An investigational new drug for androgen deprivation therapy (ADT) in prostate cancer has shown superiority over the standard therapy leuprolide, and could change practice once it is available, experts have suggested.
The new drug is relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist that is being developed by Myovant Sciences It is already approved in Japan for use in the treatment of uterine fibroids, but at a much lower dose.
Relugolix has the "potential to become a new standard for ADT and advanced prostate cancer," commented Neal D. Shore, MD, medical director for the Carolina Urologic Research Center, Myrtle Beach, South Carolina.
He is lead author of the phase 3 HERO trial in more than 900 patients, a study that met its primary endpoint, demonstrating that castration at 48 weeks was maintained in 96.7% of men vs 88.8% for patients using leuprolide.
Notably, relugolix also cut the risk of major adverse cardiovascular events by 54% as compared to leuprolide, he noted.
This could be an important advantage, he suggested. "The percentage of patients with prostate cancer dying of cardiovascular disease has surpassed the percentage of patients dying from prostate cancer itself since the early 1990s," Shore noted. "Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more of these patients have comorbid risk factors including obesity, diabetes, hypertension, and hyperlipidemia."
Shore presented the study results during the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) annual meeting, and they were also published simultaneously in the New England Journal of Medicine.
At the meeting, David R. Wise, MD, PhD, assistant professor of medicine and urology at Perlmutter Cancer Center at NYU Langone Health, New York City, agreed that the drug could be practice-changing — but he emphasized that it would be for a subset of patients only.
"For patients with a significant history of cardiovascular disease and without GI malabsorption, I will use this to avoid the injection site reactions commonly experienced with degarelix," said Wise, who was not involved with the HERO study.
He also cautioned that, as with any oral medication, noncompliance will be an issue, especially when used as monotherapy. "Patients will need to be monitored more frequently, with more frequent serum testosterone checks," he said.
Study Details
HERO was an international, open-label study that randomly assigned 930 patients with locally advanced or metastatic prostate cancer to receive either oral relugolix or leuprolide injection.
Patients received either relugolix (120 mg once daily after a single oral loading dose of 360 mg; n = 622) or leuprolide (22.5 mg [or 11.25 mg in Japan and Taiwan] by injection every 3 months; n = 308) for 48 weeksIn addition to meeting its primary endpoint, all key secondary endpoints showed superiority of relugolix over leuprolide (P < .001). These included the cumulative probability of castration on day 4 (56% vs. 0%) and on day 15 (98.7% vs. 12%) and of testosterone suppression to profound castrate levels (<20 15="" 1="" day="" deciliter="" ng="" on="" p="" per="" vs.="">
In addition, the percentage of patients with a confirmed PSA response at day 15 was 79.4% with relugolix and 19.8% with leuprolide (P < .001).
Cardiovascular Events
More than 90% of the patients taking part in this study had at least one cardiovascular risk factor, although those with a major adverse cardiovascular event (MACE) within 6 months of treatment were excluded from HERO.
Shore pointed out that tobacco use, obesity, diabetes, and hypertension were common in the cohort. "Fourteen percent of men reported a prior history of major adverse cardiovascular event such as a heart attack or stroke," said Shore. "This is lower than the 30% expected in a typical population of men with advanced prostate cancer given the study's cardiovascular exclusion criteria."
A cardiovascular safety analysis was prespecified in the HERO study to evaluate MACE. These were defined as nonfatal myocardial infarction, nonfatal stroke, and death from any cause. After 48 weeks of treatment, the MACE incidence was 2.9% in the relugolix group and 6.2% in the leuprolide group.
In men without a history of MACE, who comprised about 85% of the population, the odds of having a MACE event increased by 50%. Among those with a history of MACE, the risk of an event was 3.6% in the relugolix group compared with 17.8% in the leuprolide group.
"This reflected an almost fivefold increase in odds of having a MACE event in men with a prior history treated with leuprolide compared with relugolix," said Shore.
The most common adverse events in both groups were consistent with the known consequences of ADT, including hot flashes (54.3% in the relugolix group and 51.6% in the leuprolide group). Diarrhea was reported in a higher percentage of patients in the relugolix group (12.2%) than in the leuprolide group (6.8%), but cases were mild (grade 1 or 2). Fatal events were rare, and were reported for 1.1% of the patients in the relugolix group and 2.9% of those in the leuprolide group.
Agonist or Antagonist?
In an accompanying editorial, Celestia Higano, MD, from the University of Washington's Seattle Cancer Care Alliance, highlighted the issue of cardiovascular side effects of ADT.
ADT with a GnRH agonist (such as leuprolide) and the addition of newer, second-generation androgen-signaling blockers to ADT, have been shown to increase cardiovascular events in men with preexisting cardiovascular disease.
"When considered together, these trials raise the question of whether the use of a GnRH antagonist, either oral or subcutaneous, might result in improved cardiovascular outcomes, especially for those at highest risk," writes Higano. "To that end, it might be time to consider treating men who have preexisting cardiovascular risk factors with a GnRH antagonist rather than an agonist."
Although no level 1 outcome data exist for the superiority of a GnRH antagonist over a GnRH agonist for cardiovascular events or death from cardiovascular causes, the testosterone-suppression data for GnRH antagonists are level 1.
"Therefore, it is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist, and may be beneficial in terms of cardiovascular events that may be life-limiting," she writes.
The study was funded by Myovant Sciences.
Shore has disclosed relationships with Myovant, Amgen, Astellas Pharma, AstraZeneca, Bayer, Dendreon, Ferring, Genentech/Roche, Janssen, Medivation/Astellas, Merck, Pfizer, and Tolmar. Higano has disclosed relationships with Aragon, Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Carrick Therapeutics, Clovis, Dendreon, eFFECTOR Therapeutics, Emergent, Ferring, Genentech, Hinova Pharma, Hoffmann-La Roche, Janssen, Medivation, Novartis, Pfizer, Merck, Orion, and Tolmar. Wise has disclosed relationships with Onclive, Pfizer, Alphasights, Foundation Medicine, GLG, Guidepoint Global, Leap Therapeutics, and Silverlight.
American Society of Clinical Oncology 2020 Annual Meeting: Abstract 5602. Presented May 31, 2020.
N Eng J Med. Published online May 29, 2020. Abstract
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