BACKGROUND AND PURPOSE:

• Relugolix is an oral gonadotropin-releasing hormone receptor antagonist
  • Combined with estradiol and a progestin to limit hot flashes and maintain bone mineral density
• Giudice et al. (The Lancet, 2022) evaluated the efficacy and safety of relugolix combined with estradiol and a progestin for the treatment of endometriosis-related pain

METHODS:

• Two phase 3, multicenter, randomized, double-blind, placebo-controlled trials
• Participants
  • Women 18 to 50 years
  • Multicenter: Africa | Australasia | Europe | North America | South America
  • Women had either
    • Surgically or directly visualized endometriosis with or without histological confirmation
    • Endometriosis with histological diagnosis alone
  • Eligible women had
    • Moderate to severe endometriosis-associated pain during the 35-day run-in period
    • Dysmenorrhea Numerical Rating Scale (NRS) score of ≥4.0 on two or more days
    • Mean non-menstrual pelvic pain NRS score of ≥2.5 or a mean score of ≥1.25 that included a score of ≥5 on ≥4 days
• Interventions
  • Once-daily relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0.5 mg) for 24 weeks
  • Delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks)
  • Placebo
• Study design
  • Randomization 1:1:1
  • Efficacy and safety were analyzed in the modified intent-to-treat population
  • Post-treatment follow-up for safety, specifically for bone mineral density and menses recovery, is ongoing at the time of publication
• Primary outcomes
  • Responder rates at week 24 for dysmenorrhea and non-menstrual pelvic pain

RESULTS:

• SPIRIT 1: 638 patients | SPIRIT 2: 623 patients
• Dysmenorrhea responder criteria was significantly improved with combination therapy
  • SPIRIT 1
    • Relugolix combination therapy: 75%
    • Placebo: 27%
    • Treatment difference 47.6% (95% CI, 39.3 to 56.0); p<0.0001
  • SPIRIT 2
    • Relugolix combination therapy: 75%
    • Placebo: 30%
    • Treatment difference 44.9% (95% CI, 36.2 to 53.5); p<0.0001
• Non-menstrual pain was significantly improved with combination therapy
  • SPIRIT 1
    • Relugolix combination therapy: 58%
    • Placebo: 40%
    • Treatment difference 18.9% (95% CI, 9.5 to 28.2); p<0.0001
  • SPIRIT 2
    • Relugolix combination therapy: 66%
    • Placebo: 43%
    • Treatment difference 23.4% (95% CI, 13.9 to 32.8); p<0.0001
• Delayed relugolix combination was also associated with pain improvement (p<0.0001 for treatment difference vs placebo)    
  • Dysmenorrhea
    • SPIRIT 1: 72%
    • SPIRIT 3: 73%
  • Non-menstrual pelvic pain
    • SPIRIT 1: 58%
    • SPIRIT 2: 53%
• Most common adverse events
  • Headache
  • Nasopharyngitis
  • Hot flushes
• There were nine reports of suicidal ideation across both studies
  • Placebo run-in: 2 reports
  • Placebo: 2
  • Relugolix combination therapy: 2
  • Delayed relugolix combination therapy: 3
• There were no deaths
• Bone mineral density loss in the relugolix combination therapy groups was higher than in placebo, but was less than 1% in both studies
  • SPIRIT 1
    • Relugolix combination therapy: –0.70%
    • Delayed relugolix combination: –2.0%
    • Placebo: 0.21%
  • SPIRIT 2
    • Relugolix combination therapy: –0.78%
    • Delayed relugolix combination: –1.9%
    • Placebo: 0.02%
• Decreases in opioid use were seen in treated patients as compared with placebo

CONCLUSION:

• Endometriosis-associated pain was significantly improved with relugolix combination therapy
  • The combination therapy was well tolerated, with minimal bone mineral density losses, and mostly minor adverse side effects
• Combination therapy may allow for long-term treatment that does not rely on opioid use or repeat surgical intervention
• The authors state

The combination of relugolix, estradiol, and norethisterone acetate might provide the therapeutic benefits of GnRH receptor antagonism to suppress endogenous oestradiol concentrations and improve symptoms of endometriosis while minimising the risk of hypoestrogenic-related bone loss and vasomotor symptoms, potentially enabling long-term use

Learn More – Primary Sources:

Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2)

Related ObG Topics:

RCT Results: Does Relugolix Combined with Estradiol and Progestin Reduce Fibroid-Associated Heavy Menstrual Bleeding?

RCT Results: Relugolix Versus Leuprorelin for the Management of Endometriosis-Associated Pelvic Pain

Does Elagolix Treatment for Endometriosis Pain Also Reduce Fatigue?

Elaris EM-III and Elaris EM-IV Results: Long-Term Endometriosis Outcomes Following Administration of Elagolix