More than 96% of men with advanced prostate cancer who were treated with relugolix, an oral, highly selective gonadatropin-releasing hormone (GnRH) antagonist, maintained castration through 48 weeks, thus confirming that the oral treatment was superior to injection with leuprolide.
The finding was reported by Neal D. Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, SC, and his fellow HERO investigators in The New England Journal of Medicine and presented at the American Society of Clinical Oncology virtual meeting.
“Testosterone suppression with relugolix was both noninferior and superior to that with leuprolide, a milestone required for ultimate regulatory approval by health authorities. Relugolix was also superior to leuprolide with respect to several secondary end points: suppression of testosterone at days 4 and 15, suppression of testosterone to less than 20 ng per deciliter (0.7 nmol per liter) at day 15, and suppression of follicle-stimulating hormone at week,” wrote Celestia S. Higano, MD, of the University of Washington, Seattle, in an accompanying editorial.
Leuprolide, which is a long-acting injectable luteinizing hormone-releasing hormone (LHRH) agonist is a standard androgen-deprivation therapy to reduce testosterone levels to castration status, but there are a number of problems: LHRH can cause an initial testosterone surge, triggering “bone pain, obstructive urinary symptoms, or, rarely, ureteral obstruction or spinal cord compression,” Shore and colleagues explained. “Desensitization and down-regulation of the luteinizing hormone–gonadal axis occur over a period of weeks, resulting in delayed suppression of testosterone levels. Hence, most guidelines recommend adding an antiandrogen agent for the first few weeks after initiation of an LHRH agonist. In addition, LHRH agonists do not fully suppress follicle-stimulating hormone (FSH), a potential mitogenic growth factor for prostate-cancer cells.”
An injectable GnRH antagonist — degarelix — is FDA approved for androgen deprivation therapy and it does suppress both luteinizing hormone and FSH, but it requires monthly injections and inject-site reactions are frequent, issues that Shore and colleagues suggest have been barriers to its use.
Against that setting, relugolix, which is given orally once a day, is an attractive option.
The HERO trial randomized 934 patients: 622 to relugolix 120 mg/daily and 308 to leuprolide injections once every 3 months. The median age of patients was 71 and roughly half (50.2%) had biochemical recurrence after definitive prostate cancer treatment.
“The mean PSA level at baseline was higher in the relugolix group (104.2 ng per milliliter) than in the leuprolide group (68.6 ng per milliliter); the median PSA values were similar in the two groups (11.7 and 9.4 ng per milliliter, respectively). More than 90% of the patients had at least one cardiovascular risk factor across the three main categories assessed, which included lifestyle risk factors such as tobacco use and obesity, cardiovascular risk factors such as diabetes and hypertension, and a history of a major adverse cardiovascular event,” the study authors wrote. “In the relugolix group, 90.2% of the patients completed 48 weeks of treatment, as compared with 89.0% in the leuprolide group. The median follow-up time in both groups, including the 30-day safety follow-up period for adverse events, was 52 weeks.”
Among the findings:
- Testosterone suppression (<50 ng/dL) were sustained from day 29 through 48 weeks in 96.7% of relugolix patients and in 88.8% of leuprolide-treated patients, for a 7.9% between group difference.
- “The lower boundary of the 95% confidence interval for the between-group difference was above zero, which showed the superiority of relugolix over leuprolide (P<0.001).”
- 79.4% of relugolix patients had a confirmed PSA response at day 15 versus 19.8% of leuprolide patients (P<0.001).
- “FSH suppression was greater with relugolix than with leuprolide at all available time points, with FSH levels in the leuprolide group increasing after day 29 until the end of the trial.”
- 1.1% of relugolix patients and 2.9% of leuprolide patients died during the trial.
- A prespecified analysis of major cardiovascular events (heart attack, stroke, and death due to cardiovascular disease) favored relugolix: 2.9% versus 6.2%, thus the estimated incidence rate was “consistent with a 54% lower risk (hazard ration, 0.46; 95% CI 0.24-0.88) in the relugolix group than in the leuprolide group.”
In the editorial, Higano emphasized the importance of the cardiovascular safety findings, noting that, in a HERO subgroup analysis of men with a confirmed history of cardiovascular events, “the incidence was 3.6% in the relugolix group and 17.8% in the leuprolide group, indicating that the risk differed by a factor of 4.8.”
As expected, testosterone initially surged in the leuprolide group to a level of “625 ng per deciliter at day 4 in the leuprolide group before decreasing to castrate levels at day 29 and remaining at castrate levels thereafter. Mean testosterone levels at 90 days after treatment discontinuation in the testosterone recovery subgroup (184 patients) were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group. The percentage of patients with testosterone recovery to at least 280 ng per deciliter (the lower limit of the normal range) at 90 days was 54% in the relugolix group and 3% in the leuprolide group (nominal P=0.002).”
Finally, Shore and colleagues noted that although there is a concern about adherence to oral therapies, “adherence with oral relugolix was more than 99% and similar to that of injectable leuprolide. These findings are consistent with reported real-world adherence rates for the oral androgen axis–directed therapies used in castration-resistant prostate cancer, which have shown adherence rates of 92 to 96%.
“In the HERO trial, the oral GnRH antagonist relugolix showed sustained testosterone suppression superior to that of leuprolide and a 54% lower risk of major adverse cardiovascular events than with leuprolide,” they concluded.
Be aware that in this randomized trial, novel oral, highly selective GnRH antagonist, relugolix, was shown to be both noninferior and superior to injection with leuprolide for treatment of men with advanced prostate cancer.
Note that relugolix-treated men had a 54% lower risk of major adverse cardiovascular events than men treated with leuprolide.
Peggy Peck, Editor-in-Chief, BreakingMED™
The HERO trial was funded by Myovant Sciences.
Shore reported grants and personal fees from Amgen, grants and personal fees from Astellas, grants and personal fees from AstraZeneca, grants and personal fees from Bayer, grants and personal fees from Dendreon, grants and personal fees from Ferring, grants and personal fees from Janssen, grants and personal fees from Merck, grants and personal fees from Pfizer, grants and personal fees from Sanofi- Genzyme, grants and personal fees from Tolmar, grants and personal fees from BMS, grants and personal fees from Myovant, and grants and personal fees from Nymox outside the submitted work.
Higano reported grants from Aragon, grants and personal fees from Astellas, grants from AstraZeneca, grants and personal fees from Clovis, grants from Dendreon, grants from eFFECTOR Therapeutics, grants from Emergent, grants and personal fees from Ferring, grants and personal fees from Genentech, grants from Hoffman-Laroche, grants from Medivation, grants and personal fees from Pfizer, grants and personal fees from Bayer, personal fees from Blue Earth Diagnositics, personal fees from Dendreon, personal fees from Hinova, personal fees from Janssen, personal fees from Merck, personal fees from Orion, personal fees from Tolmar, personal fees from Carrick Therapeutics, personal fees from Novartis, and grants from Memorial Sloan Kettering/Bayer outside the submitted work.
Cat ID: 122
Topic ID: 78,122,730,122,25,935,192,241,73,172