Neal D. Shore, MD, discusses the FDA approval of relugolix in prostate cancer.
Relugolix (Orgovyx) rapidly suppresses testosterone (T) levels in men with advanced prostate cancer with a markedly lower risk of cardiovascular events than leuprolide, paving the way for a new hormonal therapy for this population. In December 2020, the drug became the first oral gonadotropin-releasing hormone (GnRH) receptor antagonist to gain FDA approval.1
The FDA approved relugolix based on data from the phase 3 HERO trial (NCT03085095) in men who required at least 1 year of androgen deprivation therapy (ADT) with either prostate cancer recurrence following radiation or surgery or newly diagnosed castration-sensitive advanced disease. Participants were randomly assigned to a loading dose of oral relugolix 360 mg on the first day followed by daily doses of 120 mg or 22.5 mg of leuprolide, a luteinizing hormone-releasing hormone (LHRH) agonist, administered via subcutaneous injection every 3 months for 48 weeks.1
Investigators found that 96.7% (95% CI, 94.9%-97.9%) of patients who received relugolix (n = 622) achieved and maintained serum T at castration levels (< 50 ng/dL) through 48 weeks compared with 88.8% (95% CI, 84.6%-91.8%) of those who received leuprolide (n = 308).2 Further, relugolix was associated with a significant reduction in major adverse cardiovascular events (MACE) compared with leuprolide in patients with advanced disease after 48 weeks of treatment (2.9% vs 6.2%, respectively).2
Currently available medical ADT options, which include LHRH agonists such as leuprolide and goserelin, have been a mainstay of treatment for men with advanced prostate cancer but are only available in injectable formulations and are associated with an elevated risk of cardiovascular disease, according to an FDA reviewed of the relugolix application. Degarelix (Firmagon), the only GnRH receptor antagonist available for prostate cancer treatment in the United States before the relugolix approval, also is an injectable formulation.3
In an interview with OncLive®, Neal D. Shore, MD, lead investigator for the HERO trial, explained how relugolix could affect the standard of care for men with advanced prostate cancer. Shore is medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina. In early January 2021, he prescribed relugolix for the first time post approval to treat a 77-year-old man with advanced disease who displayed cardiovascular risk factors.
Shore: At the end of 48 weeks, we looked at testosterone recovery in roughly 184 patients in both arms who finished treatment. Fifty-three percent of the relugolix patients were back to normal testosterone levels, ostensibly eugonadal, and only 3% of the LHRH agonist patients were back to being eugonadal at 90 days. This is really a nice advantage—the faster recovery for patients who may consider intermittent ADT or who may be on a shorter course of 6 to 12 months for adjuvant/neoadjuvant radiation therapy strategies.
This is the only oral testosterone suppressive medication demonstrated in a phase 3 global trial to have met the efficacy end point of T suppression compared with the traditional LHRH agonist.
Now patients can receive an oral treatment, 1 pill once a day, instead of an intramuscular or subcutaneous injection. So there’s an obvious convenience for many patients. And, during a pandemic, I think it’s really nice that patients don’t have to come in and receive an injection—whether it’s intramuscular or subcutaneous. They don’t get exposed to infection and neither do the clinic staff.
We’ve been debating this issue for many years: How important is it to get testosterone suppression not just below 50 ng/dL, but below 20 ng/dL? And, also to do it very rapidly with the corollary PSA [prostate-specific antigen] declines? We met all of these in our secondary end points in a highly statistically significant way. In addition to meeting our primary and secondary end points of testosterone suppression in a convenient 1-pill-per-day dose, we met all the secondary end points of profound T suppression and with corollary PSA declines.
When we looked at the safety analysis, we saw that the patients in the relugolix arm had fewer cardiovascular complications. In fact, we demonstrated a decrease of 54% compared with the LHRH agonist arm. This was a prespecified safety analysis. More than 90% of patients who start ADT―this was true in our study and has been observed in many other studies―have at least 1 cardiovascular risk factor. They may have hypertension, dyslipidemia, glucose dysregulation, prior myocardial infarctions [MI], or cerebrovascular events.
In particular, as it relates to MACE, we purposely excluded patients who had had a MACE, a nonfatal MI or cerebrovascular accident, or arrhythmia within 6 months of screening. Thus, we reduced the number of patients who had had a MACE to about 14% of those enrolled. That number at baseline is probably somewhere from 30% to 40%, depending upon where you practice.
Nonetheless, even though we purposefully reduced the number of patients who had a MACE, we demonstrated in those patients who received relugolix versus an LHRH agonist the likelihood of getting another MACE was approximately 5 times higher in the LHRH agonist arm.
I think that relugolix fits in the treatment decision making for all patients with prostate cancer who would benefit from testosterone suppression. The patient’s health care provider, whether it’s a medical oncologist, urologist, or radiation oncologist, should be fully aware of the approval of relugolix and why you would want to have a discussion regarding it versus an LHRH agonist or GnRH antagonists that are given parenterally. Patient-physician shared decision-making is key to optimizing cancer care.