Elagolix Noninferior to Dienogest for Endometriosis Pain in Phase 3 Trial

Elagolix 150 mg (Egolix; Sun Pharma) once daily was noninferior to dienogest 2 mg once daily for reducing moderate-to-severe endometriosis-associated pain in a phase 3 trial conducted across India, according to findings published in BJOG: An International Journal of Obstetrics & Gynaecology.¹

Endometriosis affects roughly 190 million women worldwide, and no large prospective head-to-head comparison of elagolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, and dienogest, a progestin, had been conducted before this study, according to the authors. The Federation of Obstetric and Gynaecological Societies of India recommends dienogest as first-line hormonal therapy, which made it the comparator. Earlier phase 3 trials, Elaris Endometriosis I (EM-I; NCT01620528) and II (EM-II; NCT01931670), found that elagolix 150 mg improved dysmenorrhea and nonmenstrual pelvic pain vs placebo, with responses sustained at 6 months.²

Primary End Point Met

The multicenter, double-blind, double-dummy trial randomized 230 of 340 screened premenopausal women aged 18 to 49 years with moderate-to-severe endometriosis-associated pain to elagolix or dienogest (115 per arm) for 24 weeks.¹ Patients with dyspareunia were excluded.

The primary end point was change in numeric rating scale (NRS) score, an 11-point scale, from baseline to day 85. Prespecified noninferiority was defined as an upper 95% CI bound below a margin of 1.5 points.

In the per-protocol population (113 patients receiving elagolix and 112 receiving dienogest), the mean change in NRS score at day 85 was −2.43 with elagolix and −2.47 with dienogest. The between-group difference was 0.04 (95% CI, −0.3 to 0.37), within the noninferiority margin. Sensitivity analyses in the intention-to-treat and modified intention-to-treat populations were consistent.

Reductions continued through day 169, when mean NRS changes reached −4.33 with elagolix and −4.37 with dienogest (P < .0001 vs baseline for both).

By day 169, dysmenorrhea scores fell by 1.56 points with elagolix and 1.59 with dienogest, and nonmenstrual pelvic pain scores fell by 1.53 and 1.59 points, respectively. Between-group differences were not statistically significant for either measure. Rescue medication use was similar (17.7% and 17.0%).

On the Patient Global Impression of Change scale, responders (those much or very much improved) made up 62.8% of the elagolix group and 71.4% of the dienogest group at day 85 (P = .1700), and 92.9% and 94.6% at day 169 (P = .5928).

Adverse Events Similar Between Arms

Treatment-emergent adverse events (TEAEs) occurred in 17 patients (14.8%) receiving elagolix and 22 (19.1%) receiving dienogest, including drug-related events in 2 (1.7%) and 3 (2.6%). No serious TEAEs occurred, and no events led to drug interruption, discontinuation, or dose reduction. No statistical comparison of adverse event rates was reported.

Gastrointestinal disorders were reported in 3.5% of the elagolix arm and 6.1% of the dienogest arm. One patient receiving elagolix had elevated low-density lipoprotein levels, and mild, transient elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were each reported in one patient.

Bone mineral density was assessed by dual-energy x-ray absorptiometry at baseline and day 169, and the authors reported no clinically relevant changes in either arm. In the earlier placebo-controlled trials, bone mineral density decreased more with elagolix than with placebo.²

Limitations and Future Directions

The authors noted that progestin resistance, which typically emerges after 3 to 6 months, was not assessed, and long-term efficacy and safety were not evaluated. Patient-reported pain scores introduce potential subjectivity, and the strict phase 3 selection criteria may limit generalizability.¹ No participants had histopathologic diagnoses, and endometriosis could be diagnosed by ultrasound rather than surgery. Patients also were not stratified by disease grade. The trial did not evaluate the 200 mg elagolix dose in patients with dyspareunia.

The study was funded by Sun Pharmaceutical Industries Limited, which manufactures the elagolix product used in the trial. Ten of the study's 25 authors are current or former Sun Pharma employees, and the company managed study operations and supported data analysis, according to the paper's disclosures.

The authors called for longer real-world studies and comparisons with danazol and levonorgestrel. They concluded that elagolix demonstrated noninferiority to dienogest "with an acceptable safety and tolerability profile."

References

1. Bhoir S, Patel J, Palve T, et al. Efficacy and safety of elagolix versus dienogest for treatment of moderate-to-severe endometriosis pain: a phase III, multicentric, double-blind, active-controlled, non-inferiority study. BJOG. 2026;133:2025-2034. doi:10.1111/1471-0528.70256
2. Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377(1):28-40. doi:10.1056/NEJMoa1700089