Evan Yu: Thanks for having me.
Tian Zhang: You're presenting a trial in progress here at GU ASCO, OMAHA-003. Tell us a little bit about the trial.
Evan Yu: So this is using a drug called opevesostat. So it used to be ODM-208, but this is a drug that is a CYP11A1 antagonist. And so if you think about how abiraterone works as a CYP17 antagonist, this just hits one step above that on the steroid biosynthesis pathway. When you think back to good old salt, sugar, sex in medical school, or even in college, we were doing biochemistry and the adrenal enzyme pathways. So this hits one step above, and that makes a big difference because you're not just taking out the sex steroid hormones, you're taking out mineralocorticoids, you're taking out cortisol as well. So the rationale behind that is that, in certain populations with metastatic castration-resistant prostate cancer, their tumor can be driven not just by sex steroid hormones, but they can be driven promiscuously by other hormones as well. And one of the perfect examples of that is some of the androgen receptor mutants that can develop, especially in response to as a mechanism of resistance to drugs like abiraterone, enzalutamide, et cetera. And so that's the rationale behind that testing.
Tian Zhang: And so, like abiraterone, are you giving it with some glucocorticoid replacement, or what does that look like?
Evan Yu: So it's a little bit different. So the rationale when you give glucocorticoids there is to serve to shut down, as a negative feedback loop, to shut down all the ACTH production that you can get, because you can develop mineralocorticoid excess with abiraterone. In this situation, since you're hitting one step earlier, you're actually taking out all these hormones. So what you need to do is you need to give some steroids, like dexamethasone, and you need to give fludrocortisone as well, more as replacement to avoid adrenal insufficiency. So it's more analogous to old-school ketoconazole. If you've been in this field, been around for a while, I used to give ketoconazole. Yeah, it's more analogous to that.
Tian Zhang: Right. Yeah. Ketoconazole used to be our poor man's ADT.
Evan Yu: It worked.
Tian Zhang: It did. And I noticed in particular that there's some nuances about the AR ligand binding domain mutation status, and you have a cohort of patients that you've capped already, and you're continuing enrollment on the other. So tell us a little bit about that and why it's important to cap that population.
Evan Yu: Yeah. Well, the sponsor for the studies are Merck. They have the compound. And so in their discussions with the FDA originally, they had dual endpoints of OS, NPF, RPFS. And the way that it worked is they have a randomization for those that have what they call wild-type androgen receptor and a randomization for those that have a mutation in the ligand-binding domain. And naturally speaking, since wild type is much more common... And just so as an aside, I'll say that, unfortunately, AR amplified also gets thrown into that group, even though they're really prognostically quite different, but that fills up much faster. And additionally, when you look at their early clinical data, it does look like that this agent should work best for those that have ligand-binding domain mutants. So I think it makes sense now, after they've filled that up, to expand the study size some and to enroll more patients that have AR ligand-binding domain mutants, because I think ultimately the highest chance of success is going to be that population. So we think enrolling more of those patients will give more power to be able to detect a true difference.
Tian Zhang: Which of the commercially available assays would pick up on that difference?
Evan Yu: Yeah, there's quite a bit. I mean, Foundation should, Guardant360 will pick that up. We do OncoPlex at our center. It's a homegrown assay. So there's a lot of different assays that can pick that up. And I think, right now, it's not primetime per se to do AR mutant testing, but I think in the future we're going to be seeing more and more of that. I think there are some studies out there that are pointing towards serial ctDNA testing and pointing towards... Especially the PROMISE Registry shows that patients that maybe didn't have a homologous recombination deficiency alteration, that if you add in things like mismatch repair, that 11% with serial testing, you'll be able to detect something later. So those should all be looked at as well, those AR mutants. They're not that hard to find. It's harder to define things like AR amplification with ctDNA, but mutation is generally pretty easy.
Tian Zhang: Yeah. You're taking me back to the days when we were looking at AR mutations for enza resistance, for example. And so it would be great if something new worked for those patients.
Evan Yu: Yeah. And there are specific assays for that. I mean, I think you're alluding to things like the splice variants, AR splice variants. And there's protein-based assays. There's also PCR-based assays, where you just drop in a couple primers and seeing from there. But it'll be interesting. I guess one could say is do you need a specific companion diagnostic for this, or are your overall generalized ctDNA next-generation sequencing panels going to be adequate? And I think since there's other things to look for, the latter's going to be the way to go.
Tian Zhang: Yeah, that's great. It is a trial in progress. So tell us, if a colleague around the country or the world is looking for the trial for one of their patients, which big centers are open and accruing?
Evan Yu: Yeah, it's an international study, so it's open in multiple places in the United States, it's open in Canada, Brazil, Chile, multiple places in South America, and also in Asia. It's open in multiple centers in China as well. In the United States, on the West Coast where I come from, obviously we have it open in Seattle, but in California, I think it's available at Stanford. It's at Southern California, Kaiser California in the Northeast. It's available at Yale in the Midwest. I think University of Chicago has it open. Miami has it open in the Southeast. So there are places. I think the bases are pretty well covered throughout the United States, there.
Tian Zhang: Awesome. It sounds like it's actively enrolling and hopefully will accrue soon so we get some answers.
Evan Yu: Yeah. Yeah, absolutely.
Tian Zhang: Well, congrats on presenting it here at GU ASCO. Thanks for joining me.
Evan Yu: Yeah. Thanks for having me. All right. Have a great day.