Is elagolix, an oral gonadotropin-releasing hormone antagonist, a safe and effective treatment for endometriosis?

This industry-sponsored trial (really a summary report of 2 trials) found that the oral gonadotropin-releasing hormone (GnRH) antagonist elagolix reduced menstrual and nonmenstrual pain, but also frequently caused hot flushes, increased low-density lipoprotein (LDL) cholesterol levels, and decreased bone mineral density. Both the benefits and harms were greater in women who took a higher dose. The high dropout rate is concerning, and long-term follow-up to assure that women do not experience cardiovascular or bone-related harms is important. Overall, this drug should be reserved as a second-line choice for women with moderate to severe pain, and women should attempt at least a 3-month trial at the lower dose before considering the higher dose. (LOE = 1b)

Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med 2017;377(1):28-40.  [PMID:28525302]

Randomized controlled trial (double-blinded)

Industry

Concealed

Outpatient (any)

Injectable long-acting GnRH antagonists like leuprolide are second-line therapies for endometriosis, after nonsteroidal anti-inflammatory drugs and progestin containing oral contraceptives. Elagolix is a new oral GnRH antagonist, and this study reports the results of 2 nearly identical trials. Both studies recruited premenopausal women, aged 18 to 49 years, with surgically diganosed endometriosis and moderate or severe pain. Women were recruited at 338 sites around the world, with each site recruiting an average of 5 women. All of the women (872 in trial 1, and 817 in trial 2) were randomized in a 2:2:3 ratio to receive either low-dose elagolix (150 mg once daily), high-dose elagolix (200 mg twice daily), or placebo. The groups were balanced, and analysis was by modified intention to treat. The study was designed with a washout period, during which women were tapered off any current hormonal therapies, and when their breakthrough pain medication was standardized to naproxen plus an opiate such as hydrocodone 5 mg plus acetaminophen. Patients were treated for 6 months, and the researchers measured menstrual and nonmenstrual pelvic pain using scales from 0 to 3, with reduction of 0.81 to 0.85 points for dysmenorrhea and 0.36 to 0.43 points for nonmenstrual pain judged to be a clinically significant response. The primary outcomes were defined as (1) dysmenorrhea at 3 months, (2) nonmenstrual pelvic pain at 3 months, and (3) decreased (or stable) use of rescue analgesic agents. Only approximately 75% of women completed their assigned treatment. The dropout rates were generally similar between the 6 treatment groups (between 21% and 27%) and were largely due to adverse events, loss to follow-up, withdrawal of consent, and noncompliance. The primary outcome of menstrual pain at 3 months was observed in approximately 75% in the high-dose groups, 45% in the low-dose groups, and 20% in the placebo groups (the exact percentages differed slightly between the 2 studies). These differences were statistically significant, and represent a number needed to treat of 2 for the high-dose groups and 4 for the low-dose groups. There was less difference between low- and high-dose groups regarding nonmenstrual pelvic pain, with reponse rates of approximately 56%, 50%, and 36% respectively, in the high-dose, low-dose, and placebo groups. Again, these were statistically significant, with a number needed to treat of 5 for high dose and 7 for low dose. The reductions in pain scores were maintained at 6 months, based on a review of the survival curves in the online appendix. Pain due to dyspareunia was reduced at 3 months in women receiving the higher dose only, although it is unlikely that a 0.2-point reduction on a 4-point scale is clinically meaningful. Approximately 10% of women in the high-dose group withdrew due to adverse events compared with about half that rate in the placebo and low-dose groups. Hot flushes were reported by approximately 45% of women in the high-dose group, 22% in the low-dose group, and 10% in the placebo group. The drug also increased LDL cholesterol levels and decreased bone density, especially in the high-dose groups.