Atish Choudhury: Yeah. Thank you for this opportunity to talk about the study.
Zachary Klaassen: So we've heard about relugolix from the HERO trial. Darolutamide, many trials now. What was the genesis for the CLEARED trial?
Atish Choudhury: Yeah. It turns out that relugolix, as you know, is a very common treatment that we use for androgen deprivation for testosterone suppression. As an oral drug, it's more convenient for many patients than the injections. There are some data around more rapid testosterone recovery after completing courses of treatment with relugolix, and there's also some data around decreased major cardiovascular events with relugolix compared to leuprolide from the HERO trial. So it's a good and well-tolerated drug for testosterone suppression, and darolutamide is a good and well-tolerated androgen receptor pathway inhibitor, with favorable quality of life data from the ARANOTE trial.
And this is a combination that we use very commonly, especially in elderly patients and those who have cardiovascular risks, but it turns out that there's no actual pharmacokinetic data on that combination. And we don't know, in indications for high-risk localized lymph node-positive or oligometastatic disease, where you might give two years of treatment, what the testosterone recovery is like with relugolix, because what was presented in HERO was after one year of treatment.
Zachary Klaassen: It's a great trial design. I mean, I think you're right. We use this combination all the time, that 82-year-old, has some comorbidities, maybe he's on a blood thinner. We just give it, but to your point, we haven't had data combining these two. So what was the study design for this trial?
Atish Choudhury: Yeah. So we enrolled 33 patients, and again, they were across that gamut of high-risk localized lymph node-positive or oligometastatic, and they're treated for two years on study and then they're going to be followed for 18 months after the end of treatment, and we're following PSAs and testosterone levels during the course of treatment and then obviously during the recovery. And the primary endpoint of the study is testosterone recovery to greater than 150 by 18 months after the end of treatment.
Zachary Klaassen: I see.
Atish Choudhury: And so what we know is that, with two years of injectable agents like leuprolide, the testosterone recovery by 18 months is around maybe 50%. So about 50% of men never actually wind up recovering their testosterone, which in a curable setting is really not an outcome that we want. So we were testing to see if the relugolix combination might achieve a testosterone recovery more in the range of 70%.
Zachary Klaassen: Excellent. And what was the high-level data you presented at ASCO this week?
Atish Choudhury: So what we basically showed in our poster is the six-month data around this combination and the pharmacokinetics. So without getting into a lot of details, the pharmacokinetics of both drugs when given in combination are really about what's expected with the single drugs, because there isn't a notable drug-drug interaction between the two. So the levels of the drug that you get on the first day and then the continuous trough levels that you get with continuous dosing are about similar with both drugs, when they're given in combination compared to the single agents.
Zachary Klaassen: Excellent.
Atish Choudhury: We also presented the PSA and testosterone reduction with this combination, and testosterone gets to less than 50 in all patients and nearly all patients got to a testosterone even less than 20, though we had one patient who stayed at 24, which is still quite an impressively low testosterone when given in combination with an androgen receptor pathway inhibitor, and all patients achieved a PSA 50 response. All patients except for one achieved a PSA 90 response by six months, and the safety was about what you would expect, fatigue, hot flashes. About three patients needed to dose-reduce darolutamide just for lower-level kind of toxicities, but there were no concerning safety signals with this combination at the six-month time point.
Zachary Klaassen: So you and I are probably talking in a couple years when this data is presented as a final presentation, but take me back to the clinic on Monday or Tuesday when we're back from Chicago. How do we take the data presented today and use it as confidence to give this combination in the clinic next week?
Atish Choudhury: Yeah, absolutely. Many people were just giving it anyway without the combination data, but there has been pharmacokinetics of the relugolix combinations with abiraterone, enzalutamide and apalutamide that have been previously published. So this fills in that data gap, that the PK seems to be totally appropriate and what we would expect. The clinical activity seems to be appropriate and what we would expect. And so if you have a patient where you think that relugolix is the best drug for testosterone suppression and you think that darolutamide is the best androgen receptor pathway inhibitor, I think very legitimately you can give them in combination, as many of us have been doing anyway.
Zachary Klaassen: That's great. Atish, always great chatting with you. Great work on CLEARED. We'll look forward to more data from that trial. Thanks for joining us on UroToday.
Atish Choudhury: Yeah, thanks so much.