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Alicia Morgans: Hi, I'm so excited to be here today with Dr. Dan Petrylak, who's joining me from Yale and also from ASCO 2024, where he presented some really exciting data on an AR degrader phase 1 study with an expansion cohort. Thank you so much for talking with me today.

Daniel Petrylak: Thank you, Alicia.

Alicia Morgans: Wonderful. So you had a fantastic rapid oral abstract presentation, really exciting. Can you tell me a little bit about the history of this drug and why AR degraders may be of interest?

Daniel Petrylak: So the history of this drug actually goes back about 12 years when I first went to Yale from Columbia, and one of my favorite seminars was a monthly seminar we had with the chemistry department and I presented some data in the landscape of prostate cancer and a fellow by the name of Craig Crews, a chemist at Yale who actually developed carfilzomib, was in the audience and came up to me and said, "Hey, have you got room for a drug that targets the androgen receptor?" And it's like, wow, this was really great coming to this institution and working with chemists to try to develop new drugs. And so after I said yes, there were about four or five people from this company called Arvinas down in my office a week later to talk about how we could develop a drug that targeted the androgen receptor.

So this is a PROTAC. A PROTAC is a drug that has three different components, a binding area, a hinge area, and then an area that basically promotes ubiquitination. Ubiquitination is the process in which our proteins are degraded, so our proteins are always being turned over. What a PROTAC does is it basically accelerates this process, it can bind to any protein. It can make a PROTAC to the androgen receptor, p-53, RAS, or whatever you'd like to make a PROTAC to, and then it basically labels it and says, please destroy me. And you can take out as many as 400 androgen receptor molecules with one PROTAC. So the parent compound, a drug called ARV-110, which we presented on previously, demonstrated activity in a variety of different androgen receptor ligand-binding mutations. We saw that there was activity and we also saw toxicity as well, particularly fatigue.

So ARV-766, which is the second-generation compound, has a broader spectrum of androgen receptor mutations. It actually hits the L702 mutation, which 110 did not. That's actually one of the more common mutations, and it also can affect wild-type receptor. It's a better-tolerated drug. So what we did was we designed a phase 1/phase 2 study where first we established the maximum tolerated dose, and then we went on to an expanded cohort, which included those patients with ligand-binding domain mutations. And what we found was the drug was safe, side effects were predominantly fatigue and some nausea. We did have some toxic deaths on study, but these were attributed to disease progression or other causes. It was not drug-related. And we found that 43% of patients who had the ligand-binding mutation had at least a 50% PSA drop, and 30% of patients with measurable soft tissue disease had unconfirmed responses.

Now, why am I saying unconfirmed? Because we just haven't had enough follow-up to get the confirmations, but at least two of those patients are potentially confirmable by subsequent scans. So we're very, very excited about this data. This portion of the study actually was a randomized portion between 100 milligrams and 300 milligrams of the PROTAC, so we saw that the pharmacokinetic curve flattened out around that area. So we just were looking at seeing whether there was any difference in efficacy or tolerability.

Alicia Morgans: Well, and that's interesting. Within a phase 1 study, obviously you have the expansion cohort to dig into that a little further, but in so many cases, phase 1s are really there to try to understand the safety profile and make sure that it's a reasonable drug to move into phase two. So already you're seeing the efficacy endpoints as you've already explained.

Daniel Petrylak: Yeah, and I think phase one trials have really evolved. I mean, 30 years ago when I first started out in oncology, phase one trials were considered to be where you send patients when you had nothing else to do and the science was evolving. Now we have better science, we have better ways of targeting drugs. The phase one trials I think are now really showing a lot of activity early on because the science is just so much better.

Alicia Morgans: I would agree with that. I think when I talk to a patient about a phase one study just to, in case there are patients watching, one of the benefits of phase one is access to a treatment that would not otherwise be available. And everybody in that study gets treatment, which is different than when you go into a randomized phase three, for example, where there might be a standard of care arm and standard of care plus this new agent. So it's a nice opportunity to access things that you wouldn't otherwise get.

Daniel Petrylak: That's a great point. A lot of patients are reluctant to go onto clinical trials because the first thing they say to me is, I don't want to go on a placebo. And really the only situations where we are using a placebo now are if you're adding a drug to a standard of care. So again, we've evolved greatly in our trial designs and our science behind them.

Alicia Morgans: Absolutely. As you think about this, and you consider these patients who had disease progression despite the treatment versus those that seem to have more of an efficacy related to the treatment exposure, where do we go from here?

Daniel Petrylak: Well, I think there are a number of different places we can go. Firstly, we know that these mutations arise at a higher rate in those patients who've received antiandrogen therapy. So we're going to see these, in my opinion, you'll see more of these develop over time because we're using apalutamide, darolutamide, enzalutamide, abiraterone earlier in the course of metastatic prostate cancer. So I think we'll see more of this. So one area which is I think a very fruitful area is right at the beginning of castration resistance, rising PSA is an oral agent and easily administered and well tolerated. So that would be a good place to do a trial in that particular situation. And then also any patient along the course of castration-resistant disease that has this mutation as well.

The thing I'd like to see be done is pre-clinically, you can give this PROTAC and also have androgen in the medium and still see effectiveness. So this would be great to look at in asymptomatic patient with a rising PSA that you don't have to worry about going on hormone therapy. This may actually be more tolerable in this particular situation. So that's another potential area this can go.

Alicia Morgans: So interesting. So to potentially spare castration and then just degrade the receptor without getting rid of testosterone.

Daniel Petrylak: Correct. Correct.

Alicia Morgans: Very, very interesting. I think there's absolutely interest from a patient perspective.

Daniel Petrylak: Absolutely.

Alicia Morgans: And of course from a clinician perspective in that as well.

Daniel Petrylak: Absolutely.

Alicia Morgans: One thing that I've seen in other solid tumors, and this is not something that is answered by your presentation, is really just food for you to think about is that sometimes, particularly when we see that there's a treatment that might be able to get around a resistance mechanism in a receptor, we ultimately find that that treatment could be given even before a drug that might be there to block the receptor that causes that resistance mechanism that the second drug was designed to get around. So do you ever see a time besides the BCR, biochemical recurrent, state where we might be able to, is there a role potentially for these AR degraders to even come potentially before those AR antagonists?

Daniel Petrylak: Absolutely. What we're doing right now is we're doing... Another arm of this trial is to combine this with abiraterone. So one could postulate giving this in hormone-sensitive disease to prevent resistance from occurring. That's going to be a big trial to really figure that one out and a long one too. But also if a patient is on abiraterone to begin with, then potentially you could add it to abiraterone to overcome resistance in that situation. So there are a lot of different ways that we can think about this.

Alicia Morgans: To really perpetuate that response in the hormone-sensitive setting.

Daniel Petrylak: Exactly.

Alicia Morgans: I agree. I love this as a new and exciting way to target an old foe and I think that we are all really excited about that. What would your message be to listeners as they're looking to understand where AR degraders in this in particular may go in the future?

Daniel Petrylak: Well, my message is that firstly, no matter what stage of disease you're in, there's hope, there are trials. Talk to your doctor about the trials that are available and also be aggressive in searching out trials that your physician or other people may not be aware of. So there's a lot of hope, but we've had patients who've really benefited from these phase one studies and we've had patients not only with 766, but with 110 who've responded for a year or more. So again, I think that participating in a phase one trial, you may be fearful of it, but you shouldn't be, you should talk to your physician and make sure that you understand what you're getting into. But also that these are being done, these are well vetted beforehand and that these are being done hopefully to benefit you as well as other patients.

Alicia Morgans: Absolutely. Just to put it out there, I think there are many patients over the years where I've gone to clinicaltrials.gov or even just to my email bank of friends and said, "Do you have a study available for my patient?" And there are, in most cases, trials available for someone like you. So I think that's great advice to patients and for clinicians to think about just reaching out, going on clinicaltrials.gov and finding those opportunities for those patients who are able.

Daniel Petrylak: You're your patient's advocate.

Alicia Morgans: Absolutely.

Daniel Petrylak: That's the most important thing. And if I don't have something that will help you, then if we can find something somewhere else so much the better.

Alicia Morgans: I could not agree more. Well, thank you so much for your time and expertise, and thank you for doing your best and your part to continue to develop novel treatments for our patients with prostate cancer. I appreciate it.

Daniel Petrylak: Greatly appreciate it. Thank you.