.

Okay. And then my other question is just you've broken down in your presentation the dose absorption characteristics of the 3 groups, and they're quite similar, but the safety profile is not broken out by cohort. I was just wondering if you could comment on how the groups differ and in particular, any differences in Grade 3, 4 adverse event rates between the groups?

Yes. Look, they're actually very similar across the 3 groups, very, very similar. The most important adverse event is the hematological adverse events. And of those, the most important of those is the thrombocytes. And you can see that those 3 curves for the platelet decline to nadir and then recovery from nadir back to grade 1 and then beyond that, recovering back to normal. Those 3 curves, when I first saw them, it was very pleased to see that they almost sit on top of each other. So that behavior for thrombocytes, platelets, but also for neutrophils is very consistent across the cohorts, and it's the same for all of the other non-hematological toxicities as well. So Laura, that will be -- the FDA will want to see that. That will be a detailed discussion with the FDA, but they -- across all 3 cohorts, they're very, very similar.

Your next question comes from Tara Bancroft from TD Cowen.

This is Nick on for Tara. Given these data, what is your level of confidence that patients who remain on drug to experience longer rPFS than Pluvicto does in the PSMA 4 trial at 12 months? Or do you believe there is a different bar to use for ProstACT Global given the combination approach?

Yes. Look, the statistics of this study basically required 9 months versus 6 months, but that's not an assumption of efficacy, of course. That's just simply for the statistical planning for the sample size based on an assumed treatment effect. So that's the assumption for the sample size planning. Now that's not to say that's what we'll demonstrate. But obviously, there needs to be a meaningful progression-free survival and a meaningful overall survival. And that will be first gauged. So we don't have any reading on that at the moment. That will be first gauged as an exploratory endpoint from Part 1, progression-free survival and radiographic progression-free survival are exploratory endpoints. And we anticipate that they will probably be available later in the year, second half of 2026. Obviously, that's a time to event, which is guided by how the patients perform. And so longer for each patient is better, and that obviously pushes that out. The next inflection obviously, is guided by the interim analysis of futility, which is a preplanned inflection after 81 progression events. So that's where we're headed.

Your next question comes from Shane Storey from Canaccord Genuity.

David, I'm going to continue just there with that statistical route, please. I anticipate that we'd probably see quite different activity and maybe effect sizes between the 3 controls in the second component of global. So just curious about how that might be handled. And maybe another way of asking that is whether any of the individual standard of care arms might themselves be powered for that primary endpoint, please?

Yes, Shane, that's a well-directed question. There's no -- there's an assumption of no significant difference in the effect size between the ARPIs and the sequence docetaxel. However, per the protocol design, and this is obviously up on ClinicalTrials.gov, there's -- these are stratification factors between whether they were elected by their investigator to have either ARPI or chemotherapy. That's a stratification factor, which means that both sides will be balanced. And that's how bias is dealt with. And yes, really, I think that answers the question, hopefully, Shane.

No, it does. So they're stratified first and then randomized second.

They are. Yes. So stratification balances out to make sure that there are more patients in one arm compared to the other getting chemotherapy or ARPI. And that's how that bias is mitigated pretty conventional sort of statistical approach.

I've got a couple more just back to this morning's data. You mentioned the, I guess, homogeneity of the safety sort of across the different cohorts. Could you speak maybe to a little bit more detail on the management of the Grade 4 hematologic events? I wondered whether in any of those situations whether transfusions or growth factors were necessary, please?

Just take myself off mute. All of those thrombocyte declines were self-limiting and resolved spontaneously. 2 patients received platelets and 2 patients received red cells. But that's very, very similar to prior studies. 2 patients received platelets, 2 patients received red cells. Now that's pretty consistent as you would expect in patients receiving chemotherapy or receiving other cytotoxic agents or radiation therapy as well. So there's not really a difference in the rate at which blood products were received compared to studies.

And my last question, David, but my last question really, and I know it perhaps might go a little bit beyond the duration of interest that we're dealing with this morning. But maybe some comments on how many cycles of docetaxel those patients went on to receive after 591. I just want to kind of rule out the idea that there are any sort of serious deviation from the dosing protocol for docetaxel.

Yes, sure. And that's a relevant question, Shane. So in standard practice, when we use docetaxel, the median number of cycles that a patient with prostate -- advanced prostate cancer would get is typically 5 to 6 cycles. Now in this study, we're very confident that we've got enough patients receiving enough chemotherapy to take to the FDA. That's what they asked us to show. We didn't go into any detail on that because that is really a question of treatment intensity. Now treatment intensity, the number of cycles that the patient gets, is not obviously an endpoint of Part 1, and it's typically discussed, as you know, when we get into efficacy discussions. And so you will see that in the Part 2 results, but it's not an endpoint and not really that relevant for Part 2. But we're very confident we've got enough data to -- on the docetaxel cohort to take to the FDA and have a meaningful discussion.

Your next question comes from Dave Stanton from Jefferies.

Just a follow-up on the previous question from Shane. So can you perhaps outline to us the next steps and potential time lines for that for FDA engagement?

Yes. Look, I'll also invite Chris to comment on that as well. But yes, look, I think these data, Dave, the data these clinical data are exactly what the FDA prescribed us to collect. We've now completed that. And it is -- I think we're overwhelmingly encouraged by these data, and we're really keen to put it in front of the FDA. Chris, I might ask you to sort of add any additional color to that, that you would like to add?

No, I don't. I mean we -- this is the first time that we've had the completed CSR from the study, which is why we've disclosed it in a timely fashion, and the team is working really hard to get the package in front of the FDA in a timely fashion. So it's a high priority to get U.S. patients into the randomized Part 2.

Understood. And perhaps just in the real world, can you talk to potential treatment options for TCP, Grade 3 or Grade 4 that a clinician might look to use and how to mitigate any -- that decline in a Grade 3 or 4 situation in the real world? Perhaps it's a question for Dr. Barata.

Maybe Dr. Barata, you'd be welcome to answer that question of Dr. David Stanton.

I appreciate that. I think I was having some trouble hearing the question until the end. I think real-world management of significant side effects. Is that what I heard or I'm sorry?

Particular -- in particular, Grade 3 and Grade 4 thrombocytopenia, please. How would you manage that in the real world to get patients through?

Got you. Got you. Yes. So I think what we've done in the protocol is pretty much aligned what happens in real world. So I can tell you that most of the time, unless you have below 10,000 platelets where transfusion, platelet transfusion is recommended because you can develop spontaneous bleed, numbers above 10,000 usually are the close monitoring with repeat labs on a regular basis and observation is what we tend to do. So the protocol in terms of managing and watching the numbers on a regular basis, repeat labs is what we would do in clinical practice, and that the periodosity or the schedule of those checks, lab checks vary. Some folks will do a little bit more often, others every week to every other week. So I would say the protocol gives you that flexibility. So what you're seeing here, it's really pretty much what we would have done in real world outside of clinical protocol.

I'll just add to that. It's certainly not an acute event. So we know the behavior of the platelet profile. And most patients in the study, as you can see, I think it's in that graph very clearly articulated that they get just below Grade 1. So Grade 1 is between lower limit of normal and 75,000 platelets. Patients spend a very, very short fleeting time below Grade 1 and then they recover. Almost all of them just by themselves back to Grade 1, which is sort of -- Dave, you're an MD, I know as well, but Grade 1 is obviously the safe zone. In fact, Grade 2 is quite safe as well, but they get back into the Grade 1, very safe zone very quickly by themselves. And then from there, most of them recover pretty quickly. So it's really, really predictable, and it's only the outlier patient that might need hematologic support with units of platelets or red cells. Now obviously, red cells declining is very, very common in radiation therapy and chemotherapy. Anemia is one of the most common side effects, but it's not characteristic with this agent.

Your next question comes from Melissa Benson from Barrenjoey.

The first one, just a quick one on the non-hematologic events, just the dry mouth or Grade 1. Should we think of that as really attributed just to the ARPI combination contribution?

Look, as I mentioned, all of the Grade, all of the dry mouth events were Grade 1, Grade 2, in other words, mild. They were very short duration as well. Now attribution is performed by the investigator. All of the attribution for dry mouth was not attributed to TLX591. So it was not attributed to TLX591. The occurrence of it has not been specifically attributed in the study. So they just -- the investigator basically says that it's not attributed. So I guess the encouraging thing is that, yes, none of the patients had Grade 3 or Grade 4 dry mouth and none of the patients had Grade 3 or Grade 4 dry mouth that was permanent, which it characteristically is with small molecules, always Grade 1, always Grade 2 and always fleeting.

Great. And just one further. You've spoken to FDA next steps. Later last year, you mentioned that you need to file a CTA with the European regulators to kind of open Europe sites. I guess just help us understand, I guess, next steps there. Are you kind of waiting first to FDA and then you'll file with Europe or that's kind of a parallel process?

Yes. Thanks, Melissa. Yes, FDA was the regulator that said we want to see Part 1 done and bring it back to show us, and we'll have that discussion for an IND amendment. European regulators did not specifically ask for that. But of course, the regulatory authorities in Europe and the United States communicate. In fact, all global regulators communicate on a regular basis. So when the European authorities saw that the FDA wanted Part 1 completed, the European agencies also wanted to take that approach as well. So now that we've got it, it will be going to the European authorities seeking permission very similar to the FDA's approach to open the study to Part 2 in the European sites.

Your next question comes from David Bailey from Morgan Stanley.

Just the SELECT trial was ARPI only and in this one, you've added docetaxel. So it's a broad question. You've kind of answered it already. But how would you expect adding docetaxel to impact the hematologic events? And is there anything from a data perspective between ProstACT Global and SELECT that you think might be explained by adding docetaxel into the treatment arms?

Yes. Good question. David, in Part 1 of the study, docetaxel is not given concurrently, as you know, docetaxel is nominated by the clinician, and it's started after 591, typically within a 10-week window. After 591, second dose has been given. Now there are patients that have had many cycles of docetaxel in this study. There are patients that have had the sort of median number of cycles and so forth. And as I said earlier, we've got enough to -- we believe we've got enough of that data to take to the FDA and have a very meaningful discussion. A lot of patients don't -- when they're feeling great after a therapy, they don't want to start docetaxel. So a lot of patients will actually decline it. I would like to invite Dr. Barata to just maybe comment on how his patients view docetaxel versus ARPI and their willingness to start it. Maybe Dr. Barata, you could comment on that.

Right? That's a fantastic question and a fantastic point, David, that you raised. So I think it's common -- it's known to all of us that patients don't love chemo, right? They're looking for nonchemotherapy options. Perhaps that's one of the reasons why there's so much ARPI switch is done at least in the United States, where we can actually do it. So from that perspective, when you give a therapy that works and you're doing well on it, you would expect or you will expect some pushback from patients and quite honestly, also from providers, right, because they don't feel as strongly regarding bringing the chemo right now as per protocol is defined versus upon progression. It's almost like you're buying time, you have tumor control. So the more you have an active agent, that provides you tumor control, evident in scans, PSA, patients doing well. Actually, I would argue, it would not be residual. The amount of patients who say, you know what, give me a break, I'm doing well, cancer is not progressing. Can we do it at a later time. So I would anticipate in these kind of designs, the amount of people who ends up not getting the sequential intervention without progressive disease is not necessarily a bad thing. It can be a consequence of patient preference because he has that ability to push back because tumor is not getting worse. So we do see that in clinical practice. And so it's something that, on one hand, we're assigning it to chemo because we think it's aggressive disease. We want to do chemo. On the other hand, if TLX591 is effective, some of the patients very likely can push it back for a later time.

David, I'll just add to what Dr. Barata said. I think we've articulated the purpose of Part 1 of the study. FDA wanted to see specific information on the priority combinations of ARPI plus TLX591 when they're intended to be given together or 591 sequenced with docetaxel following. ProstACT SELECT, as you might recall, I don't expect you to remember all of these details, you got other things that you think about no doubt, but ProstACT SELECT, the primary objective that as the title of that study said was to demonstrate that gallium PSMA tracer indicated where lutetium rosopatamab therapy was likely to go. So in ProstACT SELECT, we didn't specify that the patients had to have an ARPI or a chemotherapy agent. We allowed it, but the vast majority of patients in that trial were treated as monotherapy with 591.

Your next question comes from David Low from UBS.

Just going back to Slide 15, we saw enzalutamide group showing platelet count continuing to decline after 150 days. Just wondering what -- how we should understand that? And do you think that platelet count is manageable after day 350?

Yes. Thanks for the question. That sort of decline, if you look at where it's happening in the platelet count, it's a long way out to the right. If you look at the sort of, I guess, the scale on the bottom, the patients heading out up to a year and beyond. So really, in this advanced metastatic castrate-resistant population where they're being treated, as I mentioned in the baseline demographics, they're being treated as second-line patients, the median age of 77, this is a pretty advanced group of patients. So that lab profile is certainly not uncommon in the broader population of patients. Now whether it's any more marked with abiraterone or not, I don't think these data can conclude that for us, but that behavior of that decline sort of out beyond 250, 300 days is pretty characteristic of what you'd see to the blood counts if you took them and sent them to the lab in the average patient who was off study. Maybe Dr. Barata, you could comment in your own clinical experience, what happens to the lab counts after long exposure to abiraterone?

Yes. No, that's a fantastic point. I would argue as well. You have 25% in the baseline patients previously exposed to taxane-based treatment, right? Elderly population, median age, close to 80, 77, which is definitely higher than the overall population, if you will. We do see some cytopenias with ADT and ARPI. So I don't -- and if you look at the numbers, the numbers is definitely within the safe zone for us to definitely consider subsequent therapy. So it wouldn't got our eye in terms of concerning at this point with such a good -- I mean, a follow-up of the year, as David alluded to, it's kind of reassuring thinking that they got therapy a long time before this last cutoff. So that's, in my view, it's aligned with what we would anticipate for this patient population.

Okay. Just the other one I had, with the next steps with the FDA, what are your thoughts on what the safety criteria might be to proceed to Part 2?

Really, look, I think this will be the last question, but it's an important one. The FDA were crystal clear. FDA wanted to see safety on the concurrent use of TLX591 plus very conventional agents in the U.S., which are primarily abiraterone or enzalutamide or if a clinician like Dr. Barata wanted to provide docetaxel after TLX591. They were the 3 dosing regimens that the FDA was crystal clear on. It was prespecified by the agency go away and do 10, 10 and 10. We've actually done 11, 11 and 14. So we've done a little bit more than what the FDA asked for. But that was prespecified, pre-agreed with FDA, and we look forward to taking it back. The only other thing that the FDA would want to make sure is that the agents don't preclude subsequent treatment with chemotherapy, and we've got that data as well, and we look forward to presenting that to the FDA. So we've done what the FDA agreed, all prespecified, and we're about to take it back and show it to them. So I think that's -- yes, thank you. Great question. I think we're out of time. I'll hand back to the operator.

Thank you. Yes, that does bring us to the scheduled finish time. I'd now like to hand back to David for any closing remarks.

I'd like to acknowledge the -- obviously, the patients that have come into this trial, all 36 of them, including the 57 that were screened, but of course, dedicated clinicians that we are thrilled to work with like Dr. Barata, very esteemed investigators across North America, Europe and Australia and New Zealand. I'd like to thank those for dialing in. I hope it's been informative to you. So thank you very much.

That does conclude our conference for today. Thank you for participating. You may now disconnect.