Relugolix Continues to Showcase Encouraging Efficacy, Safety in Advanced Prostate Cancer

Neal D. Shore, MD, FACS, spotlights relugolix, a novel, gonadotropin-releasing hormone antagonist, that shows great promise in the advanced prostate cancer armamentarium.

With sustained testosterone (T)-suppression and a 54% reduction in the risk of major adverse cardiovascular effects (MACE), relugolix, a novel, gonadotropin-releasing hormone (GnRH) antagonist, shows great promise in the advanced prostate cancer armamentarium, according to Neal D. Shore, MD, FACS.

Moreover, he added, a once-daily, oral therapy would be extremely beneficial—especially during the coronavirus disease 2019 (COVID-19) pandemic.

In the global, randomized, open-label, phase 3 HERO trial (NCT03085095), relugolix demonstrated superiority over leuprolide (Lupron) in terms of sustained T-suppression through 48 weeks, rapid T-recovery following discontinuation, and a 54% reduction in risk of MACE in patients with advanced prostate cancer.

Notably, 96.7% (95% CI, 94.9%-97.9%) of patients on relugolix achieved and maintained castration through 48 weeks compared with 88.8% of those on the leuprolide arm, meeting the primary end point of the study. All key secondary end points demonstrated superiority over leuprolide as well (P < .0001).

Regarding safety, adverse events (AEs) occurred in more than 10% of patients in both arms, including hot flash, fatigue, constipation, diarrhea, arthralgia, and hypertension. MACE occurred in 2.9% of patients on the relugolix arm and in 6.2% of patients on leuprolide.

“I'm very proud of the HERO trial because this strategy could help avoid cardiovascular toxicity while achieving rapid T-suppression, rapid [prostate-specific antigen], and corollary declines—all at the same time. The trial demonstrated excellent results with T levels that went below 20 ng/dL,” Shore said. “Ultimately, with this therapy, we can be more proactive in our cardio-oncology strategies, as well as in therapeutic selections in the prostate cancer space.”

In June 2020, the FDA granted a priority review designation to a new drug application for relugolix as a treatment for patients with advanced prostate cancer, based on the HERO findings.

In an interview with OncLive, Shore, medical director of the Carolina Urologic Research Center, discussed the importance of the phase 3 HERO trial and what a regulatory approval of relugolix could mean in the prostate cancer space.

OncLive: How could an approval for relugolix be impactful in prostate cancer treatment?

Shore: Relugolix is a first-in-class, oral, GnRH antagonist for men with advanced prostate cancer. Previously, there have been other perennial therapeutics; the challenge is that they're all agonists. Therefore, their mechanism of action is to create a super physiologic rise in testosterone, follicle-stimulating hormone, and luteinizing hormone before you achieve T-suppression. The corollary prostate-specific antigen (PSA) declines as well.

Therefore, there's a physiologic surge in the hormones that you're trying to lower as quickly as possible, which is what you get with a GnRH antagonist. From a mechanism of action standpoint, this is key to the function of relugolix.

Relugolix is an oral pill that is taken once daily. With the perennial formulations [of other drugs], patients are required to come in so that the health care team can mix up the formula and prepare it prior to administration. [From the standpoint of] the clinic’s time, and the patient’s time, it is clearly not as efficient as an oral therapy that is taken once daily.

Interestingly, during the time of a pandemic, a once-daily oral medication that can arrive at the patient’s doorstep is incredibly attractive when it comes to reducing infection exposure.

Another important point about this agent is that the incidence of MACE was decreased by 54% when compared with the LHRH agonist, leuprolide. We have always had an inkling that this might be the case in retrospective studies, as well as in small phase 2 studies. Ultimately, in a large, prospective, global setting, the HERO trial demonstrated that cardiovascular AEs were markedly improved with relugolix over leuprolide. This is important because patients with advanced prostate cancer have a high likelihood of concomitant cardiovascular disease.

What was the objective of the HERO trial?

The objective of this trial was to compare the oral GnRH antagonist, relugolix, that is taken once daily to 3 months of leuprolide. The primary end point was testosterone suppression through 48 weeks. At the conclusion of the study, we not only reached this by a statistical analysis, noninferiority, but also achieved superiority regarding T-suppression of relugolix over leuprolide acetate. Patients enrolled had PSA or biochemical relapse, failed surgery, radiation, or both, had newly diagnosed metastatic disease, or newly diagnosed disease with high-risk localized disease. The demographics were very well balanced in terms of age, race, geographic region, and clinical characteristics regarding baseline PSA as well as their testosterone levels.

We tried to not include patients with MACE, which is a non-fatal myocardial infarction or stroke, within a 6-month period of the study. The percentage of patients with MACE, in both arms, was about 14%. Looking at real-world analyses, many folks in the United States feel as though that can be 30% to 50%, depending on the geography within the United States.

We achieved the T-suppression end point and saw a significant improvement in cardiovascular AEs. Interestingly, within a 90-day period, 54% of patients in the relugolix arm achieved normal testosterone levels versus 3% in the leuprolide arm. That has relevance; most patients enjoyed getting their testosterone levels back to normal. Doing so obviated hot flashes, their energy level improved, and their sexual desire improved.​

Now that relugolix has been evaluated for patients who might be considering intermittent T-suppression therapy, it could be very relevant, along with patients undergoing a course of testosterone suppression for radiation therapy who want to get their T levels back to normal. A faster onset of suppression, along with a faster recovery, is what we demonstrated in the HERO trial for relugolix.

I believe this translates to a beneficial factor for patients who want that option. Clearly lowering the risk of cardiovascular AEs is extremely important, as most of the patients we treat are elderly with concomitant cardiovascular risk factors. In fact, over 90% of patients in both arms had one or more cardiovascular risk factors. As mentioned earlier, this issue around convenience and avoidance of having to come in for a perennial administration is important.

What else is important to note about the administration of this agent?

All patients like having multiple options, as do their caregivers. When we can offer a once=daily pill instead of requiring an intravenous or subcutaneous injection, we can avoid a mandated trip to the clinic to receive therapy, and we mitigate the risks associated with COVID-19 exposure.

Even just the mere convenience of taking a once-daily pill is beneficial. Further, allowing patients to go in to see their urologist, medical oncologist, radiation oncologist when a clinical evaluation is appropriate provides tremendous flexibility. I believe that this is a breakthrough in the armamentarium.

What can be done to mitigate cardiovascular events in oncology all together?

The field of cardio-oncology, across all the different cancer types, has gained a lot of traction. When we give T-suppression, we create what's described as quasi-metabolic syndrome, where we see central adiposity. With LHRH agonists, we may also see a warning relating to arrhythmia and potential QT prolongation.

We must make sure that patients are following a better heart-healthy diet, that they're regularly exercising, and that they are having their lipid panels and cholesterol levels checked. If they have diabetes, they should be under tight glucose management, and their hemoglobin A1c should be monitored. Moreover, patients should not be smoking or living a sedentary lifestyle.


Shore ND, George DJ, Saad F, et al. HERO phase III trial: results comparing relugolix, an oral GnRH receptor antagonist versus leuprolide acetate for advanced prostate cancer. J Clin Oncol. 2020;38(suppl; abstr 5602). doi: 10.1200/JCO.2020.38.15_suppl.5602.