Exploring the Safety and Efficacy of EPI-7386 in Combination with Enzalutamide in mCRPC - Ronald Tutrone

October 21, 2023

Zach Klaassen and Ron Tutrone explore the promising data surrounding EPI-7386, an inhibitor of the androgen receptor. The conversation focuses on the phase two trial of EPI-7386 in combination with enzalutamide for treating metastatic castrate-resistant prostate cancer. Dr. Tutrone explains the unique mechanism of action of EPI-7386, which targets the N-terminal domain of the androgen receptors, unlike other agents. The drug has shown encouraging results in phase one trials, with minimal adverse events. The phase two trial aims to explore drug-drug interactions and efficacy in a larger patient cohort. Dr. Tutrone emphasizes the importance of urologists participating in such trials, as they are often the first to diagnose and treat advanced prostate cancer. Both doctors express optimism about the potential of EPI-7386 to change the treatment landscape for prostate cancer.


Ronald Tutrone, Jr., MD, FACS, CPI, Chesapeake Urology

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center, Augusta, GA

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Zach Klaassen: Hello, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center down in Augusta, Georgia. I'm delighted to be joined today by Dr. Ron Tutrone, who is the Director of Research at Chesapeake Urology. Dr. Tutrone, thank you so much for joining us. We're going to have a great conversation tonight around EPI-7386 and some exciting data that is coming out and talking specifically about the phase II trial.

Ronald Tutrone: Pleasure to be here, Zach, and thanks for having me.

Zach Klaassen: Fantastic. Let's just back up a little bit. If we look at the initial phase I results of the EPI-7386 plus enzalutamide, we had some data in the phase I setting for the first few patients presented at ASCO GU in 2023. Can you just describe for our listeners, mechanistically, how EPI-7386 is different than maybe some of the other ARIs that we're used to hearing about?

Ronald Tutrone: Sure, Zach. It's a novel inhibitor of the androgen receptor and different from the other novel hormonal agents. This binds specifically to the N-terminal domain of the androgen receptors. All of the other agents like darolutamide, apalutamide, enzalutamide, even first generation ones, they bind to the ligand binding domain of the androgen receptor.

Zach Klaassen: We saw some impressive data. Out of the 6 patients, 5 out of 6 had impressive deep PSA responses. So the phase I initial patients, a lot of excitement around that. Do you think that's that novel mechanism that the target is hitting?

Ronald Tutrone: I do, and I think one of the specific things about this agent is it hits the wild-type. Patients develop resistance to these agents because of things that happen to the androgen receptor, and this agent specifically will bind to the wild-type, any ligand binding domain, mutant ARs, and even the splice variance of the AR. So I think that contributes to the good response, albeit in a small number of patients that we saw.

Zach Klaassen: Yeah, it's a nice lead-in because we're going to see some additional phase I data in October 2023 at ESMO, probably some additional follow-up and more patients. But let's talk about the phase II, where we're going over the next several months and years. We've hit the recommended dose for phase II, so maybe just bring us up to speed on what's happened since GU ASCO 2023.

Ronald Tutrone: Sure. We actually just had the safety meeting with ESSA, the sponsor of the trial, to go over the phase I data. We completed that trial in 18 patients. The recommended phase II combination dose was chosen of enzalutamide standard 160 milligrams daily and the EPI-7386 at 600 milligrams BID. The drug was very well tolerated, there were no greater than grade 3 adverse events. There was one case in the phase I trial of a grade 3 rash that was attributed to the drug, but that's it. So that's why we settled on the highest dose. They looked at different doses of EPI-7386 once a day and then twice a day, and then they looked at two doses of Enza at 120 and 160. But ultimately, we ended up settling on the highest dose in the fourth cohort.

Zach Klaassen: Maybe just walk us through that phase II design. What are the key inclusion/exclusion criteria, randomization scheme, et cetera?

Ronald Tutrone: First, what the purpose of the whole phase two trial is is to look at the drug-drug interaction between Enza and the EPI-7386. So that's what they're kind of looking at in this. The PK is the goal. But it's an open-label randomized trial looking at EPI-7386 at 600 milligrams BID plus enzalutamide 160 milligrams QD compared to enzalutamide monotherapy with 160 milligrams daily. And that will be 2:1 randomization, so 80 patients in the combination, 40 patients in the monotherapy.

Regarding the inclusion, it's basically patients with metastatic castrate-resistant prostate cancer who have measurable metastatic disease. An interesting thing with this study that I like is that measurable disease can be on PSMA PET scan initially, it does not have to be conventional imaging. They do have to have conventional imaging, but they could just have metastases seen on PSMA PET. So that's unique to this trial that I like. They have to have disease progression. It could be PSA progression, it can be radiographic progression by RECIST 1.1 or PCWG3 for bone scans with two or more bone mets.

Important that the patients are naive to novel hormone therapy, which I thought at first may be difficult enrolling in this trial because now the standard is every patient you see with castrate-sensitive disease, you do dual therapy, put them on one of the other lutamides. But, actually, I've been very pleased with the amount of patients I've screened already for this trial. They can have had one line of chemotherapy in the castrate-sensitive state, and what's really good about this is PROVENGE is allowed and we routinely use proven as early on as we can in mCRPC, and also radium-223 is allowed as long as the latter two agents, they're 28 days out of those treatments. Patients have to be pretty well functional and ECOG performance status of 0 or 1, and they have to have adequate organ functions, liver functions and hematologic parameters. That's it.

The exclusion basically similar to all the enzalutamide trials with PREVAIL and all ARCHES and PROSPER. They can't have seizures. No dominant cancers, short of skin cancers.

Zach Klaassen: That's exciting. If you think about the PK interactions, it is very fascinating because you have a very potent inhibitor hitting two different parts of the engine receptor and one is potentially increasing the dose of the other. So there may be some really fascinating PK data aside from everything else that comes out of this trial. Right?

Ronald Tutrone: Yeah. Actually, from the phase I, they showed that the enzalutamide is not affected by the EPI-7386, as much the EPI-7386 exposure is lowered, but it's not significant.

Zach Klaassen: Let's just back up a little bit and look at, we're both urologists, we're talking the urology domain. Why is it important for urologists to be involved in, say, phase II and even phase III trials in this disease space?

Ronald Tutrone: Well, I'm very passionate about doing research and I've been doing it for 32 years, heck. I've always wanted to have newer technologies to offer my patients before it's commercially available. But, if you look in the community, which is the real world, the majority of these patients are seeing community urologists. Community urologists are at the forefront of diagnosing and treating prostate cancer and treating advanced prostate cancer that's metastatic. So urologists really have to be comfortable at treating advanced prostate cancer.

We've all been very good at prescribing bicalutamide, nilutamide, all the first generations, and now we're getting better at prescribing novel hormone, second generation novel hormone therapies, although not as good as our oncologic colleagues, but we are getting better. But to really up our game, we have to be there doing the research and promoting it with our colleagues and let them see that it's really not hard to administer these drugs and monitor the patients and treat side effects. They don't have to know what a grade 1, grade 2, grade 3, or hematologic AE is, but they have to know, "Well, maybe I'll just hold the drug here for a couple of weeks and retest them." It's not that complex.

Zach Klaassen: No, that's a great answer. Let's fast-forward 5 years, where do we potentially see EPI-7386 and everything sort of as this milieu of mCRPC treatments that we now have, which is a lot of them, how do we potentially see this combination targeting different aspects of the receptor maybe fitting into the landscape?

Ronald Tutrone: Right now, as you know, it's being tested in metastatic castrate-resistant prostate cancer. But just like the first immunotherapy that was developed for any cancer was Sipuleucel-T when it was really late in the disease, these patients had been given multiple lines of therapy and it still showed a 4.1 month survival advantage. That's what's going to happen here with this.

As we develop these agents, you have to test them later in the disease so you can see a signal in survival or rPFS, but what'll happen is it's going to be brought in through phase III trials earlier and earlier in the disease and we're going to start prescribing. Rather than ADT and another novel hormone, we're going to be using combination therapies, oral agents, hopefully, and it's going to be easier on the patients than giving them chemo with central lines and the added side effects of that. So I see it as being a routine combination. If not, they may make a combination pill of this with one of the novel hormone therapies just to increase their patent on that.

Zach Klaassen: That's a great answer. You mentioned you're starting to screen some of these patients. Where does the trial then now? When do you anticipate we may see some data enrollment, targets?

Ronald Tutrone: We've just started enrolling in the phase II. We don't. We may have the informed consent IRB approved, so it's really early. So that's a tough question, when we'll see data. I think there will be rapid enrollment on this.

Zach Klaassen: That's great. So it sounds like it's got good enrollment criteria. It sounds like you're optimistic about screening and getting people into the trial.

Ronald Tutrone: Yeah, very much so. And anytime that I'm adding a drug on that's really not going to increase the side effects. It's an easy thing to sell to patients. They'll say, "Well, what happens if I don't get the drug?" It's open-label, they're going to know they're not getting 7386. I just say, "Hey, you're getting standard of care, what I would give you normally. So if you don't go in the trial, you have 100% chance of not getting it. If you go in the trial, you have a 66% chance of getting it." That's the way I present it to the patients, very pragmatically.

Zach Klaassen: Excellent. We've had a great conversation. Is there anything else you want to hit on? Maybe a couple of take home points for our listeners?

Ronald Tutrone: I think the important thing is, I think I touched upon it already, that this novel agent is well tolerated in combination with enzalutamide, and when we do the phase III trials, we'll hopefully show that using these combinations with intensification of treatment earlier in the disease, we will increase patients' overall survival and radiographic progression-free survival.

Zach Klaassen: That's great. I think this is going to be exciting. I think seeing additional targets coming out, and basically extreme intensification of the androgen receptor in this case, I think this is going to be on everybody's radar. Thank you so much for your time tonight. It's been a great discussion. Appreciate your expertise.

Ronald Tutrone: Pleasure, Zach. Thanks for having me.

Zach Klaassen: Awesome. Thank you.