The first oral gonadotropin-releasing hormone (GnRH) receptor antagonist for adults with advanced prostate cancer is now available in clinical practice.

On December 18, 2020, the FDA approved relugolix for adults with advanced disease based on medical castration rate data from the phase 3 HERO study ( identifier: NCT03085095).1 The randomized controlled trial compared the safety and efficacy of relugolix with that of leuprolide acetate in 930 evaluable patients with advanced prostate cancer who were candidates for at least 1 year of continuous androgen deprivation therapy.

The primary end point was the medical castration rate, defined as achievement and sustainment of testosterone suppression to castrate levels (<50 ng/dL) by day 29 through 48 weeks of treatment. Relugolix was administered in a 360-mg loading dose, followed by daily oral doses of 120 mg. In the control arm, leuprolide acetate was subcutaneously injected at 22.5 mg every 3 months for 48 weeks.

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Among the 622 patients randomly assigned to receive relugolix, the medical castration rate was 96.7% (95% CI, 94.9%-97.9%). This compared with a medical castration rate of 88.8% (95% CI, 84.6%-91.8%) in the leuprolide acetate arm (n=308).

In an interview with Cancer Therapy Advisor, Daniel J. George, MD, a lead investigator on the HERO study, a professor of medicine and surgery in the department of medicine at the Duke University School of Medicine, and a member of the Duke Cancer Institute in Durham, North Carolina, discussed the approval of relugolix and its implications for the advanced prostate cancer paradigm.

Please provide an overview of the efficacy data that led to the approval.

Dr. George: “The HERO study was a definitive, international phase 3 study with representation from Asia, North America, and Europe. HERO enrolled men with advanced prostate cancer, [specifically disease] that had recurred following prostatectomy, locally advanced high-risk disease that would require hormonal therapy for a prolonged period of time, or metastatic prostate cancer. All of these men would receive standard-of-care hormonal therapy in the form of androgen deprivation therapy, and that usually entails a GnRH agonist for at least 12 months.

Patients were randomized 2 to 1 to receive oral therapy with the novel GnRH antagonist relugolix, or a 3 month injection of leuprolide. Relugolix is a novel first-in-class oral GnRH antagonist that, in prior studies, had been shown to effectively and efficiently block GnRH signaling.

The study had a primary end point of demonstrating continuous testosterone suppression over 48 weeks, which was checked every 4 weeks. Patients had to maintain a testosterone level less than 50 ng/ml, and as a goal, had to have a continuous testosterone suppression rate for the population that was over 90% for the lower limit of the 95% competence interval. There had to be really clean data to show continuous testosterone suppression.

The results were really quite remarkable. Nearly 97% of patients had continuous testosterone suppression, and the bottom level and 95% confidence interval lower limit—which had to be above 90%—was 94%. Relugolix more than met its primary end point in being able to maintain a very high consistency of continuous testosterone suppression. The HERO trial was also set up as a noninferiority study, and for that, they set a boundary of a 95% confidence interval within 10%. So, relugolix had to be at least 90% as effective as leuprolide at the 95th confidence interval. For this key secondary end point, relugolix was not only noninferior to leuprolide, but actually superior.”

Mechanistically, how does relugolix differ from existing therapies?

Dr. George: “GnRH agonists work by creating a negative feedback loop, initially resulting in a surge of leutinizing hormone [LH] and follicle stimulating hormone [FSH] from the pituitary gland that result in a rise in testicular testosterone that feeds back to desensitize the pituitary gland to the persistent GnRH agonist. This mechanism takes 2 to 4 weeks to result in a decline in testicular testosterone and is slow to reset after months or years of suppression. Relugolix is a GnRH antagonist that works to directly block GnRH signaling, resulting in a more immediate decline in LH and FSH levels and testicular testosterone suppression. Discontinuation of relugolix is therefore more easily reversible, resulting in reactivation of the GnRH signaling and testosterone production within weeks.    .

GnRH agonists have been the standard of care, but it had always been a goal to try to develop drugs that could directly block the GnRH signal for 2 reasons: [first,] because of this early onset by directly blocking, you don’t have to wait for the negative feedback loop to kick in, and secondly, when we use a GnRH agonist, we actually cause accumulation of GnRH in the body and the gonadotropin-releasing hormone may have recognized effects on other parts of the body.

Over the past 15 years, we have begun to recognize that from a cardiovascular perspective, GnRH may have effects on the vasculature of arteries and plaque formation that are proinflammatory and detrimental in a subset of patients. Using a GnRH [antagonist], we’re able to directly block the signal, and by doing so, we actually shut down the production of GnRH rather than stimulating it. This may lead to a safer profile because of that fundamental difference.

The last thing that’s really unique about this drug is its oral bioavailability, which allows patients to have greater control of their therapy. Unlike other agents that require serial injections like degarelix, which has to be given on a monthly basis, the ability for patients to administer the drug at home cuts down on the number of clinic visits for patients, especially when this is given as chronic therapy, sometimes for many years. It affords patients the ability to control when we use this drug for more defined periods of time.”

What is significant about relugolix’s tolerability?

Dr. George: “The tolerability of relugolix is an important additional clinical outcome associated with this class of therapy. Based on several prior studies with degarelix, we postulate that the use of a GnRH antagonist would potentially be safer, particularly when it comes to cardiovascular risks. One of the study’s exploratory end points was to evaluate the rate of major adverse cardiac events with each treatment. These included major averse cardiovascular events [MACE] defined as strokes, heart attacks, or sudden death in patients while on treatment. What was remarkable in the HERO study was that relugolix was associated with a 54% lower risk of these major adverse cardiac events on treatment, many of which occurred within the first 90 days on treatment.

Sometimes we think about the risk for stroke and heart attack as long-term cumulative risks due to the metabolic syndrome that androgen deprivation causes, as well as increased blood pressure, weight cholesterol, and loss of muscle mass, among other effects. The fact that we could see a separation in these events so early on suggests that the result wasn’t an indirect effect of a metabolic syndrome; rather, there was some direct effect associated with the differences in the mechanism of action between a GnRH agonist and antagonist. This is supported by prior smaller studies that previously compared degarelix with androgen deprivation therapies or GnRH agonists.

Tolerability is also important because relugolix is an oral drug, and across the board, we saw in-class side effects such as hot flashes and fatigue that were similar to what we saw with GnRH agonists. If there was a difference, it was probably seen slightly in the gastrointestinal side effects, with a little bit more diarrhea and constipation associated with relugolix than what is seen with leuprolide, but no dose reductions or interruptions were needed to manage those side effects; they were all low in severity, and I think factoring the cardiovascular risks, the side effect profile favors the use of relugolix.”

What does relugolix’s status as the first GnRH antagonist approved for adults with prostate cancer mean for the prostate cancer treatment portfolio?

Dr. George: “Relugolix is now FDA approved with a broad label for advanced prostate cancer, and this affords the use of this therapy where we would otherwise use GnRH agonists. If we think about some of the settings where this will be most impactful, we can think of patients newly diagnosed with prostate cancer who are starting androgen deprivation therapy, perhaps in the setting of radiation therapy. There’s a faster onset and a more predictable recovery with less risk for cardiovascular events in that setting.

I think a second setting where relugolix would make sense is recurrent disease following prostatectomy. Some of those patients are also getting salvage radiation therapy with hormonal therapy, and again, using hormonal therapy for a defined period of time. The advantage to using relugolix here is our ability to control the onset and off and recovery to avoid medical complications.

The third setting would be newly diagnosed metastatic prostate cancer. Many of these patients are going to be starting not only androgen deprivation therapy, but also additional therapies that could increase cardiovascular risk such as chemotherapy steroids or other secondary hormonal therapies, so minimizing the risk of cardiovascular events associated with the androgen-based therapy will be critical.

It is important to recognize that being able to develop a first-in-class oral therapy is a breakthrough pharmacologically. So many of our cancer therapies today that are targeted therapies have moved to the oral therapy formulation not just in prostate cancer, but also in many of our other cancer settings, and I think this is a really important advantage for our patient population.”

Are there any future considerations for relugolix therapy that the field should be thinking about?

Dr. George: “I think going forward, it will be important to understand how relugolix will be used in combination with other drugs so we can think about what these effects on testosterone suppression might mean in some populations. If there are populations of patients where perhaps relugolix and other agents can be given for shorter, defined periods of time, we could actually improve some of the cure rates associated with prostate cancer by intensifying and then shortening the inpatient suppression period.

Then finally, we need to understand the other settings where, perhaps in the past, we have not been able to utilize an on/off biology. When it comes to castration-resistant prostate cancer, most of the time, we keep our hormonal therapies going as men enter castration resistance, not because testosterone suppression is so critical, but because it’s hard to reverse. Now that we have a drug that potentially could allow us to easily reverse the testosterone suppression in the castration-resistant setting, it may allow us to help minimize the cumulative effects of testosterone suppression that may chronically contribute to patient frailty and certainly to a decreased overall quality of life. I think that there is a lot of excitement about how an agent like this can change dogma and our paradigms in prostate cancer, and hopefully, lead to improvements that were maybe not even anticipated in the first place.”


FDA approves relugolix for advanced prostate cancer. [press release]. Silver Spring, MD; US Food and Drug Administration; December 18, 2020.

This article originally appeared on Cancer Therapy Advisor