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Rashid Sayyid: Hello, everyone, and thank you for joining us for this UroToday recording. I'm Rashid Sayyid, a urologic oncology fellow at the University of Toronto. I'm joined today by Zach Klaassen, associate professor and program director at Wellstar MCG Health, where we'll be discussing the key updates to the 2024 NCCN prostate cancer guidelines. There have been a lot of changes in the systemic therapy for M1-CSPC but we've noticed a big change specifically regarding relugolix or ORGOVYX®, the trade name, which has become such a prominent part of these guidelines. It really has revolutionized how we can administer androgen deprivation therapy for these patients, adding the oral route as an option to the classic subcutaneous or intramuscular options that were previously available. So in this slide deck, we'll be specifically discussing the evidence for relugolix as well as the changes pertaining to this in the guidelines for systemic therapy for patients with metastatic castration-sensitive prostate cancer.

And so the preeminent evidence for relugolix comes from the HERO trial that was published back in 2020 with Dr. Neal Shore as the first author in the New England Journal of Medicine and really served as the foundation for the FDA approval of this drug later that year. And so just by way of an overview, the HERO trial was a multinational phase three open-label RCT across 155 sites where approximately 900 patients were randomized in a two-to-one fashion to either relugolix... and I want to point out here that the loading dose on day one is three times the maintenance dose of 120 given daily thereafter... versus the LHRH agonist leuprolide administered subcutaneously, not orally, every three months. And we note that this was given a lower dose at the Japan and Taiwan sites with the primary endpoint of testosterone recovery assessed at 48 weeks after the start of therapy.

So just to reaffirm the study inclusion criteria, this included adult patients with a histologic diagnosis of prostate cancer, had to be candidates for at least one year of ADT and a baseline testosterone of greater or equal to 150. So they were not castrate or hypogonadal profoundly at baseline. And a PSA greater than two if they had not received any local therapy. Essentially this trial included one of three cohorts. So, patients with either biochemical or clinical recurrence following curative intent local therapy. The second subcohort were patients with newly diagnosed metastatic castration-sensitive prostate cancer. And the third subcohort was those with advanced local disease unlikely to be cured by local therapy.

And why this is important is that we see that we have a diverse patient population across the prostate cancer disease spectrum. And so this reaffirms the external validity or the generalizability of these results to many more patients in clinical practice. And so the primary outcome is sustained castration rate and this was the cumulative probability of testosterone less than 50, which is historically what is used as the cutoff for a castrate testosterone level, from day 29... so one month through 48 weeks... so approximately one month to just up to one year. The secondary outcomes, and these were evaluated in a hierarchical testing strategy, was the non-inferiority of relugolix to leuprolide for sustained castration, there was a margin of about 10%. And also if relugolix was shown to be non-inferior then they would test in this hierarchical fashion the superiority of relugolix to leuprolide for sustained castration.

Other secondary outcomes of interest included the cumulative probability of testosterone being castrated early on at days four and day 15. The percentage of patients who had a good biochemical response, defined as a PSA response, greater than 50% at two weeks. Also looking at profound castration rate of testosterone less than 20 at day 15. The reason we look at testosterone less than 20 is that with the newer more sensitive assays that's considered really the effective testosterone castrate level. It's been shown in many series to correlate with better castrate-resistant outcomes in the future, whereas 50 was more the classical because that was the limit of detection of these assays. So we see more of a historic reference and a more contemporary reference. They also looked at the FSH level at the end of week 24 and the castration resistance-free survival, and this is the follow-up for this is ongoing and not yet reported.

In terms of results, about 1300 patients were recruited between 2017 and 2018 and then 934 randomized in a two-to-one fashion. We see relugolix about 600 and then leuprolide about 300 patients. The treatment adherence was excellent, greater than 99%. This is going to be a bit of an anomaly because this is in the context of a clinical trial. We know these patients are more motivated, the surveillance of all these patients more stringent. And so one thing to keep in mind, especially when we think about an oral medication for our patients, the median follow-up at the time of reporting in 2020 was just over a year for these patients. Now in terms of the baseline characteristics, the median age was about 71. If we look at the geographic region, it's quite diverse across North and South America, about a third of the patients. Europe about 40%, and Asia-Pacific region, classically an area that's underrepresented in these trials, about a quarter of the patients.

So a very important detail here when thinking about which patients may benefit from this drug. About 30% of patients had metastatic disease. And then when we talked about the clinical disease presentation, what subgroups of patients were included, about half of them had biochemical or clinical relapse after a local primary intervention with curative intent, so these patients that recurred after essentially radical prostatectomy or radiotherapy. Furthermore, in terms of the pathologic characteristics, we see that it was enriched for patients with intermediate or high-risk disease. We see Gleason 7 about 40% and then Gleason 8 another 40%. As is classic with these trials the ECOG performance status was excellent in the vast majority of these patients, about 10 to 13% of patients received prior ADT, and then the previous radiotherapy was about 30% for these patients.

And in terms of the mean PSA level, this was skewed as we see in these trials, 104, but the median PSA was about 9.4 to 11.7. And we note that these patients were not, for the most, were hypogonadal at baseline and so but just also greater than 150 and the median was about 400 to 440. Furthermore, this is going to be very important, we talk about the cardiovascular risk factors. Almost all patients with cardiovascular risk factors, and in terms of patients who had a history of a prior major adverse cardiovascular event or a MACE, about 13 to 15% of patients had that before and we'll talk about that in further detail, and one of the true benefits of relugolix in this setting. Now in terms of the primary endpoint sustained castration, not only was relugolix non-inferior to leuprolide as we see here, but it exceeded the 95% confidence interval.

The lower bound exceeded the superiority threshold. And so not only was it non-inferior, but relugolix was superior to leuprolide in terms of sustained castration. Subgroup analysis, essentially we see that this pattern holds irrespective of geographic region, presence of metastatic disease, age. Now, some of them cross the threshold here, 7.9%, which is the limit for the superiority but this is more of a factor of the power related to the subgroup analysis and what we lose with power when we have a smaller sample. But essentially when we look here at the median and the differences, it's all favoring relugolix strongly. So we see that across the court and it again increases our confidence in this drug in terms of the sustained castration rate and what it's doing.

Now in terms of secondary endpoints, they all favor relugolix, we'll talk about them in further detail. In terms of the sustained castration, we talked about this already, it favors relugolix quite impressively. When we look at the early testosterone suppression, so not only sustained, but also early on we see that this strongly favors relugolix. So we look here at day four, 56 versus 0%. At day 15, two weeks, 99 versus 12%. Big difference, and this also correlates with PSA levels. The better you suppress testosterone early on, the better the PSA response in these patients with androgen-sensitive disease will be. And then the cumulative probability of profound testosterone early on, also much better. And it's impressive, about 80% of patients have this profound suppression within two weeks.

So it acts early on and is sustained. And then also the mean FSH level, just as kind of a secondary outcome, a surrogate of the suppression, again significantly lower in these patients, really reaffirms what these drugs do and how fast they do it. And now I'll turn it over to Zach where he'll go over the rest of the data from the HERO trial where you focus on particularly the effects on the cardiovascular outcomes and those who have previous cardiovascular disease as well as highlight the notable changes, specifically highlighting the role of relugolix for these patients, and importantly increasing the number of tools and the way we can administer them, tailoring the treatment to these patients in order to maximize their quality of life in this advanced setting.

Zach Klaassen: Thanks so much Rashid for that great introduction. So we'll continue with the data from the HERO trial. And this figure here looks at the mean testosterone levels among all patients, and we see a rapid decrease in testosterone with relugolix. The day four mean T-level was down to 38 nanograms per deciliter. You can see here a rapid decline for relugolix with a more gradual decline up to about five weeks for leuprolide before it reached castrate levels. This figure here looks at testosterone recovery, which is also important. The percentage of patients with testosterone greater than 280 nanograms per deciliter at 90 days was 54% for relugolix and 3% for leuprolide, which was statistically significant. And you can see this outlined here nicely in the figure. What about adverse events?

So if we look at any adverse event, any grade, nearly all patients had any grade adverse event, but when we look at the MACE population, without a history of MACE, we see any grade adverse events of relugolix of 2.8% compared to 4.2%. But where there's a real benefit, as Rashid highlighted, that patients with a history of MACE only 3.6% any grade for relugolix compared to 17.8% for leuprolide. When we look at specific adverse events, very similar between the two groups, between hot flashes, fatigue, constipation, diarrhea, arthralgias, and hypertension. Looking at the cumulative incidence of MACE, so this is the cumulative incidence at the end of 48 weeks, leuprolide 5.6%, relugolix 2.8% with a hazard ratio favoring relugolix of 0.46 and a 95% confidence interval of 0.24 to 0.88, leading to a conclusion here of 54% reduction in MACE with the utilization of relugolix.

So let's get into the key updates between 2023 and 2024. So this is the first one. This was a statement from 2023 that states relugolix has not been adequately studied in combination with potent androgen receptor inhibitors such as enzalutamide, apalutamide, darolutamide, or abiraterone, nor has it been studied in combination with docetaxel or cabazitaxel chemotherapy. Potential drug interactions include induction of cytochrome P450 enzymes and reduced concentration and efficacy of relugolix with enzalutamide or apalutamide and cardiac QTC interactions with abiraterone. This states that further studies of relugolix dosing and drug interactions with commonly used agents in advanced prostate cancer are needed to ensure patient safety and proper dosing. Therefore, relugolix is not recommended in combination with other therapies at this time. So the key update for 2024 was that this above statement for 2023 was completely removed from the 2024 guidelines.

So let's take a look at some of the studies published and presented over the last year that may have led to the removal of this statement in the 2024 guidelines. The first study was a subgroup analysis of HERO looking at the impact of concomitant prostate cancer medications on efficacy and safety of relugolix compared to leuprolide. This was published by Dan George and colleagues in Clinical Genitourinary Cancer in 2023. And we see here that there was a few patients in this trial that had concomitant use of enzalutamide and docetaxel. So for relugolix in the final analysis population, 2.8% of patients received enzalutamide as well as relugolix, and 2.4% of patients had concomitant docetaxel. The first analysis they looked at was the sustained castration rate with and without concomitant enzalutamide or docetaxel, and for both relugolix and leuprolide, you can see here excellent sustained castration rates for both.

When we look at the adverse events for patients with and without concomitant enzalutamide or docetaxel in the final analysis population, generally summarized in this table there was no clinically relevant differences in adverse events observed between subgroups in either treatment groups. So from the key registration trial of HERO there is virtually no difference in adverse events or sustained castration rate with the concomitant use of relugolix and enzalutamide or docetaxel. This abstract was presented by Rana McKay at GU-ASCO in 2023. This is real world evidence in the real ADT combo study. And this study was a PPS analytics EMR analysis among 89 urology practices in the year 2021. This study had nearly 52,000 patients treated with ADT. The majority, 88.1%, were treated with leuprolide, 6% with relugolix.

And what we can see here highlighted in the red box is that there were more combinations with relugolix at 22.5% compared to leuprolide at 19.5%, and you can see here more combination with abiraterone, apalutamide, and really similar incidence of combination therapy between relugolix and darolutamide and relugolix and enzalutamide. So this is really just a prevalent study. There was no data or safety outcomes listed in this abstract. The next study we'll talk about is the phase two APA-RP trial and this was a trial that looked at high-risk patients after radical prostatectomy who had a post-op PSA less than 0.2. These patients were then given one year of ADT plus apalutamide, and a subset of these patients, 12 patients, received relugolix as their androgen deprivation therapy. And really what these 12 patients showed was that at the time of evaluation there was a castrate testosterone at both day one and at day 28, and this was maintained at day 28 without relugolix dose adjustment so these patients were then included in the overall analysis of all patients in the phase two APA-RP trial.

So this sub-study, the key takeaway was that relugolix was administered at approved standard doses and concurrently with apalutamide and it was effective in maintaining castrate testosterone levels in men with high-risk, localized prostate cancer without any new safety signals. The final study to sort of take home, this concomitant use of relugolix and NHTs was a phase one trial and you can see part one here there were 13 patients with metastatic castrate-sensitive prostate cancer, two patients with metastatic CRPC in phase two. This included 10 patients with metastatic castrate-sensitive prostate cancer. And the treatment at baseline before they started relugolix was leuprolide plus degarelix in part one or leuprolide and degarelix in part two combined with apalutamide for part two, and combined with abiraterone in part one.

These patients then received relugolix with continuation of abiraterone in part one and with continuation of apalutamide in part two. We can see here reasonable any grades adverse events as well as very reasonable grade three/four adverse events. And at the bottom we can see here baseline week three and week 13 testosterone levels remain castrate. So this is additional evidence showing the safety and the castration efficacy of relugolix combined with NHTs. The second key update for relugolix in 2024 in the NCCN guidelines is based on the following statement from 2023. This states that data are limited on long-term compliance of oral relugolix and the potential effects on optimal ADT. Ongoing monitoring for sustained suppression of testosterone can be considered and relugolix may not be a preferred agent if patient compliance is uncertain.

The key update in 2024 is subtle but important, and basically the guidelines switch the terminology of compliance to adherence. And so let's dig a little bit more into what this may actually mean. And so this is an abstract published in 2023 looking at the terminology of adherence versus compliance. And what we see here is that adherence and compliance are two words that are used interchangeably by the medical profession. But according to the literature, adherence is an active choice of patients to follow through with the prescribed treatment while taking responsibility for their own well-being, while compliance is a passive behavior in which a patient is following a list of instructions from their doctor. Thus, adherence is a more positive proactive behavior, which results in a lifestyle change by the patient and they must then follow a daily regimen such as taking their medications.

Compliance is a behavior exhibited by a patient who is simply quote, unquote, "doing as he or she is told or following instructions given by the treating doctor." So in HERO they looked at the treatment adherence and in HERO it was excellent. It was 99% adherence for relugolix, which is consistent with real-world experience of oral therapies for men receiving treatment for CRPC at 92 to 96%. So in summary, the HERO study established relugolix as an oral GnRH antagonist with rapid sustained suppression of testosterone levels superior to leuprolide with a 54% lower risk of major adverse cardiovascular events.

The NCCN 2024 guidelines have eliminated the terminology regarding relugolix plus NHT combination therapy concerns, perhaps secondary to a series of studies that were published or presented in 2023. And finally, concerns in the 2023 guidelines regarding treatment compliance have been changed in the 2024 guidelines to the more positive terminology of adherence. We thank you very much for your attention. We hope you enjoyed this UroToday discussion of the NCCN 2024 guidelines with a focus on changes regarding relugolix.