Benjamin Lowentritt: Thank you so much for having me, Dr. Agarwal. I appreciate it.
Neeraj Agarwal: We came across this very nice presentation of yours in this ongoing 2026 annual American Urology Association meeting on testosterone recovery and suppression, of course, with the Relugolix, the phase four trial. And could you tell us more about the trial?
Benjamin Lowentritt: Sure. So this is our phase four registry trial and I'm honored to be one of the steering committee members and authors of this interim analysis where we followed patients starting on Relugolix for any reason, 999 patients, and we've been getting data on them in the past several years.
Neeraj Agarwal: This is a large phase four trial, about 1,000 patients.
Benjamin Lowentritt: Yes.
Neeraj Agarwal: And we always know just to discuss some background for our colleagues out there, testosterone recovery is a challenge with traditional GnRH agonist injections. I have patients who receive leuprolide or goserelin for two or three injections and I often see testosterone not recovering even after taking the break or even after completing the course, if you will, if they're getting this for say salvage radiation therapy or for any reason. And if they want to take a break, they're not really taking a break. Testosterone remains very low. So there is a huge need out there in the society in the clinics for our patients to have something which will allow them to recover their testosterone and their life back, if you will. And personally, I have had experience with Relugolix, which is one of the GnRH antagonists. So before we get into the trial design, Ben, could you please tell us more about the mechanistic differences in the GnRH agonist versus antagonist for our audience today?
Benjamin Lowentritt: Certainly. And so the clearest answer is it's an antagonist versus an agonist, so you don't see that initial surge of testosterone and FSH that's caused when you first start a GnRH agonist. So you avoid that, which is nice. And I think a lot of us got in the habit of starting maybe an earlier generation receptor blocker, things, and you don't have to worry about that if you start a patient on an antagonist. But what we've also learned and what was present in the HERO trial, which was the clinical trial that led to the approval of Relugolix, was that for patients that are stopping their therapy, this antagonist does seem to, at least in that trial, seem to allow a more rapid return to a normalized testosterone after stopping, so so many indications now are for an abbreviated course, whether it's six months, 18 months, two or three years, where there is that assumption that you want them to recover afterwards. The idea was not to make them castrate for life.
So that is certainly one thing that we wanted to explore was, was that going to be the experience in the real world once we started seeing how patients were getting this drug and how doctors were using it across the disease state?
Neeraj Agarwal: So in the phase four OPTYX trial, which you are presenting, tell us please about the results, what you are seeing.
Benjamin Lowentritt: Certainly. So this was an all-comers trial. Part of what we were learning was how people are using it. What were the indications people that are using it for? And some of those will be presented in our abstract, but many of those details will be presented as we go forward. This was our interim analysis where we had a six-month view on every patient. We're going to be following at least two years. So this is just the first analysis of that. And what we're able to see is that well over 90% of patients were achieving a castrate level of testosterone where we had measures to measure it.
I do think that was one thing and I'd love for our colleagues out there to make sure we're doing is it was enlightening and maybe a little bit disappointing how few of our patients had clear documented testosterones prior to therapy and then how rarely or not frequently they were getting it tested after they started on therapy to verify that they were castrate. But for patients where we did have a good baseline testosterone and good follow-up testosterones, over 90% of patients did achieve a castrate level, even as going out to six months and it was in excess of 93% to 95% depending on the timeframe.
And then we followed the patients and for those patients that we had a good baseline study and then had stopped and we had follow-up visits, we saw that the majority of patients that we had a normal testosterone beforehand achieved a normal testosterone within that six-month period. It was also very interesting that in this cohort, it appears that only about half of the patients had normal testosterones to begin with when we did check them. But for those that did, they did return to a normal level, which was very encouraging.
Neeraj Agarwal: There's another digression I would like to take for a second. What are the predictors of recovery of testosterone in your patients? I'm not even talking about OPTYX trial, I'm talking about your experience. So we have always known that older our patients are, it is harder for them to recover their testosterone, but it looks like baseline testosterone is a good marker of that.
Benjamin Lowentritt: Certainly. I think that is something that we're going to tease out more as time goes on with this trial, which is actually very interesting. But absolutely, knowing what the baseline testosterone, we don't expect patients to get a testosterone level that's better or higher than it was before starting, even if they recover. So part of it is just setting an expectation. For patients that maybe weren't symptomatic but now are going on some sort of androgen-deprivation therapy, it's important to let them know where they started so they don't get disappointed about where they end up because a lot of times the numbers don't always reflect in the symptoms. So you want patients to be back at their normal state. We're not talking about trying to make people eugonadal always if they were borderline before trying to get to some artificial number.
So I do think that's a great point is that baseline testosterone level is really, really important. Age, we've known, appears to be important, although we haven't broken that down yet with this cohort and we do hope to be able to tease out some of those other things. And certainly duration of therapy is well known in the agonist space. Still need to sort of tease out whether or not if someone's on it for two years and stop, how quickly and how reliably do they recover? So a lot of things that we hope to continue to get from this.
Neeraj Agarwal: So age, long duration of treatment with GnRH agonist, baseline testosterone, all those factors which may influence the recovery of testosterone after discontinuing the treatment, but looks like with Relugolix in this phase four OPTYX trial, the recovery time is six months, which is remarkable compared to what we have witnessed with the GnRH agonist. I have patients who have not recovered their testosterone for two to three years, even longer. If I check their testosterone, many of them never recover their testosterone especially if they are in late 70s or 80s. So coming to the next point, assuming we see what we are expecting to see that Relugolix is consistently leading to good suppression of testosterone and when you stop treatment, the recovery is brisk, is quick in those who had good baseline testosterone, what do you see the implications of these results in the near future?
Benjamin Lowentritt: Well, I think we're moving towards a period of time where we talk about intensification of therapy in appropriate patients and we talk about de-intensification of therapy in-
Neeraj Agarwal: Even in metastatic settings.
Benjamin Lowentritt: Exactly. And so I think it's important to say that this registry also included a good number of patients that were on combination therapy with an ARPI. So we're going to get more information about how those combinations impact even for patients that may have had a defined course with a planned break for high-risk BCR or for local regional spread with radiation and some of the protocols that have been established in adding an ARPI in that case to ADT. So we're going to learn a lot about those situations as well, but I think it's fascinating to know both a big part of what we're also going to be looking at as this goes forward is quality of life because I think there is a feeling that testosterone is probably the closest thing linked to quality of life for these patients, especially those that we're hoping to take off at some point. So we'll actually be able to demonstrate that and see if that's true, but we also all have patients that do perfectly fine on these medications and don't necessarily have the worst effects.
So I think we're looking forward to understanding some of those just baseline quality of life and experiences for the patients. We also are collecting PSA and clinical progression data to see if... I mean, there's certainly always that question, is some of the historical data that we have on benefit of certain therapies related to that tail of testosterone blockade that we see often from an agonist? So I think the data will help us define that over time, but in general, what we know so far about the antagonist is that it seems to be very effective and seems to do exactly what I think you and I would want to be offering to our patients, which is to turn off the testosterone when we want to and to allow it to come back when we're ready to allow it to come back.
Neeraj Agarwal: To have that control for our patients.
Benjamin Lowentritt: Exactly.
Neeraj Agarwal: I have a young man in his late 40s, young family, and I often hear from him about gaining the control on his testosterone level. Can we do that? Exceptional responder, PSA is undetectable after six months of ADT plus ARPI. And he would love to have some breaks knowing that he has metastatic disease, will be on ADT for rest of his life. And if we can allow these patients to take even three to four months break with eugonadal testosterone levels, that can be life-changing for them. That gives them hope that they can resume their normal life at least for four months and a year, that's a big deal for them.
Benjamin Lowentritt: Absolutely.
Neeraj Agarwal: And GnRH agonists do not allow them to do that. Before we finish, any cardiovascular data you are looking at in this trial?
Benjamin Lowentritt: No, it's a great point. And we realized pretty early on, because that was an area of interest, that this study was not really set up to achieve those kind of goals because the rigor needed to really show any kind of cardiovascular outcomes. I think this wasn't the appropriate type of study to do kind of an all comers, just a lot of... We're really just trying to get what the real world experience was as opposed to that mechanistic or causality with cardiovascular.
Neeraj Agarwal: And we have robust cardiovascular data from the HERO trial.
Benjamin Lowentritt: Yes.
Neeraj Agarwal: With a remarkable decrease in major cardiovascular events in those patients who had cardiovascular events. There was a five-fold decrease in a second MACE in those patients who had a MACE within six months of starting protocol treatment through the HERO trial and about 50% decline in overall population. So we have that, but I think we are really looking forward to the testosterone suppression and recovery data in a published form down the line.
Benjamin Lowentritt: Yes.
Neeraj Agarwal: Which will probably allow us more confidence to use GnRH antagonist, specifically Relugolix, which is already being used quite often in my clinic, but I would love to see more data to get more confidence in the medication.
Benjamin Lowentritt: Well, we're excited to continue to evaluate what we have and present more in future publications in congresses.
Neeraj Agarwal: Thank you for taking this initiative and congratulations.
Benjamin Lowentritt: Thanks so much.