Safety of 48 months of elagolix with add-back therapy for endometriosis-associated pain.

Background: Elagolix (ELA) 200 mg twice daily is an oral treatment approved for moderate-to-severe endometriosis-associated pain. However, the clinical use of ELA is limited by potential hypoestrogenic effects, including the loss of bone mineral density (BMD). The addition of hormonal add-back (AB) therapy (1-mg estradiol/0.5-mg norethindrone acetate once daily) may attenuate BMD loss. Objectives: To provide long-term safety results from a 48-month phase 3 trial assessing ELA+AB therapy in premenopausal women with moderate-to-severe endometriosis-associated pain. Study Design: This multicenter, phase 3 trial was conducted between July 7, 2017, and December 6, 2023, and included a 12-month double-blind treatment period, a 36-month open-label extension period, and a 12-month post-treatment follow-up (PTFU) period. At the beginning of the double-blind period, premenopausal women (aged 18-49 years) with moderate-to-severe endometriosis-associated pain were randomized 4:1:2 to ELA+AB therapy, ELA monotherapy for 6 months followed by ELA+AB therapy for the remaining 6 months, or placebo. After the double-blind treatment period, all patients were treated with open-label ELA+AB therapy (referred to as the ELA+AB/ELA+AB, ELA/ELA+AB, and placebo/ELA+AB groups) for the remainder of the 36-month open-label treatment period. Safety was assessed throughout the open-label treatment period. BMD was measured by dual-energy X-ray absorptiometry in the lumbar spine, total hip, and femoral neck during the screening period and every 6 months throughout the study. BMD was analyzed using an analysis of covariance model with treatment as the main effect and baseline values as covariates. Results: Among 380 patients who entered the open-label period, 140 (36.8%) completed the treatment period, and 240 (63.2%) discontinued, primarily due to withdrawn consent and adverse events (AEs). In total, 159 (74.0%) patients in the ELA+AB/ELA+AB group, 41 (69.5%) patients in the ELA/ELA+AB group, and 80 (75.5%) patients in the placebo/ELA+AB group reported at least 1 treatment-emergent adverse event (TEAE) during the open-label period. TEAEs were generally mild or moderate and nonserious. The most commonly reported TEAEs were COVID-19, bone density decreases, and sinusitis. No serious AEs were reported in >1 patient in any study group. BMD remained generally stable, with a least squares mean percent decrease from baseline to week 48 <2% in all groups and at all anatomical sites. Similarly, the least squares mean decrease from baseline in BMD was <2% in the ELA+AB/ELA+AB group at all anatomical sites and all time points throughout the study period. For patients in the ELA+AB/ELA+AB group with ≥48 months of treatment and reduced BMD at the final on-treatment visit, the majority (lumbar spine, 13 [59.1%]; total hip, 8 [53.3%]; femoral neck, 12 [57.1%]) partially or fully recovered at month 12 of the PTFU period. Conclusions: This study extends findings from a previously reported 12-month analysis of the efficacy and safety of ELA+AB therapy in premenopausal women with moderate-to-severe endometriosis-associated pain. The safety profile of ELA+AB therapy was generally consistent with that observed in prior studies. BMD remained mostly stable through 48 months of continuous treatment. This analysis represents the longest safety study of ELA+AB therapy to date and supports long-term treatment with ELA+AB therapy.