Predictors of response for elagolix with add-back therapy in women with heavy menstrual bleeding associated with uterine fibroids

Abstract

Background: Uterine fibroids are one of the most common neoplasms found among women globally, with a prevalence of approximately 11 million women in the United States alone. The morbidity of this common disease is significant because it is the leading cause of hysterectomy and causes significant functional impairment for women of reproductive age. Factors including age, body mass index, race, ethnicity, menstrual blood loss, fibroid location, and uterine and fibroid volume influence the incidence of fibroids and severity of symptoms. Elagolix is an oral gonadotropin-releasing hormone receptor antagonist that competitively inhibits pituitary gonadotropin-releasing hormone receptor activity and suppresses the release of gonadotropins from the pituitary gland, resulting in dose-dependent suppression of ovarian sex hormones, follicular growth, and ovulation. In Elaris Uterine Fibroids 1 and Uterine Fibroids 2, 2 replicate multicenter, double-blind, randomized, placebo-controlled, phase 3 studies, treatment of premenopausal women with elagolix with hormonal add-back therapy demonstrated reduction in heavy menstrual bleeding associated with uterine fibroids.

Objective: This analysis aimed to evaluate the safety and efficacy of elagolix (300 mg twice a day) with add-back therapy (1 mg estradiol/0.5 mg norethindrone acetate once a day) in reducing heavy menstrual bleeding associated with uterine fibroids in various subgroups of women over 6 months of treatment.

Study design: Data were pooled from Elaris Uterine Fibroid-1 and Uterine Fibroid-2 studies, which evaluated premenopausal women (18-51 years) with heavy menstrual bleeding (>80 mL menstrual blood loss per cycle, alkaline hematin methodology) and ultrasound-confirmed uterine fibroid diagnosis. Subgroups analyzed included age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume (largest fibroid identified by ultrasound). The primary endpoint was the proportion of women with <80 mL menstrual blood loss during the final month and ≥50% menstrual blood loss reduction from baseline to final month. Secondary and other efficacy endpoints included mean change in menstrual blood loss from baseline to final month, amenorrhea, symptom severity, and health-related quality of life. Adverse events and other safety endpoints were monitored.

Results: The overall pooled Elaris Uterine Fibroid-1 and Uterine Fibroid-2 population was typical of women with fibroids, with a mean age of 42.4 (standard deviation, 5.4) years and a mean body mass index of 33.6 (standard deviation, 7.3) kg/m2 and 67.6% of participants being black or African American women. A wide range of baseline uterine and fibroid volumes and menstrual blood loss were also represented in the overall pooled study population. In all subgroups, the proportion of responders to the primary endpoint, mean change in menstrual blood loss, amenorrhea, reduction in symptom severity, and improvement in health-related quality of life were clinically meaningfully greater for women who received elagolix with add-back therapy than those who received placebo and consistent with the overall pooled study population for the primary endpoint (72.2% vs 9.3%), mean change in menstrual blood loss (-172.5 mL vs -0.8 mL), amenorrhea (50.4% vs 4.5%), symptom severity (-37.1 vs -9.2), and health-related quality of life score (39.9 vs 8.9). Adverse events by subgroup were consistent with the overall pooled study population.

Conclusion: Elagolix with hormonal add-back therapy was effective in reducing heavy menstrual bleeding associated with uterine fibroids independent of age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume.

Trial registration: ClinicalTrials.gov NCT02654054.

Keywords: BMI; age; elagolix; fibroid location; fibroid volume; heavy menstrual bleeding; leiomyoma; menstrual blood loss; race; subgroups; uterine fibroid; uterine volume.

Copyright © 2020 AbbVie Inc. Published by Elsevier Inc. All rights reserved.

Figures

FIGURE 1. Odds ratios for primary endpoint by factors contributing to disease severity

The odds ratios with 95% CIs are shown graphically and listed in the table to the right for each disease severity subgroup treated with elagolix with add-back. Odds ratios were determined by pooling the results from a logistic regression model including treatment and study as the main effects and baseline menstrual blood loss volume as a covariate in each data set from multiple imputation under each subgroup level. Median values for uterine and primary fibroid volumes were based on the overall median of the pooled Elaris Uterine Fibroids 1 and Uterine Fibroids 2 data set. CI, confidence interval; E2, estradiol; FIGO, International Federation of Gynecology and Obstetrics; NETA, norethindrone acetate.

FIGURE 2. Mean changes in UFS-QOL scores from baseline to month 6 for disease severity subgroups

A, The mean change in symptom severity score for each subgroup is depicted. B, The mean change in total HRQoL score for each subgroup is depicted. For symptom severity, a higher score indicates worse symptom severity. For HRQoL, a higher score indicates better quality of life. Data are presented as LS means, with error bars representing the standard error of mean. The change from baseline to month 6 in each parameter was analyzed using an analysis of covariance model with treatment as the main effect and baseline value as a covariate. Median values for uterine and primary fibroid volumes were based on the overall median of the pooled Elaris Uterine Fibroids 1 and Uterine Fibroids 2 data set. The asterisk symbol (***) indicates P<.001. FIGO, International Federation of Gynecology and Obstetrics; HRQoL, health-related quality of life; LS, least-squares; UFS-QOL, Uterine Fibroid Symptom and Health-Related Quality of Life.