Tian Zhang: Hi and welcome to this episode of UroToday. I'm Tian Zhang. I'm a GU medical oncologist at UT Southwestern in Dallas, Texas, and I'm joined today by my good friend and colleague, Dr. David Wise, associate professor and service chief of GU medical oncology program at Perlmutter Cancer Center at NYU Langone. Welcome, David. Thanks so much for touching base during ASCO 2025.

David Wise: Yeah, it's great to be here.

Tian Zhang: So we're talking about your presentation here. Congratulations on ramping up this really exciting drug, a phase I study of Gotistobart, BNT316, ONC-392, in combination with lutetium-177, in patients with metastatic castration-resistant prostate cancer. So tell us a little bit about the trial and why you're excited and what we should be thinking about.

David Wise: All right, absolutely. So this was a concept, actually, that I developed together with Mark Stein at Columbia. And we were talking one day about the problem that I think many of us face, which is that we treat patients with lutetium. We see great responses in a significant subset of patients, around 50% based on the studies that have been published, with very few patients who have primary progressive disease.

And so patients are really often very happy with their initial response. We see a fair duration of response. But then very soon after discontinuation of therapy, which is usually a maximum of six cycles, in the United States, we see very rapid progression.

And then we have to start again and find patients, their next option, and what looks to be quite initially very exciting. It becomes very, very disappointing. And that's particularly so because lutetium is so well-tolerated. And so it really, after often based on the VISION trial, patients have had docetaxel which worked OK for them. But they had a lot of toxicity. So it was never a great experience.

They now get this treatment lutetium. And they have much better tolerability and a great response. And it's like, well, is the cancer gone, and am I going back to normal?

And in my experience as their oncologist, it's a very big crash when their cancer starts progressing again because it's just so shocking. And unfortunately, the durability of lutetium is really not that different than the durability of docetaxel. Once you finish the treatment, the disease tends to progress.

So I was sitting with Mark and talking about what we can do to try to extend durability. And we've always had this interesting hypothesis in the field, of course, about the interplay between the immune system and radiation-based treatment and whether we can potentiate or extend the durability of responses to radiation by somehow modulating the immune system. Of course, that hypothesis has been tested over and over again for the last 30 years.

But I think that recently, there's been more of a focus on the regulatory T cells. So these are a suppressive cell population that really do seem to be relatively resistant to radiation and seem to persist and seem to potentially create this suppressive immune microenvironment in the setting of radiation that prevents the effector immune system from coming in and killing more of the minimal residual disease. And so we actually partnered with an immunologist at Columbia as well to look at this data and at NYU as well.

And we found that indeed, there really was data suggesting that the effector T cells were depleted by radiation, whereas the T regs were not. And this was data from Katie Spina, a radiation oncologist and immunobiologist at Columbia. And so, we put this together and said, oh, well, then maybe we really need to deplete the regulatory T cells.

And so Mark and I pitched this concept to OncoC4 at the time. And so that started this really exciting process to think about how to design a trial like this. And with a new radioligand essentially to the field a few years ago, this was just sort of something that there were still challenges with insurance, with sourcing, and being able to get access.

And thankfully, we were able to partner with a very excited company and a very ambitious company. And now BioNTech is involved as well, and so very ambitious and really trying to move the field forward. And so we thought that it would be exciting to partner with a radioligand where there was systemic radiation and try to systemically deplete Tregs in the tumor microenvironment and see if the combination of those two treatments would do better than with lutetium alone.

And so we partnered with OncoC4, because they developed a next generation CTLA-4 binding antibody called ONC-392 at the time, which was a pH-sensitive CTLA-4 binding antibody which enabled the antibody to essentially be recirculated to the cell surface together with CTLA-4, preventing lysosomal degradation of the CTLA-4 within the cell. And so it essentially created higher steady-state levels of antibody-bound CTLA-4 on the cell surface, enabling macrophage-mediated depletion of those CTLA-4 positive cells, which, as we know, are predominantly Tregs, within macrophage-rich tumor microenvironments. And so that would enable more of a tumor-selected Treg depletion in the microenvironment and potentially less Treg depletion in the periphery and potentially important suppressive immune cell function in areas where we don't want there to be essentially unrestrained effector T cell activity, like in the gut.

And so there was also some thought that this would be a less toxic version of IPI, right, and so less colitis, which is certainly the notorious toxicity from IPI. And so the potentially better toxicity profile and this unique biological mechanism is what excited us about combining with lutetium, which essentially has a pretty good gut profile.

So we weren't all that nervous about that, but certainly, we felt like we needed to do a dose escalation and a dose optimization to make sure that there was a good, safe exposure and safe irAE profile of this combination and then expand into a randomized study after we identified a good phase II dose.

Tian Zhang: Yeah, so, really exciting. Just to recap, a CTLA-4 novel therapy that hopefully potentiates and improves that-- depletes the Tregs in the microenvironment really helps the effector T cells and then to try to improve that durability, right, of lutetium responses. So, really important in our prostate cancer populations to try to go for deeper durable responses. And so what did you find?

How many patients did you treat on this phase I? As a side note, I'll just say that we participated. So it's a really nice multi-center effort that you've led, and just tell us patients, what kind of characteristics, and how did they do?

David Wise: Great. So yeah, the study thus far, it really has been a great multi-center effort, including your center and your participation, Tian. And a study like this really can't happen at a single center.

So it's been a great collaboration across the country, really. And so in this study, in this cut of the data that we're reporting at ASCO, we're reporting the initial phase I dose escalation and dose optimization where we have now reported on a 2 to 1 randomization. And so we wanted to make sure to have some Pluvicto-only patients included as well.

And so we've treated at this point on the study, and we report 24 patients on the combination, seven patients lutetium only. And what we've found now in terms of safety really looks like we're really not seeing an increased rate or severity of the magnitude of irAEs, which was really our main concern. But we're not seeing anything really above and beyond what you'd expect from a lutetium-treated population. So the typical rates of cytopenias we're still seeing, the typical rates of fatigue and the severity.

We're really not seeing a higher rate of irAEs either or severity. And so, we were excited to see that this is a combination that we can give safely. And so we're moving along, as you know, really well in the phase II now. And so I'm hoping to really get this study completed very soon.

Tian Zhang: Yeah, tell us what's next. So as lutetium gains another label in the pre-docetaxel phase, the landscape changes a little bit. What does that mean for this trial?

David Wise: Yeah, exactly. So we were following that from the time of design of this study and certainly thinking about whether and how to allow prior docetaxel exposure and how to adjust that over time. It turns out that the progression-free survival with lutetium, whether a patient has or has not had docetaxel is quite comparable, which is really interesting.

And so in fact, we probably could have done this study in a stratified by docetaxel exposure. Of course, the main limitation was the availability and the insurance coverage and the concerns about giving off-label dose lutetium in patients naive to docetaxel. So the trial was originally designed as a VISION population study of docetaxel-experienced patients.

We've now amended the trial in this setting of the PSMAfore approval to allow a cohort of patients who are docetaxel-naive. To answer your question, obviously, the future is most patients and oncologists, I believe, are going to be wanting lutetium before docetaxel, particularly they have clear PSMA-avid disease. And so we do think that for this combination to be successful, we're really going to need to develop it further in the taxane-naive space.

Tian Zhang: Perfect. Thank you. And there's just-- there is more than just lutetium on the stage. And so which radiopharmaceuticals are you excited about outside of what we're seeing so far with lutetium?

David Wise: Yeah, I mean, I think it's definitely a hot topic right now. It's been that way for really the last five years. We know that lutetium is primarily working through single-strand DNA breaks and certainly, external beam radiation, and the efficacy that we see there is really driven by a double-strand DNA break mechanism. And so radionuclides like alpha particles, like actinium and lead, are certainly super exciting for the ability to induce double-strand DNA breaks.

I would say that-- so those are studies that I'm involved with. They're very exciting. I think the jury is still out. I think what we're hoping for certainly is that durability. I think that's really what we're looking for.

I think that it's not just the single versus double-strand break repair mechanism. It's also the retention and the targeting mechanism. So there's definitely issues in terms of targeting micrometastatic disease with small-molecule agents like lutetium, PSMA-617. And so other modalities like antibodies, mini-bodies, potentially may give us different retention and performance features. And there are several of those in study right now conjugated to alpha- or beta-emitting radionuclide.

So I'm excited about those. I do think that we still need to look for more durable effects, and I'm not sure that we're going to get there with the current generation of molecules. And I think that there have been some really exciting studies trying to combine. And I think this is one strategy that we're presenting here, but there are certainly several other very interesting strategies that have been pursued around the world right now.

There are studies that are exciting to me combining with cabazitaxel-- so, standard of care treatments. Of course, there are trials combining radium with docetaxel. The DORA trial through Alliance is exciting.

There are multiple PARP inhibitor combination strategies, and those may make sense with double-strand DNA break repair mechanisms or single-strand. And I think that there's been some exciting data combining lutetium with PARP inhibitors. And I think that there's also trials combining with platinum. So I think that there's a lot of different avenues of inquiry which are critical because we want to cure, not just control. And I think that this immunotherapy angle is one, but it's just one of many that are going on that are exciting to me.

Tian Zhang: Yeah, that's awesome. Certainly so many things that hopefully are coming down the pipeline to help our patients live longer and better. Anything else you want to add about this particular trial for ONC-392 or Gotistobart?

David Wise: No, I think that summarizes it. I think that certainly, the efficacy signal is early. We certainly have some promising individual results.

But I think we all know that we need some more time to really get more mature data. And that's why we're really excited that we have a randomization in here so that we can really get a sense of what is the components, the contribution of these different components. And so hopefully, like I said, we're really moving quickly in the expansion and hope to finish the study soon and hope to present it at a conference coming up really soon.

Tian Zhang: I think we're all really looking forward to finishing out this trial and seeing what the activities are. So thank you so much again for joining us today.

David Wise: Yeah, of course. Thanks for having me.