Maha Hussain: Sure, absolutely. And thank you so much, Oliver, for the opportunity. So basically, I want to highlight one thing, is that when we started in the field, there was very, very little stuff available in terms of management for hormone-sensitive and castration-resistant prostate cancer. And where we are right now in 2026, I call it N+ moving forward, there are multiple treatment options for patients. And the beauty of what's happening, there is much more investment in understanding the biology and the evolution of the disease, and identifying new pathways and potential targets going all the way from the hormone-sensitive and castration-resistant disease. So I think there are some very interesting pathways, including AR degraders, the radioligand right now with the alpha-emitters, EZH2 inhibitors, the proteolytic targeting chimeras, T-cell engagers, CYP11A inhibition, MYC inhibitors, MYC and MIC, both of them are two separate pathways inhibitors. And all of these agents are being investigated in either the castration-resistant disease or the hormone-sensitive disease.
Oliver Sartor: Well, it's delightful to see the progress, and I could not agree more. When we started, we really didn't have anything. Honestly, flutamide, bicalutamide was a new drug. We had nylumin, flutamide, and bicalutamide, and then we had suramin, and that didn't work. And it was pretty dismal out there. This is totally different. So I know you don't have time enough to cover everything, but I wonder if you might cover some of the highlights and things that you like the most. What makes Maha happy?
Maha Hussain: So I would say at this point, I am going to be focusing on... Let's do this. I am going to start with the castration-resistant disease, because technically, this is the end-stage disease. And in the days when we started, Oliver, remember mitoxantrone was the only drug that was approved, not because of prolonging life, but for other reasons there. So at this point, the interesting drugs, I think one of them is the AR degraders. And this is a BMS agent, which is an AR degrader and an AR blocker. And essentially, this agent is tested in heavily-pretreated patients with metastatic castration-resistant disease. Dr. Rathkopf presented it at ESMO, and the early data was published in Annals of Oncology. And technically, there was really interesting activity in the setting of patients who have not seen prior chemotherapy, where the median PFS was about a little over a year, 16.5 months.
But for those with prior chemo, it was about five and a half months, so almost six months in there. So that's an interesting drug. There is a phase-three trial that's been looking at, it's called the rechARge trial. And essentially, there is different allowing control arm of different active agents and looking at that again. And this was actually presented by Dr. Chi in ASCO 2025, this is the updated data. Now, there are other drugs that are looking, as I mentioned, the T-cell engagers. There is the epigenetic regulators with Mevrometostat, and this is in combination with enzalutamide. And the target is EZH2 inhibition, AR-directed therapy. There's different, again, agents that we're talking about here.
The other part that I think is interesting is the PARP inhibitors. They're sort of moving into the hormone-sensitive in the castration-resistance state, but also in the hormone-sensitive space. The TALAPRO trial basically is now evaluating the talazoparib plus ENZA versus ENZA in the frontline castration-resistant disease. So that's another one. And then there is the PSMA, and this is your expertise, obviously, the AcTFirst trial, which is looking at the 25 Ac-PSMA-617, which is combining actinium with PSMA-617 for castration-resistant disease. And the objective is looking at radiographic progression-free survival, obviously, versus in the setting of patients who had standard of care treatment.
Oliver Sartor: Let me just go briefly into the T-cell engagers, Maha, because I think there's been a lot of hoopla about those. I actually think the hoopla may be deserved. I wonder if you could talk about both the STEAP1 and the KLK-2 T-cell engagers and just get your thoughts on those. I think they're both very interesting.
Maha Hussain: So the Pasritamig is basically, it's a next-gen first-in-class KLK-2 plus CD3 drug. And it really is an interesting agent, I have to say, and for sake of time, I'm not going to go through the details. But basically right now, there are two ongoing phase-three clinical trials with it. One of them is it's in the setting of frontline castration-resistant disease comparing to chemotherapy. And the other one is the combination with the basic, with AR agents, but in the setting of whatever standard of care versus just a placebo plus standard of care. For the first one in the setting of castration-resistant disease, the primary endpoint is radiographic progression-free survival. The other one in the late-line castration-resistant disease is the overall survival is the primary.
Oliver Sartor: Maha, you mentioned the MYC inhibitors and the CYP11 inhibitors. I wonder if you might touch on each of those in turn, because the MYC inhibitors are really quite interesting. And I'm a little bit surprised to say be ready in two years, but on the other hand, there's a lot of excitement around those.
Maha Hussain: Yeah, absolutely. And I guess there are two MYCs, the MIC and the MYC. So are you assuming you're talking about the MIC drug?
Oliver Sartor: We can go either way, whichever you prefer.
Maha Hussain: No, no, the reason I say that, the MYC is actually still in the early phases, and it's a drug that came out of our SPORE, prostate cancer SPORE. And it's very much early, we haven't even gotten the phase one trial.
Oliver Sartor: That's what I was thinking. That's the one. The MYC was the one [inaudible 00:07:53] focus on.
Maha Hussain: Yeah, it's still in development. The trial, we drafted it, but the trial is not ready. There's a lot of stuff going on in terms of the development of the drug. And when I say available, my focus in the whole thing is what will be potentially available for patients. So in two years, this will not be available, in terms of standard of care or access to the drug in a major trial.
Oliver Sartor: Just out of curiosity, how do you regard the rPFS in this setting? It has some controversy. I'd like to hear your perspective.
Maha Hussain: Absolutely. I think part of the issue at this point, when we're getting into these phases of trials that are moving, a lot of the agents we're looking at in the context of castration-resistant disease, especially in the first-line or even second-line, the fact that we have so many drugs available for these patients, the readout for the overall survival will take much longer, number one. Number two, I think the overall survival may be confounded by the fact that patients have access or don't have access to agents and depending on the balance and everything else. So I do think radiographic progression-free survival is a reasonable endpoint, understanding that it's complicated in prostate cancer. And the question is, what imaging are you using? What clinical criteria are being used? And all of these factors. The other part, as I was mentioning, a lot of these major phase three trials are international, and when they're done, they're done technically a good chunk of the accruals. I'd say probably majority of the accruals are happening outside the US.
And the complexity there is the fact that many of the centers in the world do not have access to the same drugs we have access here in terms of standard of care in that situation. So all of these things, I think, confounds the OS data there. So I do think having the PFS as the... It comes up as a cleaner endpoint in terms of that specific drug. Now, clearly, the issue comes up is this, is if a drug does improve PFS, but not OS, is that worth it? And I would say the answer, the devil is in the details. How much of a PFS is improved? We're talking a few weeks versus months or years, which makes a huge difference.
Oliver Sartor: Absolutely. Well, it is remarkable. And I like the way you started the discussion by emphasizing the biology and the investigation that has led us to all of these different mechanisms. We have the AR targets, we have the EZH2 targets, we have KLK2, we have STEAP1, we have the PARP inhibitors, which are obviously targeted to HRRs, we have the CYP11. So it's become a beautiful field and honestly advanced more quickly than I would've anticipated. I wonder if you share that sort of impression.
Maha Hussain: Oh, yes, absolutely. Absolutely. And I think the fact that prostate cancer has become a focus for investment in research is really dramatic. And as you know, when we started even 10 years ago versus now, we've really moved quite a bit into different disease settings and improvement in there. And I do think moving the different targeted treatments into the earlier phase of the disease, basically the hormone-sensitive space, which as you're aware, I mean, all kinds of radioligands are being looked at, there's really a very, I would say, very exciting trial, the EvoPAR study with the PARP1 inhibitor. Saruparib is another drug that is looking at the hormone-sensitive space there. And again, we're talking about the different other pathways that are being evaluated, the EZH2 and so on. So I do think it's really exciting time, and I am really thrilled for our patients. But the reality of it is this. Let me see if I can share this slide.
So this is actually from Arul Chinnaiyan, which as you know, he is the absolute king of all these genomics evaluation in prostate cancer, starting from the days of the standup to cancer. But one of the critical things, which I think is interesting, they do have a project where they're looking at the genomics across the different states of prostate cancer. And what you see here is you're looking at the localized versus recurrent versus de novo metastatic versus castration-resistant disease. You can see the complexity and the evolution of prostate cancer with regard to the genomics.
Oliver Sartor: I like that as well. And it does emphasize that potentially earlier intervention
Maha Hussain: Exactly.
Oliver Sartor: ... to deal with the cancers that are less heterogeneous, and therefore more susceptible to targeted therapy, which I think is a very important point.
Maha Hussain: Yes. And in fact, the other part, again, basically, the issue with it here is the fact that the disease is evolving, and whatever data you look at is in the context of when these patients were exposed to different treatments. But as you know, by today's standard, they've seen much more drugs at different phases of the disease. So I do think the complexity of the disease and how it's evolving is an absolute must investigate thing as we go forward to better understand mechanisms of resistance that is evolving, and the odds of response and different pathways that might be emerging.
Oliver Sartor: Maha, we're going to need to wrap up here in just a moment, but I wonder if you might have a few closing remarks for our listeners that you'd like to share.
Maha Hussain: Oh, absolutely. So basically, I feel like we have certainly come a very long way with tremendous progress that we've seen in managing the different states of prostate cancer, literally from the newly diagnosed all the way to end-stage disease. And with the focus of my presentation is the hormone-sensitive and castration-resistant disease, and significant improvement in the overall survival. So technically, the median survival in the, say, the late 80s with castration-resistant disease, or even the early 90s, was about nine months. And now we have moved to three plus years easily. And for some patients, I have men who are five years out or six years out and they're castration-resistant, but they are responding to treatment. And the hormone-sensitive space, again, in the 80s, the median survival was about two and a half years. Now, we have really entered a more than double that median survival.
And in this regard, I have to say, I'm sure, Oliver, you have the same thing, I have men who are literally 10 years out with hormone-sensitive diseases still in remission. The one thing that I think is critical to understand, and I call it, prostate cancer continues to be very complex cancer. And the reality of it, there's a lot of inter and intrapatient heterogeneity. And so clearly, the therapy development that we are doing has to focus on the totality of the disease biology, better understanding of the molecular evolution of the disease, mechanisms of resistance and so on. And clearly, we've entered the era of multi-targeted strategies. If you recall, for a long time with prostate cancer, only one drug was used, like you add something to ADT, or in the castration resistance disease, only one drug like chemotherapy, docetaxel or something like that. But now, we've actually moved into combination strategies.
So I do think one of the critical issues that need to be investigated, and I hope this is something that is an effort that is going to be evaluated internationally, is as we move effective treatment into earlier stages of the disease where we get a better return on investment as it relates to outcomes for patient, the question is, how will this impact response to the same in class agent in the castration-resistant disease, and what are the resistance mechanisms that are evolving? And critically, what we need is really well-designed trials and collaborations to better delve deeper into these processes.
Oliver Sartor: Maha, could not agree more. Thanks for making America happy again. And with that, we'll sign off. Always a pleasure to see you.
Maha Hussain: Thank you. Pleasure is mine, my dear, and thank you so much for including this.