Elagolix with add-back therapy promising for endometriosis-associated pain: Ongoing phase 3 trial reveals

The study, published in the American Journal of Obstetrics and Gynecology, showed that compared with placebo, elagolix with add-back therapy led to significant, clinically meaningful improvement in nonmenstrual pelvic pain, dysmenorrhea, and fatigue at six months that continued until month 12 for both nonmenstrual pelvic pain and dysmenorrhea.

In addition, elagolix combined with add-back therapy demonstrated good tolerability overall. Over 12 months, patients receiving this combination showed a slightly higher reduction in bone mineral density (BMD) compared to those on placebo. However, the decrease in BMD with elagolix plus add-back therapy was less than 1%, significantly lower than the bone loss seen in patients receiving elagolix alone.

Elagolix, an FDA-approved oral treatment for managing endometriosis-associated pain, is known to induce hypoestrogenic effects when used alone. Incorporating hormonal add-back therapy has shown promise in counteracting these effects. Considering this, Charles E. Miller, the Advanced Gynecologic Surgery Institute, Park Ridge, IL, and colleagues aimed to evaluate tolerability, efficacy, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol /0.5 mg norethindrone acetate (add-back) therapy once daily than placebo in premenopausal women with moderate-to-severe endometriosis-associated pain.

The ongoing, 48-month, phase 3 study comprised a 12-month, double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for six months followed by elagolix with add-back therapy, or placebo.

The study's co-primary objectives were to determine the proportion of patients showing clinical improvement, termed "responders," in dysmenorrhea and nonmenstrual pelvic pain by month 6. The study presents the 12-month findings on the effectiveness of elagolix combined with add-back therapy compared to placebo in reducing symptoms of nonmenstrual pelvic pain, dysmenorrhea, dyspareunia, and fatigue. Tolerability assessments included monitoring adverse events and evaluating changes in bone mineral density from baseline.

The study led to the following findings:

• A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193).
• Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% versus 23.7%) and nonmenstrual pelvic pain (51.3% versus 36.8%) at six months.
• Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints, including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6).
• The incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo.
• The rate of severe adverse events did not meaningfully differ between treatment groups.
• Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%).
• Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of −2.43% (lumbar spine), −1.54% (total hip), and −1.78% (femoral neck) at month 6.
• When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of −1.58% to −1.83% at month 12.
• Patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in BMD (<1% change) at months 6 and 12.

The initial findings offer hope for improved treatment options and enhanced quality of life for women with chronic pain and complications of endometriosis.

Reference:

Miller, C. E., Kim, J. H., Kroll, R., Simon, J. A., Soliman, A. M., Thomas, J. W., Xu, Y., Ng, J., & Snabes, M. C. (2024). Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: 12 months of an ongoing randomized phase 3 trial. American Journal of Obstetrics and Gynecology. https://doi.org/10.1016/j.ajog.2024.06.040