Read the Full Video Transcript

Zachary Klaassen: Hi, my name is Zach Klaassen. I’m a urologic oncologist at the Georgia Cancer Center. I’m delighted to be joined on your show today by Dr. Christian Gratzke, who is a urologist at the University of Freiburg in Germany. Today, we’re going to be discussing an SEO presentation from 2024 by Dr. Gratzke entitled, “Phase III MK-5684-004, the Study of CYP11A1 Inhibitor Opevesostat Versus Next-Generation Hormonal Agents in Patients With mCRPC Who Have Already Received a Prior NHA Agent.” And we appreciate you joining us, Dr. Gratzke. Thank you so much.

Christian Gratzke: Thank you. Thank you so much for the invitation. Happy to be here.

Zachary Klaassen: Fantastic. So this is a trial in progress. I’d love for you to walk through the background of this trial and where we’re going with recruitment, and your thoughts on where this may fit into the landscape.

Christian Gratzke: Fantastic. So if you don’t mind, I’ll pull up some slides so it’s a little easier to follow what I’m saying. This is basically my SEO poster, but because it is a little hard to read, I thought it would be better to pull together some slides. Here are my disclosures.

I think what it really is about is the androgen receptor, and the fact that we know that so often, mutations of the AR are a common mechanism for AR-targeted treatment and resistance to those treatments that are AR-directed. So we believe that it is worth targeting the androgen biosynthesis upstream, because we think it may provide a good alternative over currently available AR-directed therapies for patients with mCRPC.

So this new drug called opevesostat, or ODM-208 (which is the working name), is actually an oral nonsteroidal inhibitor of cytochrome P450 11A1, which catalyzes the first and also the rate-limiting step of the steroid biosynthesis. Because that’s a little hard to understand, I think it’s easier to walk you through this little graph here, where you see the mechanism of action.

You see tissues producing steroid hormones in the male body, and you see cholesterol, which is the beginning of androgens and its precursors, glucocorticoids, and mineralocorticoids. As you can tell, we have been using abiraterone for a while; we know it’s effective, and it’s an inhibitor of CYP17. And as you can see, if you inhibit CYP17, you do effectively inhibit testosterone, but you still are left with a number of precursors. So if you go upstream one step and you inhibit CYP11, you also inhibit the production of all these precursors, and thereby you have a more complete inhibition of testosterone biosynthesis.

You also, of course, can—I remind you that you also inhibit mineralocorticoids and any other hormones, which then have to be substituted. So how are we going to handle this? Dr. Karim Fizazi, who did all the groundwork for this trial, the CYPIDES trial, published the phase II trial in the New England Journal of Medicine Evidence earlier this year. And this is the outcome of our phase III trial: we enroll patients that have mCRPC, but they are unselected for AR ligand-binding domain mutations. They have to have had one NHA for HSPC or non-metastatic CRPC, and also prior NHA in combination with docetaxel for HSPC is permitted.

We stratify by metastatic volume. We also stratify by the androgen receptor ligand-binding domain mutation status and prior docetaxel for HSPC use (yes or no). Then 1,500 patients will be randomized to arm 1 and 2. Arm 1 is patients receiving opevesostat in combination with dexamethasone and fludrocortisone, as I said, as a substitution which is needed. Arm 2, the comparator, is an NHA switch (abiraterone for patients that have been receiving enzalutamide or apalutamide before, or enzalutamide if patients have received abiraterone before).

We have a dual primary endpoint, which is radiographic PFS and also overall survival. And as you see on this list, there’s a number of secondary well-known endpoints that include time to initiation of the first subsequent anticancer treatment, overall response rate, time to PSA progression, PSA response rate, and all the others, including safety and tolerability.

Now, this trial is ongoing in 313 sites in Africa, Asia, Australia, Europe, North and South America, and it’s enrolling well—so around a third of patients have been enrolled already. And I can just hint at the so-called “sister trial,” the 003 trial, that’s also enrolling patients in similar locations, which is a little bit different in a similar setup but does look at patients that have a little bit different pretreatment consisting of an NHA and also a taxane—so more heavily pretreated patients at a later line. Thanks so much.

Zachary Klaassen: Wonderful. I really appreciate you showing that steroid biosynthesis pathway because for two reasons: one, it brings us back to our examination days when we had to study this pathway the day before the test, because it really can be confusing. But it also shows where abiraterone is inhibiting and where opevesostat is, and it’s really upstream. So maybe just speak to a little bit—have you seen similar side effects to ODM-208 versus abiraterone? Is there any difference in terms of—I know we’re adding dexamethasone plus fludrocortisone—is there a different side effect profile at this point?

Christian Gratzke: So this is a brilliant question, because following the earlier trials, we were, of course, thinking about adrenal insufficiency and what the number of patients would be that suffer from AI. And this is not the case, obviously. We’re at very low rates, and this seems to be a very safe treatment regimen. So in contrast—and the reason for this is that we actually dosed down the substance a little bit—we came in too high, and that caused adrenal insufficiency. Now, with the right dosing regimen, that doesn’t seem to be the case. There is an emergency kit available for patients, but they don’t seem to need it. So what we anticipated, or were thinking might happen, didn’t actually happen in real life.

Zachary Klaassen: Excellent. Excellent. And this is a big trial, 1,500 patients. Let’s fast-forward. Let’s say this trial is positive—the mCRPC space is really getting convoluted in a good way, lots of treatment options. Where do you potentially see opevesostat fitting into the landscape for treatment?

Christian Gratzke: Thank you for this question. So we have now an early mCRPC trial, and we have a late-line mCRPC, and we’ll see what the outcome of the trials will be. But if you ask me, we’re always talking about changing the mechanism of action when we see our patients. Now we have basically two routes to go into mCRPC, which is one receiving patients receiving doublet NHA plus ADT or, in addition, chemotherapy, and then they eventually enter the mCRPC stage.

Of course, we would like now to change mechanism of action. We have radioligand treatment, we have various other treatment regimens, but the androgen receptor is still the mainstay in the majority of our patients. If you look at PARP inhibitors, there’s a lot of discussion about how we can work out the best way to deliver our patients the best care by selecting the right patients, and we’ve been talking about this for years now.

And if you inhibit testosterone synthesis on a better, more complete level, you end up with a more complete response. What the sequence after this could be is open for discussion, of course, but I truly believe that if you administer this treatment for the patients with an acceptable tolerability profile, patients would profit. That’s my guess.

Zachary Klaassen: Absolutely. And I know you mentioned about one-third accrual, which sounds pretty good. Everybody wants to know when we’re going to see data. Any idea when we may see some early data, and how accrual is going?

Christian Gratzke: With the way accrual is going right now with the study—and actually 003 is faster than 004—accrual will be done probably quickly. It’s hard to say, of course, but assuming the speed goes on the way it is right now, it is going to be occurring very quickly, and then we’ll see the results as soon as we can.

Zachary Klaassen: Wonderful. And that’s the beauty of these conversations—I can ask you these questions. It’s exciting. This is great. We’re starting to see novel agents continuing to come into the disease space, which is great for options and great for our patients. Christian, always great chatting. Maybe a couple of quick take-home messages for our listeners?

Christian Gratzke: I think there are new trials in mCRPC, but also in mHSPC. It’s exciting for us as doctors, but more so for our patients, because we’ll find out more, we learn more. Every three or six months, when there’s a major meeting in uro-oncology, we’ll learn more about new drugs. And several have failed—it’s not like every drug would succeed. We’ve seen a couple of trials leading to negative results. We were involved in the pembrolizumab trials, finding out this doesn’t work in prostate cancer, and then we learn more.

The biggest task that we have is finding out the best sequence and the best drug for the right patient, selecting our patients appropriately, having better biomarkers. That’s where we have to get better. And opevesostat could be a drug that fits in this pattern very well.

Zachary Klaassen: Wonderful. Always great chatting with you, Christian. Always grateful for your time on your show today. Thanks so much.

Christian Gratzke: Thanks so much. Have a great day. Thanks, Zach.