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Petros Grivas: Hello, I'm Petros Grivas. I'm a Medical Oncologist at The Seattle Cancer Care Alliance and an Associate Professor at the University of Washington and Fred Hutchinson Cancer Research Center. I am really excited and thrilled today to host Dr. Neeraj Agarwal, who is a Full Professor of Medicine and a Physician Investigator at the Huntsman Cancer Institute at the University of Utah. He is the Director of the Genitourinary Oncology Program there. He is also directing the Center of Investigational Therapeutics and he is co-leading the Experimental Therapeutics Program and serving in the cabinet of the Director of the Cancer Center. Neeraj, thank you so much for your time, welcome.

Neeraj Agarwal: Thanks for having me, always a pleasure.

Petros Grivas: Neeraj, you have done really, really amazing work in the field. You have contributed to practice-changing trials in the field of genitourinary cancers across the board and I would like to pick your brain here about this new agent that is really a new option for patients with prostate cancer and I'm referring to relugolix, this orally available anti androgen deprivation therapy agent that Dr. Neal Shore and colleagues published in the New England Journal of Medicine a few months ago. And I think this is an interesting agent for many reasons which was shown in the data at ASCO GU 2020 at the virtual meeting. And I would like to ask you your opinion about how this fits into the treatment algorithm and what are the differential characteristics of this agent, based on this paper and presentation.

Neeraj Agarwal: Absolutely. Relugolix as you said, is an oral GnRH antagonist. So it does not lead to initial flare in the LH, FSH hormones, and doesn't lead to a flare of testosterone once we start treatment. So I will talk about relugolix's unique characteristics in a moment, but let me take a step back and tell you about the clinical trial, large clinical trial, almost 900 plus patients trial, data were presented by Dr. Neal Shore at ASCO GU. And it was a simultaneous publication in The New England Journal of Medicine.

So relugolix is an oral GnRH antagonist. It doesn't lead to testosterone flare, as I said just a second ago. This trial actually looked at patients with advanced prostate cancer and they could have had locally advanced prostate cancer as well as metastatic prostate cancer. And they were supposed to undergo androgen deprivation therapy for one year or more. They were randomized to relugolix versus standard androgen deprivation therapy with a GnRH agonist in a two to one fashion. And the primary endpoint was how effective the castration is at the end of this 52 weeks? Not surprisingly, the castration level was similar, and relugolix was as efficient as a leuprolide or GnRH agonist in maintaining castration. And I am not really swayed by the data, we expected that.

But the more important thing in my view was the two other endpoints. Number one was when you stop relugolix, how rapidly testosterone recovered. And the second was the safety of relugolix in patients with cardiovascular disorders, so patients who have a major cardiovascular event in the six months prior to registration on the trial. And this is where I think the juice is if you will.  Regarding the recovery of the testosterone, we all know that for GnRH agonists, testosterone does not recover for months. Sometimes I have patients with testosterone levels that do not recover for years. With relugolix, testosterone recovery happened within three weeks. That was really remarkable. And I'll tell you in a second, what are the implications of this finding. Number two was, there was a five-time decrease, five-fold decrease in the risk of another major cardiovascular event in patients who had a major cardiovascular event in six months, preceding registration on this trial. And in general, across the board, relugolix was associated with decreased cardiovascular events, which also has implications. So let's talk about the implications. Number one, patients who are undergoing intermittent androgen deprivation therapy who are really counting on feeling better with good testosterone levels during those breaks, there is no point if they do not recover their testosterone. There is no point in doing intermittent therapy if they don't recover testosterone. So in those patients wishing, aspiring to have an appropriate level of testosterone during the break period, this is an ideal drug.

So the first use of relugolix in my practice is for those patients who are wishing to get their testosterone back and are undergoing intermittent androgen deprivation therapy. These are the patients who are in biochemical, recurrent disease settings after the failure of prior definitive therapy, but they have not developed metastatic disease yet. And this is a sizeable number of patients out there in the community. Number two, especially younger patients.  Number two, patients who have cardiovascular disease and who are on monotherapy with androgen deprivation therapy. I think this is, there is no doubt in my mind that for patients with significant cardiovascular history who are undergoing monotherapy with androgen deprivation therapy, relugolix is my preferred option for those patients. I definitely bring it up during my conversation.

And the third is, where the role of relugolix is not clear yet because it was used as a monotherapy in the trial, it is the combination of relugolix with enzalutamide, apalutamide, abiraterone, or even docetaxel chemotherapy for patients with metastatic castration sensitive prostate cancer.  It is not clear entirely whether I am going to use relugolix instead of leuprolide for those patients.  I do not know yet. But beyond that, I want to reiterate, a sizeable number of patients who are undergoing intermittent androgen deprivation therapy for PSA only recurrent disease after failure of definitive therapy, relugolix is a very attractive option because it allows testosterone recovery to happen during the break, and patients who have significant cardiovascular risk, cardiovascular diseases, I think relugolix may turn out to be a very preferred option for those patients in the next two or three years, starting from now.

Petros Grivas: Thank you Neeraj, for a really crisp approach, into practical implications, as you said, when you have many options, you try to find individual characteristics that may influence the totality of your decision factors there. So thank you for shedding some light on this plethora of options when it comes to androgen deprivation therapy.

Neeraj Agarwal: And I'd just like to add that the next step for relugolix is to combine relugolix with intensified androgen deprivation... to test relugolix in the intensified ADT fashion. So to combine relugolix with abiraterone or enzalutamide or apalutamide and show non-inferiority, but improved safety profile. I think that is the next step for relugolix, if a trial needs to be conducted in that setting,

Petros Grivas: Great point Neeraj, and as always, thinking about the next step here is important in clinical trial designs and in terms of further development and next steps. So thank you for sharing your thoughtful approach. Thank you for all your contributions in the field and thanks for your time today.

Neeraj Agarwal: Thank you very much for having me.

Petros Grivas: And thanks to the audience.