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Alicia Morgans: Hi. I'm so excited to be here today with Dr. Christos Kyriakopoulos, who is joining me from the University of Wisconsin. Thank you so much for being here with me today, Christos.

Christos Kyriakopoulos: Hi, Dr. Morgans. Very happy to be here with you.

Alicia Morgans: Wonderful. Well, I always love talking with you, and today I really wanted to talk with you about a really exciting study that you presented at ESMO looking into EPI-7386, also called masofaniten, this newer agent. Could you please tell me a little bit about what you presented?

Christos Kyriakopoulos: Sure. This is a very exciting phase one two study with experimental drug EPI-7386 in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer. A few things about EPI-7386, that's a novel drug that basically targets the N-terminal domain of the androgen receptor. In contrast to other drugs like enzalutamide, apalutamide or darolutamide, as well as the androgens that bind to the ligand-binding domain of the AR inhibitor of the androgen receptor, this drug binds to a different area, and actually because of that, it doesn't depend on the presence of any splice variants or any mutations of the androgen receptor.

This is a phase one, two study combining EPI-7386 with enzalutamide in patients with metastatic castration-resistant prostate cancer. The phase one part of the study aimed to look for the safety of the combination, the recommended phase two dose, as well as drug-to-drug interaction, and of course to look at preliminary data of efficacy. In this phase one portion of the study, we enrolled a total of 18 patients that received treatment at four different dose levels. The starting dose of the combination was 600 milligrams once daily for EPI-7386 in combination with a lower than the standard dose of enzalutamide at 120 milligrams daily. Progressively, we increased the dose of the EPI-7386 to 800 milligrams once a day, 600 milligrams twice daily. The last cohort, we kept the same dose of EPI-7386, but we also increased the dose of enzalutamide to the standard dose, which is 160 milligrams daily. The rationale for starting at a lower dose of enzalutamide is because there are some preclinical data that have shown that EPI-7386 inhibits the enzymes that metabolize enzalutamide, and as such potentially can increase the levels of enzalutamide in the bloodstream.

Alicia Morgans: Well, that certainly makes sense and it's really exciting. I think that you and the team were actually able to get back up to that standard dose of enzalutamide and to titrate the appropriate dose of the EPI-7386 or masofaniten. What did you ultimately find? What were the final doses that you were planning to go into the phase two with and what did the side effect profile look like?

Christos Kyriakopoulos: First of all, we were able to establish the safety of the combination of the two drugs and also find the appropriate recommended phase two dose for the combination. In terms of the side effects, it appears that the combination is very well tolerated. We didn't notice any new side effects or most of the side effects were very similar to what we see when we treat patients with enzalutamide alone. From all the patients who enrolled in the study, there was only one dose-limiting toxicity at the higher level. That was a grade three maculopapular rash, and eventually, that patient came off the study due to disease progression.

Alicia Morgans: Tell me, what is the rationale for combining with enzalutamide? I think this is a really interesting piece of the design, and how do you think that that combination of these drugs is going to be more effective than one on its own?

Christos Kyriakopoulos: That's a very good question. Both drugs are considered hormonal therapies, meaning both of them target the androgen receptor. However, from different angles. The enzalutamide binds to the ligand-binding domain, and of course, the activity of enzalutamide depends on the presence of splice variants as well as mutation in that area. On the other hand, EPI-7386 binds in a different location in the androgen receptor, and as such is independent of those alterations in the androgen receptor.

Alicia Morgans: That sounds great. I wonder, do you and the team think that this combination is going to prolong the time to resistance or perhaps even rescue patients if they've had progression on an AR signaling inhibitor before? How does this help patients ultimately if we do move this forward in the clinic and ultimately get it out there?

Christos Kyriakopoulos: I think that's a great question, and actually that is the rationale behind combining the two drugs, that we're going to get better responses with a combination rather than with enzalutamide alone. Currently, the study is designed as a combination study of the two drugs. Yeah. EPI-7386 is not given as a rescue treatment. However, this potentially could be the design of a future study.

Alicia Morgans: That's great. As you're thinking about this and moving it into the phase two portion, it would be great to hear was there any early efficacy? I want to acknowledge and make sure the audience is aware in a phase one study, we're really looking for safety, tolerability, so efficacy in these studies is not something that is required and is not always seen, but I think you did assess some PSA 50 and PSA 90 response rates, at least in terms of that PSA response. Can you share a little bit of that data?

Christos Kyriakopoulos: Sure. Of course, like this phase one study, the primary endpoint was safety, pharmacokinetics and drug-drug interactions. However, we did evaluate for response to treatment. From the 18 patients who enrolled in the study, 16 of those patients were evaluated for efficacy. What we observed is that 88% of patients who enrolled in the study actually had a 50% or more decrease in their PSA. I think this is very, very important.

Of course, we also looked at what were the rates of decrease in the PSA by 90% or even more. Actually, at the time of presentation of this data at the ESMO meeting, the rate was 69%. That was 11 out of 16 patients. Also, we looked at how many patients had a PSA of less than 0.2, and actually, we noticed that in nine out of 16 patients, so that was like 56%. There has been an update on that data, the PCF retreat just a couple of weeks ago, and the update actually showed that there were more patients who have seen more than a 90% decrease in their PSA, and actually that was 81%, 13 out of 16 patients. These results are really great, even though we have to acknowledge that this is a small study, it's a phase one study, but it looks very promising.

Alicia Morgans: That is really exciting and it makes sense that with longer follow-up, more patients might be able to achieve that PSA 90 as they did in the subsequent analysis there that you said you presented at PCF. What are the next steps? What is the next trial design moving forward, if you know? It's okay to say we haven't gotten it yet.

Christos Kyriakopoulos: First of all, the phase two part of the study is ongoing. That's going to be a two-to-one randomized study comparing the combination of EPI-7386 plus enzalutamide versus enzalutamide alone for the same patient population. Future directions, I think that technically this EPI can be added to enzalutamide in any indication that we're currently using enzalutamide. However, for the future, I know that there are some thoughts about additional clinical studies in earlier disease states. I know that there have been discussions about investigator-initiated trial in the neoadjuvant space as well as an investigator-initiated trial in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. The idea is to combine the same drugs, EPI-7386 plus enzalutamide.

Alicia Morgans: I think this is really exciting, and certainly in other malignancies, we have seen that some of these newer approaches to blockade these receptors, even combinations, can prolong the time to resistance, get really more robust responses and help patients have these more durable, long responses and hopefully better disease control. I really, really look forward to seeing how this moves forward. What would your message be to listeners if they were thinking about this and excited to hear where we were going, but what is the message?

Christos Kyriakopoulos: Again, I think this is a very exciting study. So far we have not observed any additional toxicities and any concerning toxicities. It's a regimen that is well tolerated. We have seen very promising results in terms of efficacy, so we're very excited to move forward with the phase two study and potentially any additional future studies that will help patients with prostate cancer.

Alicia Morgans: Fantastic. Well, I sincerely appreciate your time today. I thank you and your colleagues and of course the patients who have participated for putting forth this study and sharing that information with us today.

Christos Kyriakopoulos: Great. Thank you very much.