2021 Update on abnormal uterine bleeding
Expert perspectives on a new cryotherapy device for endometrial ablation, the importance of quality of life issues in women with fibroids, and keeping up with randomized trials of elagolix with hormonal add-back therapy
What have we learned over the past year about elagolix for uterine fibroids?
Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med. 2020;382:328-340.
Simon JA, Al-Hendy A, Archer DF, et al. Elagolix treatment for up to 12 months in women with heavy menstrual bleeding and uterine leiomyomas. Obstet Gynecol. 2020;135:1313-1326.
Al-Hendy A, Bradley L, Owens CD, et al. Predictors of response for elagolix with add-back therapy in women with heavy menstrual bleeding associated with uterine fibroids. Am J Obstet Gynecol. 2021:224-72.e1-72.e50.
Data from the Elaris UF-1 and UF-2 6-month, phase 3 trials3 and the results of the Elaris UF-EXTEND trial with a 6-month extension (totaling 12 months of use)4 were published in 2020, and the 12-month results were discussed in OBG Management (2020;32[7]:35, 39-40). 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
Design of the elagolix plus hormonal add-back therapy trials
The initial UF-1 and UF-2 trials were 2 identical, double-blind, randomized, placebo-controlled, 6-month, phase 3 trials designed to evaluate the safety and efficacy of elagolix and hormonal add-back therapy.3 UF-1 was conducted at 76 sites in the United States from December 2015 through December 2018, whereas UF-2 was conducted at 77 sites in the United States and Canada from February 2016 through January 2019; the trials were registered separately. Both trials had a 2:1:1 randomization of elagolix (300 mg twice daily) with hormonal add-back therapy (estradiol 1 mg and norethindrone acetate 0.5 mg daily), elagolix alone (300 mg twice daily), or placebo.
In the 6-month studies, the primary end point was both menstrual blood loss of less than 80 mL and at least a 50% reduction of menstrual blood loss as measured by the alkaline hematin method.3 Among several secondary end points was the assessment of QoL using the Uterine Fibroid Symptom QoL questionnaire (UFS-QoL).
Trial results. In UF-1, 68.5% of 206 women, and in UF-2, 76.5% of 189 women, respectively, taking elagolix with add-back therapy met the primary objective. Among women taking elagolix alone, in UF-1, 84.1% of 104 women, and in UF-2, 77% of 95 women, respectively, met criteria. There was improvement in UFS-QoL scores in women receiving elagolix plus add-back therapy with a reduction of symptom severity of -33.2 in UF-1 and -41.4 in UF-2, as compared with the placebo-treated groups (-10.3 and -7.7, respectively).
Adverse effects. Elagolix was associated with a low incidence of serious adverse effects, and the addition of hormonal add-back therapy attenuated the decreases in bone mineral density observed with elagolix alone. In both UF-1 and UF-2 trials, bone mineral density did not differ significantly in the groups of women who received elagolix with hormonal addback therapy versus placebo.
The extension trial results
Of note, in the 12-month study (6-month extension), the authors reported that 87.9% of the women taking elagolix with hormonal add-back therapy met the primary objective.4 Among the women taking elagolix alone, 89.4% met the primary objective.
In a review of the AbbVie-funded extension study, the editorial comments in the Obstetrical and Gynecological Survey expressed concern over the high proportion of data loss, comparing the number of patients joining the extended trial, patients who completed an additional 6 months of treatment, and patients who completed the posttreatment follow-up period of “up to 12 months.”6 Approximately one-third of patients were lost between initial enrollment to the subset who completed follow-up. There was concern that “losses of that magnitude pose a serious threat to validity.”6
Effectiveness in subgroups
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. As well, in terms of QoL, among all subgroups, the mean change in symptom severity score as well as health-related QoL total score from baseline to month 6 was statistically significantly greater than the mean change in the placebo group.
The bottom line
Elagolix with hormonal add-back therapy appears to be a safe and effective method to reduce menstrual blood loss associated with uterine fibroids. It also has a favorable effect on QoL and appears to have benefits in subgroups of women of varying ages, races and ethnicities, baseline menstrual blood loss, body mass indices, fibroid location, and uterine and fibroid volume. ●
Elagolix plus hormonal add-back therapy provides several advantages to fibroid care, including a pill form that, as a gonadotropin-releasing hormone (GnRH) antagonist, provides much quicker action than GnRH agonists. The hormonal add-back feature seems to improve QoL measures and has a favorable reported bleeding reduction rate. It also appears to be reasonably safe. Although the studies reviewed here may have some weaknesses, it helps to have another therapy to offer to women who have blood loss associated with fibroids. Deciding on the drug’s optimal clinical use has not been fully explored, as it may be a short-term solution to a long-term problem and may not be ideal for all patients with fibroids. Elagolix and hormonal add-back therapy may be advantageous for patients who need to stop bleeding quickly and are trying to decide about their reproductive plans, for patients close to menopause who need a therapy to bridge this gap, and for patients trying to obtain relief between pregnancies.
