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David Crawford: Hi everyone. My name is E. David Crawford, and I'm a professor of urology in the Department of Urology at the University of California San Diego. I'm excited to announce that we at UroToday are launching a new program called Crawford's Corner, and I am very honored to have, as my first guest, an internationally renowned clinician and also a very good friend, Dr. Dan Petrylak from Yale Medical Center, where he is both a professor of medical oncology and also urology.

Several years ago, Dan discussed with me something he was working on and is very exciting in the arena of advanced prostate cancer, revolving around a resistance mechanism in the androgen receptor. Dan is here today with us to share the exciting results of the early parts of the study, a phase I/phase II study with this drug called ARV-766, called a PROTAC agent, which works at sort of an androgen receptor ligand-binding domain. This study, I think, is very encouraging. Dan, you presented it at the ASCO meeting, and thanks for being with us to share some of the early results of this and where you think this is going.

Daniel Petrylak: Thank you. I think this is a very, very exciting area. I think it's important to describe, first, what a PROTAC is. Our body has a natural way to scavenge proteins. For example, we're constantly turning over different parts of our body, whether that be the skeleton, whether that be in the cell, as far as proteins are concerned, and the ubiquitin ligase pathway is a way that we dispose of proteins that are old or that are mutated. And what a PROTAC is, is something that accelerates that process. So you can actually have PROTACs that bind to a variety of different proteins, and basically it's like putting a marker on that protein to say, "This protein needs to be eliminated from the system."

A number of years ago, I was at a chemistry symposium at Yale, and Craig Cruz, who was a chemist in the Department of Chemistry at Yale, was working on PROTACs and said to me, "Would you have room for another drug that targets the androgen receptor?" And so this is where this whole concept of using PROTACs to target the androgen receptor and degrade it comes from.

The first compound that we worked with was something called ARV-110, which showed activity in castrate-resistant prostate cancer, but it did have toxicities, particularly nausea and fatigue. ARV-766 is a second-generation compound that has less fatigue in phase I trials, but most importantly, it has a broader spectrum of activity against the androgen receptor, particularly those areas in the ligand-binding domain. There are a variety of different ways in which hormone resistance can occur, and one is that there can be mutations in the area where testosterone binds, and it's been shown that as your exposure to antiandrogens such as enzalutamide, apalutamide, abiraterone increases, the rate of androgen ligand-binding domain receptor mutations increases as well. So this study looked at patients with castrate-resistant disease, and we administered ARV-766. Initially, there was a dose-finding phase; it's orally administered. What we found was that in those patients who had ligand-binding domain mutations, 43% had at least a 50% PSA decline, and about a third of patients had responses in measurable soft tissue lesions.

David Crawford: A lot of interesting points. Before we get into the study too deeply, we know that testosterone is king in prostate cancer, and we've been playing around with trying to manipulate that since the early '40s with Huggins and Hodges, and SWOG, you and I together and others, have looked at combinations. We looked at various ways to block the androgen receptor and androgens and the adrenal, and things have really moved along. So we've got triplet therapy now and so forth. So what you're saying is this is novel, is that this is a resistance mechanism, correct, with the androgen receptor?

Daniel Petrylak: Exactly.

David Crawford: We see that all the time in metalloproteinases and many other things in prostate cancer. I congratulate you on picking up on this and doing it. So we've got something to target the androgen receptor. What percentage of men actually have this mutation? I assume it's the men that have been on abiraterone and things like that and Enza, right?

Daniel Petrylak: It's about a quarter of patients overall, and this can be detected.

David Crawford: 25% of patients.

Daniel Petrylak: Yeah.

David Crawford: That's important. That is a lot. So what you're doing is you've identified a subset, now, and you're doing a study. So our audience understands that. Did I get that right?

Daniel Petrylak: Got that right. Basically, we use liquid biopsies to assess whether these patients have the ligand-binding domain mutation or not. For this portion of our presentation, those patients who had the ligand-binding domain, we were reporting on those. We also treated other patients as well who had a wild-type androgen receptor. The results of that are still going to be under analysis.

David Crawford: So tell me what happened.

Daniel Petrylak: 43% of patients had at least a 50% PSA decline, and 30% of patients who had measurable soft tissue lesions had an objective response. So we're seeing significant activity. We're also seeing that this drug is well tolerated. The predominant side effects are nausea and fatigue, and in my experience, it's not as much as it was with the 110 compound. So certainly this is a well-tolerated drug.

David Crawford: The earlier drug you said had more toxicity?

Daniel Petrylak: Right. The earlier drug we studied had more toxicity.

David Crawford: What you're saying is it's pretty well tolerated?

Daniel Petrylak: It's very well tolerated, yes.

David Crawford: Okay. And any other major side effects or anything?

Daniel Petrylak: No, those are the major ones. We did have a couple of deaths on study. These were not attributed to the drug. One was attributed to disease progression, one was attributed to unknown causes, and another was from a pulmonary embolism. So we did not see any drug-related toxicity.

David Crawford: It is pretty impressive results, even though it is a subset in men who have failed our major big guns. What's the length of the PSA progression that you saw, the 50%?

Daniel Petrylak: It's still early. We don't have the time to PSA progression at this point, but there are some patients who've been on treatment and have had responses for up to a year.

David Crawford: Well, that certainly surpasses some of the other things we've seen that have gone along, that they've gotten approval. So again, this is exciting. Where is this going? What's the next step?

Daniel Petrylak: As part of the phase I trial, there is a section where we're combining ARV-766 with abiraterone. Number one is to define toxicity, but eventually we'd like to know whether this could reverse resistance to abiraterone. There are randomized trials being designed to look at this at first progression in the castrate-resistant state, so this will move into a phase III trial at some point.

David Crawford: That's exciting, and actually, the benefit may exceed the 25% that have the mutation because you might not get the mutation in people. This could be a major new step forward in the treatment of prostate cancer. Abiraterone is a very effective drug. It's been used in a lot of studies, and you can extend that. What's your prediction?

Daniel Petrylak: My prediction would be that this would be a treatment for those patients with ligand-binding domains. Whether this has the same degree of activity in wild-type androgen receptors, I think that's going to be a subject of study in the future. But certainly, the ligand-binding domains point out that the frequency of these mutations is what we see with DNA repair, same frequency. So this, I think, would have a significant impact on the treatment of prostate cancer.

David Crawford: Congratulations. Again, this is something that started out in the lab and that you took to this point and something that has a major impact in prostate cancer. When do you see a phase III trial starting?

Daniel Petrylak: I'd say probably sometime within the next year.

David Crawford: So you're a medical oncologist, a good friend. I'm a urologist. Do you think a person like me could give this drug? These two, I've given abiraterone a lot and then enzalutamide and all that. So now we have something that you're telling me is reasonably well tolerated, is this something urologists can give or people that are focused on advanced prostate?

Daniel Petrylak: I would think that urologists could give this. Certainly, the toxicity profile, it's more benign than abiraterone, so I certainly think that this could be easily administered in the urology clinic.

David Crawford: With the abiraterone, are you still giving 10 milligrams or 5 of prednisone with it?

Daniel Petrylak: Correct.

David Crawford: Okay, good. Any closing remarks, Dan?

Daniel Petrylak: Well, this is an exciting area. Other drugs are being developed in this particular space as well, but now I think we're learning more about the biology of the androgen receptor and how we can manipulate it. It's really taking steps beyond abiraterone, enzalutamide, darolutamide, and apalutamide, so I think it's a very exciting area.

David Crawford: Great. Thank you, my friend. Great job.

Daniel Petrylak: Thank you.