Bone mineral density with elagolix plus add-back therapy in women with heavy menstrual bleeding and uterine fibroids: open-label and post-treatment results of a 60-month phase 3 trial.

Background: The gonadotropin-releasing hormone antagonist elagolix (ELA) plus hormonal add-back (+AB) therapy reduces menstrual blood loss in women with heavy menstrual bleeding (HMB) associated and uterine fibroids. Prescribed ELA+AB therapy is limited to 24 months due to concerns about the hypoestrogenic effects of potential decreased bone mineral density (BMD). Objectives: To evaluate 48-month safety and BMD effects of ELA+AB therapy in premenopausal women with HMB associated with uterine fibroids. Study Design: This phase 3b, multicenter study (NCT03271489) was conducted September 13, 2017-June 28, 2024. Three study periods included a 12-month randomized, double-blind treatment period (months 1-12), a 36-month open-label extension (OLE) period (months 13-48), and a 12-month post-treatment follow-up period (months 49-60). Premenopausal women aged 18-50 years with HMB associated with uterine fibroids were randomized 2:1 to receive ELA+AB therapy (ELA 300 mg twice daily plus estradiol 1.0 mg/norethindrone acetate 0.5 mg once daily) or placebo during double-blind treatment. All patients entering the OLE received ELA+AB therapy for 36 months, including those switching from placebo (placebo/ELA+AB group) and those remaining on ELA+AB therapy (ELA+AB/ELA+AB group). BMD was assessed every 6 months at the lumbar spine, total hip, and femoral neck using dual-energy X-ray absorptiometry. Data were analyzed using an analysis of covariance model with treatment as the main effect and baseline values as covariates. Safety assessments included incidence of treatment-emergent adverse events (TEAEs). Results: Overall, 277 patients entered the OLE period, with 103 completing treatment. In the ELA+AB/ELA+AB group, the mean percent decrease in BMD from baseline was <2% in the lumbar spine, total hip, and femoral neck at all scheduled visits through 48 months of treatment. Categorical analysis of percent BMD recovery showed that the majority of patients in the ELA+AB/ELA+AB group who had decreased BMD at month 48 achieved partial or full BMD recovery 12 months after treatment at each anatomic site. In the OLE, TEAEs were reported in 59 (70.2%) patients in the placebo/ELA+AB group and 124 (64.2%) patients in the ELA+AB/ELA+AB group. Most TEAEs were mild or moderate and nonserious, with no severe TEAEs occurring in >1 patient in either treatment group. The most frequent TEAE (excluding COVID-19) was decreased BMD (placebo/ELA+AB, 8 [9.5%] patients; ELA+AB/ELA+AB, 27 [14.0%] patients). BMD-related TEAEs (including osteopenia and bone fractures) in the OLE occurred in 12 (14.3%) patients in the placebo/ELA+AB group and 31 (16.1%) patients in the ELA+AB/ELA+AB group. Decreased BMD was the most common TEAE leading to treatment discontinuation (placebo/ELA+AB, 7 [8.3%] patients; ELA+AB/ELA+AB, 24 [12.4%] patients). Conclusions: BMD was stable throughout ELA+AB therapy and across anatomical sites in premenopausal women with HMB associated with uterine fibroids. In patients with decreased BMD at month 48, BMD recovery was observed in many patients 12 months after treatment cessation. Therefore, the effects of ELA+AB therapy on BMD can be reversible though not in all patients. The long-term use of ELA+AB therapy was well tolerated, with no new safety signals identified. These findings support the potential of long-term ELA+AB therapy for HMB associated with uterine fibroids.