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 (18e51 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/m 2 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 healthrelated quality of life were clinically meaningfully gre...

Efficacy and safety of elagolix with add-back therapy in women with uterine fibroids and coexisting adenomyosis

“…This subset analysis in women with fibroids and coexisting adenomyosis showed that elagolix with add-back therapy resulted in better quality of life than did placebo on the basis of mean improvement from baseline to month 6 in symptom severity and health-related quality of life total scores. In fact, the symptom severity and health-related quality of life scores of the adenomyosis subset after elagolix with add-back treatment were consistent with the UFS-QOL scores validated in healthy women without fibroids (mean [standard deviation]: 22.5 [21.1] and 86.4 [17.7], respectively) ( 21 ). In addition, the mean changes in the scores from baseline to month 6 were considered clinically meaningful ( 21 ).…”

“…In fact, the symptom severity and health-related quality of life scores of the adenomyosis subset after elagolix with add-back treatment were consistent with the UFS-QOL scores validated in healthy women without fibroids (mean [standard deviation]: 22.5 [21.1] and 86.4 [17.7], respectively) ( 21 ). In addition, the mean changes in the scores from baseline to month 6 were considered clinically meaningful ( 21 ).…”

“…Women in our studies with uterine fibroids and coexisting adenomyosis had smaller uterine volumes and fibroid (average and largest) volumes than those without an adenomyosis diagnosis at baseline, which is consistent with retrospective studies ( 1 , 2 ). A previous publication on these elagolix phase 3 trials demonstrated that elagolix with add-back therapy was effective in reducing heavy menstrual bleeding, irrespective of fibroid location, uterine volume, primary fibroid volume, age, body mass index, race, ethnicity, and baseline MBL ( 21 ). In parallel, here, we demonstrated that with a reduction in heavy menstrual bleeding, women with uterine fibroids and coexisting adenomyosis treated with elagolix with add-back therapy had a reduction in ultrasound-measured uterine volume from baseline to the final month, as did women without an adenomyosis diagnosis at baseline and the overall pooled study population.…”

2021 Update on abnormal uterine bleeding

“…Al-Hendy and colleagues analyzed data from the Elaris UF-1 and UF-2 trials to see if the outcomes for elagolix with hormonal addback therapy demonstrated safety and efficacy in subgroups of patients of varying ages, races and ethnicities, baseline menstrual blood loss, body mass indices, fibroid location, and uterine and fibroid volume. 5 Results. In all subgroups, they found a statistically significant reduction in blood loss in mean menstrual blood loss volume for those treated with elagolix plus hormonal addback therapy compared with those treated with placebo.…”

“…An additional data analysis from the same researchers assessed the effect of elagolix with hormonal add-back therapy in a number of patient subgroups. 5 These 3 publications have added to our knowledge of this therapy, and it is worth reviewing them in this context.…”