Shore Shares Promise of Relugolix for T-Suppression in Advanced Prostate Cancer

Relugolix is slated to become the new standard for testosterone (T)-suppression in advanced prostate cancer, and importantly, according to Neal D. Shore, MD, FACS, the toxicity data indicate that the agent is safe and well tolerated.

Results from the global, pivotal phase 3 HERO trial (NCT03085095) showed that relugolix showed superiority over leuprolide (Lupron) in sustained T-suppression through 48 weeks, rapid T-recovery following discontinuation, and a 50% reduction in major adverse cardiovascular events in patients with advanced prostate cancer.

Overall, 96.7% of patients who received relugolix achieved and maintained castration through 48 weeks versus 88.8% of those who were given leuprolide; the difference of 7.9% showed noninferiority (margin -10%) and superiority (P <.0001) of relugolix to leuprolide. All key secondary end points tested also demonstrated superiority over leuprolide, according to Shore.

Importantly, in the prespecified analysis, the incidence of major adverse cardiac effects (MACE) was reported to be lower in the relugolix arm at 2.9% versus 6.2% in the leuprolide arm.

“In 2011, the FDA put a warning on LHRH agonists regarding the cardiovascular toxicity issues. There have been prior retrospective analyses and publications on a recent phase II study that has further brought attention to this concern of cardiovascular toxicity,” said Shore. “I'm proud that, in the phase 3 trial that we published and presented, we’ve given great evidence on the differential between antagonists and agonist therapy, particularly, cardiovascular toxicity risk for elderly males [with prostate cancer].”

In an interview with OncLive, Shore, the medical director of the Carolina Urologic Research Center, further discussed the pivotal HERO trial, the promising safety data observed with relugolix, and the next steps for the agent in advanced prostate cancer.

OncLive: Could you provide some background on relugolix and what makes it unique?

Shore: First, we previously performed 2 phase 2 studies that looked at the molecule relugolix, which is a rather unique, oral, once-daily GnRH antagonist. Historically, the mechanism of action of an antagonist has been designed to avoid testosterone surge and potential clinical flare of symptoms. [Relugolix] has a superior conceptual mechanism of action versus traditional LHRH agonists. Even though a parenteral version of a GnRH antagonist has been available since 2009, this is the first time we could reach potential regulatory approval by way of conducting a phase 3 study of a once-daily oral GnRH antagonist. In addition to looking at the end point of testosterone suppression, we also examined testosterone recovery, and very importantly, the potential for adverse cardiovascular events. Notably, [we have seen] a prior signal that antagonist formulations don't have the same likelihood of these cardiovascular toxicities as the agonist formulations.

What was the design of the HERO trial and what was the goal of this research?

The phase 3 HERO study was a multinational, open-label, parallel group designed to evaluate the safety and efficacy of relugolix in men with advanced prostate cancer. Over 900 patients were enrolled on this global study. Patients were randomized 2:1 to receive either the once-daily relugolix versus 3-month intradermal or subcutaneous leuprolide. The primary end point was monitoring testosterone suppression through week 48. We had numerous hierarchical secondary end points. We also looked at testosterone recovery in a subset of approximately 184 patients.

What were the findings of this trial?

We initially looked at the testosterone suppression through 48 weeks. In the relugolix arm, we reported 96.7% testosterone suppression with a definition of 50 ng/dL as the threshold and 88.8% in the leuprolide arm. The difference between the groups was 7.9% and the lower-bound confidence interval was met, at a -10% noninferiority margin. In effect, that allowed us to claim superiority of the testosterone suppression [with relugolix] through week 48.

We then looked at all of our key secondary end points, which included testosterone suppression that we described as profound or below 20 ng/dL at day 15, as well as levels of testosterone suppression throughout the study. Additionally, we looked at the corollary prostate-specific antigen responses and the mean FSH levels at week 24. When looking at these secondary end points, relugolix was better than the leuprolide arm; the P values for all those end points were [determined to be] highly statistically significant.

In our testosterone suppression recovery analysis at week 49, when patients stopped leuprolide or relugolix, 54% of patients by 90 days in the relugolix arm achieved eugonadal levels of testosterone as opposed to only 3% on the leuprolide arm. As such, the testosterone recovery was markedly better [with relugolix], and we demonstrated this in our previous phase 2 studies as well.

Could you shed light on the safety profile of the agent?

For years now, we've recognized that testosterone suppression is not a “free lunch, “as we say in the vernacular; it clearly lessens prostate cell adenocarcinoma progression, but there are significant associated adverse effects that are well known to everyone who treats these patients. The cardiovascular events and the all-cause mortality that is related cardiovascular versus prostate cancer, has been known to be rather striking in this elderly male population.

When we looked at cardiovascular events, we found that 7.1% of patients on the leuprolide arm experienced cardiovascular events versus 3.9% in the relugolix arm. When we looked at major adverse cardiovascular events (MACE), these events were reported in 6.2% of the leuprolide arm and 2.9% in the relugolix arm. We presented at the meeting and in our recently published New England Journal of Medicine article, a 54% reduction in the risk of major adverse cardiovascular events [with relugolix].

What are the next steps for this research?

A new drug application [for relugolix] has been submitted to the FDA. I'm certainly optimistic and hopeful that the drug may see approval and availability in the United States before the end of 2020.

If this drug does become available, how do you think it's going to be best used?

Over the years, we've had LHRH agonists coming in different formulations; this started back from daily to monthly to every 3 months, 4 months, 6 months, and even annually. Those LHRH agonists can be given subcutaneously or intramuscularly. We also have an antagonist that was approved that is given subcutaneously on a monthly basis. Now, we will potentially have an option of an oral pill, given once a day, with or without food. This provides us with a great opportunity to consider flexibility in terms of administration of a testosterone suppressive medication.

Reference:

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 15):5602. doi:10.1200/JCO.2020.38.15_suppl.5602