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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University. I'm so excited to have here with me today Dr. Dan George, who is a professor of medicine and surgery at Duke, as well as Dr. Neal Shore, who is the director of the Carolina Urologic Research Center. Thank you both for being here with me today to talk about some data that was presented at GU ASCO 2021 thinking about the HERO data. This was actually the impact of concomitant prostate cancer therapy on the efficacy and safety of relugolix versus leuprolide in men with advanced prostate cancer. And it's a subgroup analysis from that phase three HERO study looking at men who received different treatments in addition to relugolix during that trial. Thank you so much for talking with me today.

Dan George: Our pleasure. Nice to see you, Alicia, and happy to give you a brief update on our poster.

Alicia Morgns: Thank you. Dr. George, can you tell us a little bit about what exactly you looked at and if you could just remind everyone of the design of the HERO study as well?

Dan George: Sure thing. The HERO study, it's a pivotal trial of a novel, really first oral GnRH antagonist for the treatment of androgen deprivation therapy(ADT) in prostate cancer. And it really focused on men with advanced prostate cancer, really three groups; those with the recurrent disease following local therapy, so rising PSA after surgery or radiation, men who had metastatic disease at diagnosis, and then a group of men who had locally advanced disease that was really deemed relatively incurable and they were going to be starting on hormonal therapy for a year or more, and that group of men was allowed to have concomitant radiotherapy. And that was one of the subgroups that we wanted to look at in terms of the HERO study.

Dan George: And the other aspect of the HERO study was that it was a 48-week treatment course. It looked at continuous testosterone suppression over that entire 48 weeks. And relugolix actually demonstrated superiority to leuprolide in terms of that continuous testosterone suppression. It also demonstrated really immediate declines at three days and at one week and two weeks associated with that immediate testosterone suppression that was statistically significant from leuprolide.

Dan George: And then finally, in another subgroup analysis, a sub-study, pre-specified, it demonstrated testosterone recovery by 90 days.  Whereas we saw very little with the leuprolide group, so demonstrating, I think, really different kinetics of testosterone suppression, level of testosterone, and continuous suppression. And then the last really key aspect of it was the side effect profile.  Alicia, it demonstrated a 54% reduction in the risk of major adverse cardiovascular events. And Neal can speak on this more, but these were heart attacks, strokes, or sudden death, and a 54% reduction over the 48 week treatment period.

Dan George: Our sub-group analysis really focused on then a certain aspect of this study, which was the addition of systemic therapy with either enzalutamide or docetaxel in particular. And this was for patients that demonstrated evidence of disease progression during that 48 week period, and whether they are on leuprolide or relugolix, they were allowed to have concomitant therapy. The one therapy not allowed was abiraterone because that can also suppress testosterone. So, concomitant therapy was allowed.

Dan George: And then we looked at continuous testosterone suppression in the context of that concomitant therapy, just making sure there weren't drug interactions that interfered with the ability of relugolix to keep suppressing testosterone. And interesting in both [inaudible 00:04:15] arms, whether it was leuprolide or relugolix, we saw continuous suppression. Again, we saw higher rates of continuous testosterone suppression with relugolix and enzalutamide or docetaxel than we did with leuprolide.

Dan George: We also looked at side effect profiles and there weren't any obvious side effects signals with the concomitant therapy. We did see higher rates of toxicity associated with concomitant therapy, whether it's enzalutamide or docetaxel. And it wasn't different between relugolix and leuprolide. They both increase the rates of these toxicities, including these major adverse cardiovascular events. And so we concluded that relugolix is an effective therapy, even in the setting of adding enzalutamide or docetaxel or radiotherapy. And we had almost 15% of our patients with radiotherapy concomitantly and again, we saw that continuous testosterone suppression. It really opens the door up for using relugolix, not just as monotherapy, but potentially in the context of radiation therapy or additional therapies as patients move into metastatic castration- sensitive disease settings, or even metastatic castration-resistant disease.

Alicia Morgans: Thank you so much for going through all of that with us, Dr. George. And I think to me, this has amazing clinical relevance because it seems like the rare patient who is going to be getting hormonal suppression alone with an ADT lone agent. But I'm just curious from your perspective, Dr. Shore, as a urologic oncologist, you treat a lot of patients with early relapses, with advanced disease as well. How important is this kind of data? How does this affect your comfort with things like relugolix?

Neal Shore: Thank you, Alicia. I think this is important to get out to the larger community. As Dan said, this is the first and only oral ADT, and it has the advantage of being an antagonist and not an agonist, which just intuitively makes greater sense in terms of rapid T suppression, avoidance of a super physiologic surge and the more profound and rapid PSA declines, which is something that patients oftentimes are really wedded to.

Neal Shore: Using, as Dan said, combination therapy now in MCSPC and MCRPC is really the standard. It is no longer monotherapy. And we need to be sure that there is not a challenge with safety and efficacy. Drug, drug interactions are always important to evaluate. We have additional studies planned to look at relugolix with concomitant abiraterone. I know there will be some investigator-initiated studies planned with relugolix and apalutamide, and these are all really important.

Neal Shore: Some of our colleagues, appropriately so, bring up the concern that we've been so used to giving parenteral administrations for ADT. Why or how likely will there be compliance taking one pill once a day? My response is how we offer oral oncolytics throughout all of GU oncology and other cancers outside of GU. Patients will take medication daily if it is going to prolong their survival.

Neal Shore: But more importantly, or as importantly as Dan said, we saw a 54% reduction in cardiovascular-related toxicity over the 48 week period. And Alicia, you've been tremendous in your work in cardio-oncology. And the field of cardio-oncology is here today. It's not about will we need to think about this, but we need to do a better job of screening our patients upfront. Interestingly, the LHRH agonists all have a black box warning regarding their cardiovascular potential toxicity since 2013. Not true for degarelix, the parenteral drug, nor is it true for relugolix and their product information label.

Neal Shore: And as Dan said, the cardiovascular toxicity comparison was a pre-specified safety evaluation in our trial. And oftentimes, it's hard to always assess correctly the cardiovascular risk, although most of our patients have them just by the nature of being elderly, oftentimes overweight, obese, having dyslipidemia or glucose dysregulation, or a prior history of myocardial infarction or a stroke or family history. Personally, I find it extremely compelling that the HERO data in conjunction with other important papers and analyses have been telling us for a long time that the antagonists have a potentially enhanced safety profile for cardiovascular risk.

Alicia Morgans: I could not agree more. And I think that in particular, when I think about using these agents with things like abiraterone or enzalutamide, and to be fair, abiraterone was not included in this analysis for reasons that Dr. George alluded to, but I think that these drugs on their own seem to have a cardiovascular signal, so if we are able to use a backbone's ADT that does not have as big of an increase in the risk of cardiovascular events, to me, that seems like a win because we'll be able to reduce the overall cardiovascular risk. And so I completely agree. I don't know, Dr. George, if you have any comments on that.

Dan George: Yeah, Alicia, this is such an important topic that Neal raised because we are moving these drugs earlier and earlier in the disease sequence now when you think about where they were first developed in the pivotal trials or in castration-resistant disease. Of course, there was a higher rate of cardiovascular events seen in that setting, but we almost said, "Well, we can't accept that because we're dealing with really late-stage lethal disease." Now we are starting to use these drugs, and you are going to see more and more data in combination with hormones and radiation therapy and curative sets, or in patients that have recurrent disease after surgery, they have a life expectancy of 10 years or more. And we may be looking at delaying metastasis, but we are far from death. Even these non-metastatic castration-resistant prostate cancer patients, their average time on treatment is like three years.

Dan George: So now we're looking at a patient population where the cumulative risk of these events, even if it might only be a few percentages a year, is going to escalate over time. And those events early in that disease course, to me, are almost more devastating. Because it's one thing to have a heart attack or stroke in your last six months of life but if you have that early in your prostate cancer journey, that changes everything, not just your quality of life, but your survival and how we can treat you. I think the impact is really dramatic as we start considering these disease settings.

Alicia Morgans: Well, to that point, I think that the safety evaluation that you did, or at least the concomitant use evaluation that you did in terms of patients receiving radiation is really a critical part of this subgroup analysis. What are your thoughts on that in these early disease patients, Dr. Shore?

Neal Shore: Well, I think as Dan points out very correctly, I mean, having a cardiovascular event if you are receiving radiation treatment, in a shorter course, whether it's four, six, 12, 18 months, and you are looking for a cure and you sustain a cardiovascular event of significance, such as an MI, that is a lifelong issue that trails you consistently. The testosterone recovery, the rapidity which we've now demonstrated in this trial, as well as in an earlier phase two study that we published in European Urology, Dave Dearnaley, a radiation oncologist very well-known to all of us and from the UK is the first author, and we looked at a comparator study and intermediate-risk patients receiving radiation, comparing relugolix to degarelix.

Neal Shore: And so I think what is very nice for patients who really are tremendously discomforted by the hot flashes, the fatigue, let alone the hidden findings of bone demineralization or the lack of quick testosterone recovery with parenteral drugs really will enjoy the rapidity of testosterone recovery with relugolix. I think this was a real clinical subjective advantage for patients in that particular patient population.

Alicia Morgans: I completely agree. And as we start to wrap this up, and congratulations to both of you for your work on this particular analysis, I'd love to hear your summary then, Dr. George, on what is the message for clinicians and patients who are thinking about ADT and its use concomitantly with some of these other treatments?

Dan George: Well, Alicia, I think that these are still early days for relugolix or orgovyx in practice, but I think this data supports the use of concomitant enzalutamide and docetaxel with orgovyx, particularly in your patients with metastatic castration-sensitive prostate cancer or in patients maybe with metastatic castration-resistant disease that you are worried about or maybe has had a mace event. Switching to an agent like this is reasonable, even in the setting of these concomitant therapies. It certainly supports that. I think we need more data. I think we'd like to see more prospective studies done with this, but in the meantime, I think you can feel comfort at least that this drug still works in those disease settings.

Dan George: I think with radiation therapy, now this is a more substantial data set, and I think it really does support the use of concomitant relugolix with radiotherapy in patients with locally advanced disease. And as Neal pointed out, I think that is really important because that is the group of patients where testosterone recovery is a really important aspect of survivorship for these patients. And you've got a clear differentiating signal therebetween relugolix and leuprolide. And as you pointed out, I think more studies with other concomitant agents are needed, but to me, this really represents a whole new field for us with oral GnRH antagonism and really a whole new base therapy to build off of with potentially less risk of major adverse cardiovascular events.

Alicia Morgans: Thank you. And Dr. Shore, what are your thoughts?

Neal Shore: I agree with everything Dan said. Let me just try and add a couple of other considerations. Let's not forget it is a once-a-day pill and during a pandemic where a drug can be shipped to your house, that is awfully convenient both for patients and for our clinics, avoiding exposure and inconvenience. Even if we weren't in a pandemic, the challenges of driving to and the costs and hassle of transportation can be daunting for many of our patients, depending upon where they want to get their injection, to get their parental administration. It also frees up your clinic to do other things as well. Convenience is a real consideration.

Neal Shore: I would add, the cost is a consideration. And it's a new drug, and so it is costly as really all of our new advances. And I think I look forward to health economic outcome reporting measures looking at all the different factors that we've talked about, not only convenience, but clearly toxicity and cardiovascular effect, and trying to get a really good understanding as to where that plays out and balances vis-a-vis parenteral LHRH and even GnRH antagonist injectables.

Alicia Morgans: I think those are great comments. And so whether the work is done looking more prospectively at some of these combination therapies and cardiovascular events and other toxicities, whether the work is healthy economics evaluations, there is more work to be done. There always is in cancer care, but I sincerely appreciate the two of you doing the work that you have done sharing this subgroup analysis with us and for taking the time to talk it through with the listeners today. Thank you so much for your time.

Dan George: Our pleasure.

Neal Shore: Thank you.