Tom Keane: Good afternoon, everybody. This is Tom Keane coming to you from Charleston, South Carolina, and from UroToday. Once again, I'm going to actually discuss oral relugolix for androgen deprivation therapy in advanced prostate cancer. I thought we should go through the trial itself and perhaps discuss some of the aspects of it. The abstract is interesting. It goes through leuprolide as the standard agent for achieving androgen-deprivation therapy for prostate cancer. That is despite its initial testosterone surge and subsequent delay in therapeutic effect.

Relugolix was developed as an LHRH antagonist. Now, as people know, there is degarelix available, which is in injectable form, but the novel thing about relugolix among other things is that it's now the first oral agent to come along.

Now, this was a Phase 3 trial, which is called the HERO Trial, where patients were randomly assigned with advanced prostate cancer in a 2:1 ratio to get relugolix at 120 milligrams orally once daily or leuprolide injections every three months. The study had a duration of 48 weeks.

The primary endpoint was sustained testosterone suppression to castrate levels. The castrate level is defined as less than 50 nanograms per deciliter, which of course, most of us now realize is too high. Most of us would like to see that reduced to 20 at least. It was through 48 weeks, as I mentioned. Secondary endpoints were non-inferiority with respect to the primary endpoint, castrate levels of testosterone on day four and profound castrate levels less than 20, which were achieved on day 15. Then testosterone recovery was evaluated in a subgroup of patients.

The results showed that there were a total of 622 patients who received relugolix. 308 received leuprolide. Relugolix achieved a 96.7% castration rate, which is through 48 weeks as compared to an 88.8% achieved with leuprolide over the same time. The difference of 7.9 percentage points showed non-inferiority and superiority of relugolix.

All other secondary endpoints showed superiority again for relugolix. The percentage of patients with castrate levels of testosterone on day four was 56% with relugolix and of course, zero with leuprolide because it was at that point in the surge. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 nanograms per deciliter in the relugolix group and only 58.6 nanograms per deciliter in the leuprolide group. That showed that a has achieved more patients were castrate, more patients achieved profound castration rate, and there was a quicker recovery. Now I would say, however, that as you look at the time points that were given, it's not surprising that relugolix was better because everybody accepts the fact that the agonist does have a surge. So I think, again, this just shows us that the surge delays the treatment effect of the agonist. I think if we were to follow [inaudible 00:03:43] further, we would have found that there was reasonable testosterone recovery for the agonist also. But the fact is that this achieves castration quicker and you come out of the castration phase quicker.

I also want to change to the next slide, which basically is the data. This is the demographics. Patients were age 71 years of age in both groups on average, 90% ECOG 0, 10% ECOG 1. 50% of patients had biochemical recurrence after local therapy, 30% clinical metastasis. Median PSA for the relugolix group was 11.7, for the leuprolide group 9.4. 90% of patients had one cardiovascular risk factor. I should mention that if you had had a major cardiovascular event within six months, you were excluded from the trial.

It detailed the cardiovascular risk factors on this slide. 14% in both groups had, had an MI or a CVA. The adherence was over 90% of the total prescribed doses taken. Was 90% for the relugolix group and 89% at 48 weeks.

This slide shows you basically, it's a summary of the whole trial. You can see there were five key secondary endpoints, which were found to be superior to leuprolide, and they're listed here. Now, again, I've dealt with this and one would expect to see a more rapid suppression of testosterone. At the time points of day 15, you would expect that more patients were castrate of course. And then when you look at the cumulative probability of profound suppression, again at day 15, you see significantly more patients who've gone below 20 in the relugolix arm. In fact, 78.4 versus 1%.

Now more importantly in my book is the mean FSH level at week 24. That was 1.72 international units per liter versus 5.95 international units per liter. FSH is the other element that is significantly reduced on hormonal therapy or supposedly. We see LH levels drop significantly, but FSH levels, if you're using an agonist, do not drop significantly. They drop initially for about 28 or 30 days, and then they start to creep back up. I've always felt that when you're using androgen deprivation therapy, we're really affecting the LH levels, but not the FSH levels. That tends to be the side that's ignored. This drug doesn't ignore it. It does achieve very low levels. Then we look at the testosterone level at 90 days post-treatment discontinuation. Again, there was a profound difference, testosterone of 288.4 for the antagonist versus 58.6 for the agonist.

That of course brings up issues of testosterone recovery. One of the aspects would be perhaps if you recover quicker, do we identify patients who are failing quicker? Therefore, are we in a position to be able to introduce different treatments or newer treatments or subsequent treatments earlier? Again, interesting points.

Among all patients, the incidence of major adverse cardiovascular events was 2.9% versus 6.2% favoring relugolix. Relugolix demonstrated non-inferiority and superiority to leuprolide in sustained testosterone suppression through 48 weeks and it was 96.7 versus 88.8 respectively. But I would say that if we were to perhaps look at those days or extend that time period out, you would probably see an improvement in the agonist side of things.

We look at the adverse events. The typical adverse events that one would expect for somebody who's undergoing a castration treatments are listed here. There were no really significant differences between the two groups. However, when one takes a deeper dive into the cardiovascular events, we do see a difference.

In terms of MACE, patients with a history of MACE, you can see the number of total events for the relugolix versus the leuprolide, and they are significantly different. 2.8 versus 4.2%. That's for patients without a history of MACE. If you did have a history of MACE, then you had an even more significant difference. You can see 3.6% for the antagonist versus 17.8% for the patients on the agonist. That notes a difference of a 4.8 increased risk of developing a cardiovascular MACE event if you're on leuprolide. The same was not observed in the relugolix group.

The primary outcome, as I mentioned, relugolix 96.7% of patients maintained castration at 48 weeks. Leuprolide 88% of the patients remained castrate at 48 weeks. Secondary outcomes day four, 56% of the patients were castrate in the relugolix arm versus 0% in the leuprolide.

Then again, looking at the rapid recovery after cessation of treatment, again, significantly in favor of the relugolix group. When we looked at the cardiovascular events, which I've just been through, overall there was a 54% lower risk for the patients on the antagonist. Then here's the slide, which shows you actually the cumulative incidence of MACE, and you can see once again on this, there's a very obvious difference between the two groups.

Looking at the last slide on this, this is sustained castration is A, you can see, and then on B you see the surge, and then the reduction of testosterone down to castrate levels, which occurs between week four and week five for the agonist as opposed to the antagonist. And then you see the slides for the testosterone recovery significantly faster for the antagonist.

This is a real groundbreaking trial. This changes the arguments for agonist versus antagonist because one of the main arguments against using an antagonist has been injection site reactions and has been the fact that the patient has to have repeat injections every 28 days when the agonists have three months, four months, and six-month formulations available.

That's now gone as far as I'm concerned. Having an oral treatment really makes a very substantial difference and kind of nullifies the injection site reaction debate. Also, you've got to consider who's likely to benefit or who's likely to change their practice when you compare agonists and antagonists. Well, I think from a urologist viewpoint, this is going to be used extensively. This is Tom Keane coming to you from UroToday. I hope you've enjoyed this review. Thank you.