By Rebecca H. Allen, MD, MPH, Editor
SYNOPSIS: In this prospective, open-label, single-arm trial of 149 individuals with heavy menstrual bleeding and uterine leiomyomas, daily relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg) resulted in a mean menstrual blood loss reduction of 90%, and 70% of the participants achieved amenorrhea by the end of the 52-week period. Similar results were found for other arms of the trial among women who crossed over from placebo and relugolix-only therapy to relugolix combination therapy.
SOURCE: Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al. Long-term relugolix combination therapy for symptomatic uterine leiomyomas. Obstet Gynecol 2022;140:920-930.
Uterine leiomyomas are common and can cause heavy menstrual bleeding and pelvic pain and pressure symptoms. The combination therapy of relugolix 40 mg (a gonadotropin-releasing hormone [GnRH] antagonist) estradiol 1 mg, and norethindrone acetate 0.5 mg, has been approved in the United States to treat heavy menstrual bleeding associated with uterine fibroids and the pain of endometriosis. This trial reported on the long-term safety and efficacy of this treatment for uterine leiomyomas up to 52 weeks.
This was a multinational, open-label, single-arm trial that enrolled premenopausal women aged 18 to 50 years with heavy menstrual bleeding (80 mL or greater per cycle for two cycles or 160 mL or greater for one cycle) associated with uterine fibroids diagnosed via ultrasound. Patients who already had completed 24 weeks of the study were eligible to enroll in the extended trial. There were three original groups in the study: 1) those who received relugolix combination therapy for the entire study duration; 2) those who started with relugolix alone for 12 weeks and then went to relugolix combination therapy; and 3) those who started with placebo for 24 weeks and then crossed over to relugolix combination therapy.
Participants were monitored every four weeks and the primary endpoint was the proportion who achieved or maintained a menstrual blood loss of less than 80 mL and at least a 50% reduction in menstrual blood loss volume from baseline to the end of the study as measured by the alkaline hematin quantification method. Other clinical data were collected, including age, race, baseline uterine leiomyoma volume, body mass index (BMI), hemoglobin level, and bone mineral density, as well as several validated questionnaires, such as the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) scale, Bleeding and Pelvic Discomfort (BPD) scale, and Health-Related Quality of Life scale.
A total of 477 (78%) eligible participants enrolled in the extended study and 363 (76%) completed 52 weeks. Baseline patient characteristics were similar between the study groups. The group receiving relugolix combination therapy continuously for 52 weeks (n = 149) had a response rate of 87.5% for the primary outcome. The mean percent reduction in menstrual blood loss was 90%, with efficacy seen as early as week 4 and sustained through 52 weeks, and 70% of the patients achieved amenorrhea. There also were documented improvements in the BPD and UFS-QOL scale scores. Uterine leiomyoma volume also decreased by 18%. The group starting with relugolix alone and then switching to combination therapy (n = 163) had a response rate of 80%. The group starting with placebo and then crossing over to combination therapy (n = 164) had a response rate of 75.6%. Treatment effect was independent of race, BMI, baseline menstrual blood volume, and baseline uterine leiomyoma volume.
The most frequently reported adverse events were hot flashes and headaches. There were few serious adverse events in the groups. Bone mineral density did not substantially change (baseline to 52 weeks, -0.80% in the lumbar spine), since patients with substantial changes (a decrease of 7% or more) in the first 24 weeks were excluded from the extension study (n = 40).
COMMENTARY
The authors of this study previously had demonstrated that relugolix combination therapy was effective for the treatment of heavy menstrual bleeding associated with uterine fibroids, leading to U.S. Food and Drug Administration (FDA) approval for this indication.1 This extension study up to one year showed that the results were sustained over time and well tolerated. The study certainly is limited by the fact that only a subset of the original trial participants enrolled in the extension study, introducing selection bias. Indeed, patients who were tolerating the treatment well and seeing improvements in their clinical symptoms obviously would be more likely to continue. However, this is similar to what would happen in the real-world setting, where patients try a medicine to see if it works for them and may or may not continue. However, the current label for the study medication does limit its use to 24 months because of potential bone loss.
Current medical treatment options for heavy menstrual bleeding associated with uterine leiomyomas include nonsteroidal anti-inflammatory drugs, hormonal contraceptives such as combined oral contraceptives, oral progestins, the 52-mg levonorgestrel intrauterine device if the uterine cavity is not distorted, and tranexamic acid.2 GnRH antagonists are a new medication option for patients, and two of them, relugolix and elagolix, are approved for use in the United States. GnRH antagonists competitively bind to pituitary GnRH receptors and suppress gonadotropins and, in turn, ovarian production of estrogen and progesterone. Because of this, they can be associated with hypoestrogenic effects and often are given with estrogen and progestin add-back therapy to mitigate these effects (such as hot flashes and bone loss).
Nevertheless, there is an estrogen-threshold hypothesis where the goal is to lower estrogen concentrations enough to reduce leiomyoma growth, but not so much as to cause these hypoestrogenic adverse effects, so a balance must be struck.1 Similar to relugolix, elagolix, in combination with estradiol and norethindrone acetate, was approved by the FDA for the treatment of heavy menstrual bleeding caused by fibroids for up to 24 months of use. However, in contrast to relugolix, elagolix requires twice-daily dosing. The theory is that, since these medications more profoundly suppress ovarian steroidogenesis compared to hormonal contraceptives, they will be more effective at treating not only the endometrium, but also the leiomyoma itself.
The GnRH antagonists, as newer medications, still are brand-name and may be less likely to be covered by insurance companies or only covered if other treatments fail, requiring prior authorizations. It is unclear whether patients can stay on the medication for longer than 24 months if their bone mineral density remains normal. I confess I have not added these medications to my standard patient counseling regarding uterine leiomyoma treatment. However, it seems that this new class of medications is the wave of the future in gynecology. Already both medications are being used to treat the pain of endometriosis. These medications may help some women avoid more invasive treatments for fibroids, such as myomectomy and hysterectomy. Therefore, elagolix and relugolix both are appropriate treatment options for patients if they are able to obtain the medication at a reasonable price.
REFERENCES
- Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med 2021;384:630-642.
- American College of Obstetricians and Gynecologists. Management of symptomatic uterine leiomyomas. Practice Bulletin Number 228. Published June 2021. https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2021/06/management-of-symptomatic-uterine-leiomyomas
