Oral gonadotropin-releasing hormone receptor antagonist shows benefits

HERO, the phase 3 clinical trial investigating relugolix for the treatment of advanced prostate cancer, met its primary end point showing that the oral gonadotropin-releasing hormone (GnRH) antagonist provided sustained testosterone suppression to castrate levels through 48 weeks of follow-up.

The FDA recently granted a priority review designation to a new drug application for relugolix for the treatment of patients with advanced prostate cancer, according to Myovant Sciences, the manufacturer of the oral GnRH receptor antagonist.

Additional findings from the randomized, controlled study (NCT04352946) showed that men treated with relugolix achieved faster and more sustained testosterone suppression than the control group treated with subcutaneous leuprolide and had a markedly lower risk of having a major adverse cardiovascular event (MACE), said Neal D. Shore, MD.

Shore presented data from HERO as a late-breaking abstract for the 2020 American Urological Association virtual meeting. He is the lead author of an article reporting the study’s findings that was published online in the New England Journal of Medicine on May 29, 2020.¹

“Prostate cancer is the most common cancer diagnosis in the United States, and cardiovascular mortality is the leading cause of death among patients with prostate cancer. Luteinizing hormone-releasing hormone receptor agonists, such as leuprolide, that are used for androgen deprivation therapy [ADT] in advanced prostate cancer have several drawbacks. They are associated with an early testosterone surge, do not fully suppress follicle-stimulating hormone [FSH], which may be a mitogen for cancer cells, and since 2011 have carried an FDA mandated label warning about an increased risk of myocardial infarction, sudden cardiac death, and stroke,” said Shore, the medical director at Carolina Urologic Research Center in Myrtle Beach, South Carolina.

“Through a direct inhibitory effect on pituitary GnRH receptors, relugolix more completely suppresses both luteinizing hormone and FSH compared with leuprolide, and relugolix avoids an early testosterone surge. Based on the results of HERO, relugolix has the potential to become a new standard for ADT in men with advanced prostate cancer.”

HERO is a multinational, open-label trial that randomized 934 men 2:1 to treatment with relugolix (360 mg on day 1, then 120 mg once daily) or subcutaneous leuprolide 22.5 mg (11.25 mg in Japan and Taiwan) every 3 months. Eligible men had confirmed advanced prostate cancer with a biochemical or clinical relapse, newly diagnosed metastatic disease, or advanced localized disease and were deemed as candidates for at least 1 year of ADT. Men with a history of MACE within the prior 6 months were excluded.

The relugolix and leuprolide patient groups were well-balanced at entry in their demographic and clinical characteristics. Approximately 90% of men in both arms completed the 48-week
trial, and the treatment compliance rate was 99% in both groups.

More than 90% of men in each treatment arm had at least 1 cardiovascular risk factor, and approximately 14% had a history of MACE.

“Approximately 30% of men with advanced prostate cancer would be expected to have a history of a MACE. The lower rate in HERO reflects the study’s exclusion criteria,” Shore noted.

Relugolix demonstrates noninferiority, superiority to leuprolide

The primary end point analysis showed that 96.7% of men treated with relugolix and 88.8% of the control group achieved sustained suppression of testosterone to castrate levels (< 50 ng/dL) from day 29 through week 48. In statistical analyses, relugolix demonstrated both noninferiority and superiority to leuprolide.

Relugolix also demonstrated statistically significant superiority compared with leuprolide in all key secondary end points, which included measures of onset of prostate specific antigen response and testosterone suppression, FSH reduction, and sustained castration rates (P <.0001 for all end points), Shore said.

“By day 4, 56% of men treated with relugolix achieved testosterone suppression to castrate levels. In the leuprolide arm, the testosterone level showed the expected initial surge, reaching a mean of 625 ng/mdL, and the mean did not fall to castrate levels until day 29,” he reported.

A substudy investigating testosterone recovery showed that by day 90 after treatment was stopped, serum testosterone returned to the normal range in the relugolix group (mean, 288 ng/dL), but the mean testosterone level was just 58.6 ng/dL in the leuprolide group. At day 90, 54% of relugolix-treated patients versus just 3% of leuprolide-treated ones achieved testosterone recovery, Shore reported.

In both study groups, > 90% of men experienced at least 1 adverse event (AE). The rate of a grade 3 or higher AE was 18% in the relugolix group and 20.5% in the leuprolide group. The fatal AE rate in the relugolix and leuprolide groups was 1.1% and 2.9%, respectively.

“The known consequences of ADT, including hot flashes, were the most common adverse events in both groups. The rate of diarrhea was higher in the relugolix group, but these events were mild or moderate and did not lead to treatment discontinuation,” Shore said.

The HERO protocol included a prespecified analysis of MACE, which included nonfatal myocardial infarction, nonfatal stroke, and death from any cause. At 48 weeks, MACE rates were 2.9% in the relugolix group and 6.2% in the leuprolide group. A Kaplan-Meier analysis of cumulative MACE incidence over the 48-week treatment period showed a 54% risk reduction in the relugolix group relative to the leuprolide group.

“The MACE event rate was almost 6-fold higher in the leuprolide group compared with the relugolix group among men with a history of MACE (17.8% vs 3.6%) and was 50% higher in the leuprolide group compared with the relugolix group in men without a history of MACE (4.2% vs 2.8%),” Shore said.

Disclosure: Myovant Sciences provided funding for the study. Dr Shore does research for and is a consultant to AbbVie, Ferring Pharmaceuticals, Myovant Sciences, and Tolmar.

Reference

1. Shore N, Saad F, Cookson M et al. Oral Relugolix for androgen-deprivation therapy in advanced prostate cancer. N Eng J Med 2020; 382(23):2187-2196. doi:10.1056/NEJMoa2004325