Elagolix with add-back therapy reduces heavy menstrual bleeding

The combination of elagolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, with hormonal add-back therapy significantly reduces heavy menstrual bleeding (HMB) in premenopausal women with uterine fibroids, according to two phase III studies.

Elaris Uterine Fibroids 1 and 2 (UF-1; n=412 and UF-2; n=378) were two identical, double-blind, placebo-controlled, phase III trials that evaluated women (aged 18–51 years) with HMB* associated with uterine fibroids. Participants were randomly assigned to receive elagolix 300 mg twice/day with hormonal add-back therapy once/day (oestradiol 1 mg and norethindrone acetate 0.5 mg), elagolix alone twice/day, or placebo for a 6-month treatment period. Alkaline hematin method was used to measure the amount of menstrual blood loss. The primary endpoint for both studies was menstrual blood loss of <80 mL at 6 months and ≥50 percent reduction in menstrual blood loss from baseline to 6 months. [N Engl J Med 2020;382:328-340]

In both trials, a significantly higher percentage of women treated with elagolix + add-back therapy achieved a greater decrease in menstrual blood loss than those treated with placebo at 6 months (68.5 percent vs 8.7 percent; p<0.001 in UF-1 and 76.5 percent vs 10.0 percent; p<0.001 in UF-2).

A greater reduction in menstrual blood loss was also observed among women who received elagolix alone compared with placebo in UF-1 (84.1 percent vs 8.7 percent) and UF-2 trials (77.0 percent vs 10.0 percent).

However, those on elagolix alone demonstrated a greater reduction than those on elagolix with add-back therapy in terms of bone mineral density (BMD) at the lumbar spine (mean change from baseline, -2.95 vs -0.76 and -2.94 vs -0.61 for UF-1 and UF-2, respectively), total hip (mean change from baseline, -2.12 vs -0.15 and -1.80 vs -0.12, respectively), and femoral neck (mean change from baseline, -2.46 vs -0.83 and -1.19 vs -0.39, respectively).

Although a higher incidence of any adverse events (AEs) was observed among women on elagolix with add-back therapy in UF-2 (75.7 percent vs 63.0 percent; p<0.05) and elagolix alone in UF-1 (90.4 percent vs 71.0 percent; p<0.001) than those on placebo, most AEs were considered mild or moderate in severity, the researchers noted.

Hot flushes occurred more frequently in the elagolix with add-back therapy and elagolix alone arms vs the placebo arm in UF-1 (20.4 percent vs 8.8 percent; p<0.01 and 64.4 percent vs 8.8 percent; p<0.001, respectively) and UF-2 (19.6 percent vs 4.0 percent; p<0.001 and 43.0 percent vs 4.0 percent; p<0.001, respectively).

Metrorrhagia was also significantly more frequent among women on elagolix + add-back therapy than those on placebo in UF-1 (6.3 percent vs 0.0 percent; p<0.01).

“[Nevertheless,] elagolix was associated with a low incidence of serious AEs; none of these events were related to drug-induced liver injury, and there were no clinically meaningful endometrial abnormalities,” noted the researchers.

“[Moreover,] elagolix with add-back therapy attenuated decreases in BMD [as] seen with elagolix alone treatment, … [wherein] the decreases from baseline in BMD that occurred in women who received elagolix alone were significantly greater than in those who received elagolix with add-back therapy … [or placebo],” said the researchers, who added that this finding was “consistent with the results of other trials of GnRH analogues”. [Hum Reprod 1994;9:1618-1625]

“[In conclusion, both UF-1 and UF-2 trials showed that] elagolix with add-back therapy was effective in reducing [the risk of] HMB in [premenopausal] women with uterine fibroids,” they said.

*HMB: Defined as >80 mL of menstrual blood loss per menstrual cycle for ≥2 separate cycles