Pedro Barata: Hello, everyone. Welcome for another video of UroToday, this time covering novel therapeutics or interventions in patients with advanced prostate cancer. Today joining us we have Dr. Andrew Hahn. He's an assistant professor of medicine at the MD Anderson. He's a GU medical oncology expert. So thank you, Andrew, for joining us today.

Andrew Hahn: You're welcome, Pedro. And thank you for the opportunity to present and summarize some of the exciting findings that we presented recently at the AACR Targets meeting, which is an early phase drug development meeting.

Pedro Barata: I actually want to pick your brain on that. You did present this data. It sounds like it's not going to be the last time we're going to be hearing about it. First in class, this RIPTAC, which is this binding androgen receptor. You did this, you and many sites enroll patients around really a multi-institutional effort in men with metastatic castration-resistant prostate cancer. So maybe I would suggest if you could walk us through the basics in terms of the mechanism of action and who was the patient population, the preliminary findings of your work.

Andrew Hahn: Yep. I'll take you through it. I'll run through a few slides here for everybody and then they can see what we found with initial results from this oral RIPTAC therapy, HLD-0915. All right. So the first question is, this is a totally novel mechanism of action. So what is a RIPTAC? So RIPTACs are Regulated Induced Proximity Targeting Chimeras work by a hold and kill mechanism. RIPTACs induce proximity of a tumor specific protein. So for 0915, that's the androgen receptor and a protein with an essential function, which for this drug is bromodomain 4. It creates a stable ternary complex and that leads to inactivation of the essential protein on bromodomain 4 and results in cancer selective cell death.

With the preclinical data that the team had generated as well as this novel mechanism of action, it led to this phase 1 first in human dose escalation and backfill study. So there were a minimum of three patients at each dose escalation with a maximum of 12 going in at backfill. In order for patients to be eligible, they needed to have metastatic castration-resistant prostate cancer with a rising PSA on their prior treatment. They needed to at least have previously received one ARPI and experienced disease progression. They may have received up to two prior taxanes and or one radioligand therapy such as lutetium-177 PSMA-617. And the first patient was dosed in February of 2025. The program received fast track designation in August of 2025, and you can see the objectives for the study listed on the bottom left, which are pretty typical for a phase 1 first in human study.

Here are the different dose levels. So six patients enrolled at the 12 and a half milligram dose, seven at the 25 milligram dose, 14 at the 50 milligram dose and four at the 100 milligram dose. Here's a summary of the treatment related adverse events. So with this oral once daily pill, there were only three adverse events that occurred in 10% or more patients and that was nausea, anemia, and fatigue. There were only three adverse events that were grade 3 or higher, and that was one patient who experienced a decrease in their lymphocytes, another who had an elevation in their triglyceride levels, and then a patient who experienced an increase in their AST, ALT and bilirubin. There was one serious treatment related adverse event and two patients who experienced a treatment-related adverse event that led to treatment discontinuation. The maximum tolerated dose has not been reached and then all grade 3 or higher treatment related adverse events were reversible.

So here's a PSA waterfall plot for the 22 patients who've received at least two cycles or six weeks of treatment. And what you see here is that irrespective of dose level, there's activity with PSA 50s across all four dose levels and PSA 90s at the three lowest dose levels, the 12 and a half through the 50 milligram dose. And then the 25 and 50 milligram dose have been selected as the recommended doses for expansion. You can see that the PSA 50 in the 50 milligram dose was 70% of patients and 40% of patients experienced a PSA 90.

This is a waterfall plot depicting the best percent change in target lesion sum of diameters for patients who had RECIST-evaluable disease and had had an on treatment scan. So this is a total of five patients and you can see that all five patients have already experienced a partial response. There was an additional patient at the 25 milligram dose shown in blue who has a mixture of a soft tissue and bone target lesion where there was entire resolution of the soft tissue component at the first restaging scan.

Here's a summary of the efficacy data. I'm going to narrow your focus in on that red box looking at the PSA 50 and 90 response rates in patients who'd have received at least six weeks of treatment. And you can see that the total PSA 50 response rate was 59% and the PSA 90 response rate was 32% with this oral once daily medicine.

In conclusion, HLD-0915 orally once daily is well tolerated with minimal and manageable treatment related adverse events. It is demonstrated encouraging activity across all doses tested and the 25 and 50 milligram doses have been selected for dose expansion to determine the dose for registrational studies. All right, Pedro, that's what I've got for the initial summary for you guys, but then I definitely want to have some discussion around it as well.

Pedro Barata: So, Andrew, great data. You're really exciting. I'm not surprised about the accelerated approval pathway. This is really provocative. And what got my eye is you do have heavily treated patients in here and it appears that this therapy works even in diseases where you would expect biology to more aggressive like visceral disease including liver mets. Would you agree with that?

Andrew Hahn: Yeah, absolutely. I think that's a clear distinction to make about this RIPTAC medicine and how the RIPTAC medicine differs from other oral AR-directed therapies. So first thing, and I didn't show all the slides, there's a total of 20 slides and you can find those on the Halda website. I'm sure there'll be a link in the UroToday. But median 4 prior lines of therapy, median age 75, so pretty old for a metastatic CRPC for the first-in-human study, patients going up to eight prior lines of treatment. And we have a slide that actually shows there's activity irrespective of prior lutetium-177 PSMA-617. Patients receiving multiple taxanes and multiple ARPIs. There's even activity in two patients who previously received an AR degrader.

And so it brings up this really good question, how can you keep showing activity after patients are heavily pretreated when we know there are heterogeneous drivers of resistance to treatment in those patients? And that's I think because of this really novel mechanism of action. So what the RIPTAC is really doing is it's binding to AR with high affinity initially, and then that results in a conformational change that drives up its affinity for bromodomain 4. So this is using AR, but it's just using it to get to bromodomain 4 and kill the function of bromodomain 4, which is a key essential protein within the cell cycle. So you're really going at the cell cycle.

And I think that's really well suited for metastatic CRPC. We've seen this with other experiences where whether it's AR degraders or GR antagonists. You can try to target all these different resistance mechanisms, but the cancer just keeps popping up alternative ways to get into the cell cycle. And you and I both know that some of the nastiest cancers are those that have multiple tumor suppressor losses and that just don't care about AR anymore and they don't care about anything. We seem to see activity in those patients where the drug can still get down there, get to bromodomain 4 and kill bromodomain 4. So I think that's what's really distinct about this medicine is it's just using AR to get to a core essential protein.

Pedro Barata: And the other piece I would say is, "Oh my God, it looks really well tolerated." Patients did remarkably well. And this is monotherapy, right? So it's quite remarkable to see that and no question that it's going to continue their drug development process in a very fast way, I would imagine. Can you give us a glance about what the plans might be, what we expecting to see in the near future?

Andrew Hahn: So keep your eyes out for more data coming from the dose escalation component. So there's a total of 40 patients now who've been enrolled. There are 31 dosed at this cutoff point, but you're going to get all 40 patient data. Hopefully you'll be seeing that in GU-ASCO. We'll see where that comes out. But hopefully in the near future you're going to be seeing some updated data. Then what's the next steps for this study? Well, there's expected to be a protocol amendment to go through very soon for the Project Optimus dosing with the two recommended doses for expansion. That's the 25 and 50 milligram doses where we're going to be randomizing patients to those two doses and adding in a bigger group. And then I think after that it's going to be looking at a couple other questions. You could imagine, how does this work very early in disease, I think is going to be an interesting question for the whole community. And then the final one is going to be if we continue to see encouraging activity, start thinking towards later phase development as monotherapy potentially.

Pedro Barata: I agree with you Andrew. This is super exciting. I really appreciate you coming, taking time and sitting down with us and walk us through these novel therapeutics and congratulations for the oral presentation at AACR. It's definitely well-deserved and this is a reflection of a lot of good work from a lot of institutions working on this, both at the national but also international level. So congratulations and I'm looking forward to hearing more about this.

Andrew Hahn: Thanks, Pedro. I really appreciate the opportunity and do want to give a shout-out to the patients, the other investigators and the sponsor, Halda Therapeutics. They've all been instrumental in this study.

Pedro Barata: Thank you, Andrew.