Alicia Morgans: Hi, I'm so excited to be at ESMO 2022 where I have the opportunity to speak with Professor Karim Fizazi. Thank you so much for being here.

Karim Fizazi: My pleasure, Alicia.

Alicia Morgans: Wonderful. I wanted to speak with you about the CYPIDES Presentation that you gave at ESMO this year. Can you tell us a little bit about this? A really interesting agent with an update from the data that you presented, I think at GU ASCO.

Karim Fizazi: Absolutely. The compound is called ODM-208. This is a CYP11 inhibitor at CYP17 like abiraterone. We decided to develop this compound with Orion, the company who invented it, because CYP11 is really the very first enzyme, below cholesterol, that allows making all precursors for mineral steroids, corticosteroids, and sexual hormones. You may ask why cut so high. We all know, I guess, that there are sometimes androgen receptor mutations and they tend to appear under pressure, under therapeutic pressure, mostly with abiraterone, enzalutamide, probably also apalutamide, darolutamide, and the incidence of this mutation is approximately 20% in these men who have exhausted these agents.

What's interesting with this mutation is that they tend to make different ligands able to stimulate those mutated androgen receptors. I'm speaking, for example, about progesterone, which of course is present in males, not only in females, but also corticosteroids, which can really stimulate these mutated androgens. Which means that in these men, with these mutations, we can do whatever we want against androgens. It may not work, simply because other hormones will stimulate the AR pathways. So, for these men, if the theory is true, we should actually prevent the making of these other hormones.


In CYPIDES, which is the Phase I-II trial, we tested ODM-208 in men who have exhausted at least one AR drug, but often two, to be honest, and at least one taxane and, same, often two. What we saw in the Phase I part was that, first this is active, but also we started just too high as an initial dose based of course on animal experience with 50 milligrams twice a day and it was, it's kind of funny because usually in a Phase I you tend to just escalate. We did the exact opposite. We started again with a hundred milligrams a day and we ended up with six to 10 milligrams only.


Even in the Phase I part, all the hypothesis was partially confirmed in the way that most men who benefited from ODM-208, were actually men who had the androgen receptor mutations. Having said that, in the Phase I part, there was one big issue, which was adrenal insufficiency, which happened in approximately a third of men. Mostly, of course, at higher doses and so the challenge for the Phase II expansion cohort was to see whether we could demonstrate efficacy in men with AR mutations, but also with a much lower toxicity. So in the Phase II part, we were able to accrue approximately 40 males. All of them were selected as, again, having post AR progression, post AR drugs progression, post taxane. Most of them also had received both abi/enza, both docetaxel, and cabazitaxel, and most importantly we also selected them as having an AR mutation based on liquid biopsy.


All these men were entered prospectively in the trial. ODM-208 was given five milligrams, twice a day. So, low doses based on our Phase I experience with supplementation using both dexamethasone and fludrocortisone. So, actually, with some good news, efficacy is confirmed very clearly.


Most patients in this setting, with these mutations derived some benefit by PSA decline. More than half of them achieve a PSA 50 response. Sometimes it's very durable. I do have patients still on drug after one to two years. This was also, it's hard to show of course on a screen, but it was also associated with clinical improvement in many of these men, even if they had exhausted almost all existing therapies. Of course, we have, a big thing we were watching was really toxicity. The other good news is that the degree of adrenal insufficiency observed in this expansion cohort is much lower, with less than 7%, as opposed to a big third in the Phase I experience, with no drama at all in this experience. I think I feel quite comfortable saying that we have an active drug. We probably have quite a robust biomarker to help us for selection and we fixed the toxicity issue, which really was one during the Phase I. We're probably ready to move this drug in for development in this disease, which is great.

Alicia Morgans: That is great because I think importantly the early data suggested that there were some toxicity things to work out. Were there phase, were there grade five events within the...?

Karim Fizazi: There were not. There was no death. Still, it is never nice when you have to hospitalize a patient because he's exhausted. The wife would call you and say, "Do something, he's totally exhausted." I mean it's reversible quite rapidly when it happens, really. Patients could be out of the hospital by typically two days or something after hydration and disruption of drugs and discontinuation of the drug and higher doses of steroids. But still it's not nice and you are always scared that something really bad may happen with adrenal insufficiency. So yes, findings associated with less than 7% incidence is really good.

Alicia Morgans: Yes, it really is. From a patient tolerance perspective, and I know you weren't reporting that data, but just from your clinical experience, how did patients seem to feel or suggest they were tolerating the drug?

Karim Fizazi: Generally speaking, they were fine. There was minimal fatigue or even low adrenal insufficiency incidence. We didn't really see that in the patients and also because obviously the treatment is so active against their cancer, they feel better. I remember this man coming back after a month and he had terrible pain even on high dose morphine, it was really hard to fix, the pain issue, came back to me saying, "Wow, thank you, and of course you cannot show these things, which are actually the most important on the screen, but it's fully the experience with that drug. When it works, it works and for patients, at least with mutations, it seems to be really active.

Alicia Morgans: That's really exciting and encouraging and thank you for sharing that story because I think those are the compelling things that keep investigators so eager to continue to develop, but certainly are meaningful in our clinical practices. It sounds like this drug is potentially moving into additional maybe phase three studies.

Karim Fizazi: I think so. I think the companies or two companies now are discussing these things and nothing is public domain, but it's obvious, it makes all sense to carry on with bigger development.

Alicia Morgans: Especially in such a heavily pretreated population as you describe.

Karim Fizazi: Agree.

Alicia Morgans: Bottom line for this, what would you say is the take-home message for CYPIDES?

Karim Fizazi: I think this is perhaps the second time for prostate cancer that we have an example of precision medicine after the PARP inhibitor story and I know the PARP inhibitor story is even challenged regarding whether this is true precision medicine. I believe it is, but I know others have different opinions. Here I think we really have a quite clean example and of course we need probably more data to support what I'm saying, but from our experience, it really seems that patients with mutations are the ones who benefit while patients without mutations are much less likely to benefit. So, this could be really helpful for decision-making and for development. Many tests or in many institutions are originally looking at mutations because the test we're using is looking at the AR in parallel to other proteins. So we do have information and actually we had information about AR mutations for a while, but we didn't know what to do with it, and now we probably know what we should do.

Alicia Morgans: Fantastic. Well, I look forward to hearing more and to seeing the next steps in this program. Thank you so much for sharing the information from ESMO 2022. Always appreciate your expertise.

Karim Fizazi: Thank you very much for having me today. Thank you.