Achieving Minimal-to-No Pain in Women with Endometriosis Treated with Relugolix Combination Therapy: SPIRIT Extension Trial

Endometriosis is an inflammatory disease where ectopic endometriotic lesions grow in anatomic sites outside of the uterus. 1 It is predicted to affect 10–15% of all women of reproductive age, including 70% of women with chronic pelvic pain. 2 , 3 There are often substantial delays in diagnosis due to confounding symptoms and under-recognition by healthcare professionals, 3 meaning that true prevalence may be underestimated. 4 Common endometriosis symptoms include dysmenorrhea, pelvic pain, and dyspareunia, with symptoms typically presenting during the reproductive years. 1–3 Symptomatic endometriosis is typically managed by surgical or medical intervention to reduce disease load, suppress disease progression, and manage pain symptoms. 3 Surgical techniques, including excision of the endometriotic implants, nerve ablation, electrocautery, and hysterectomy, are somewhat effective for pain relief. 1 , 3 However, surgery may carry the risk of reduced ovarian reserve and recurrence of pain or endometriosis post-surgery. Recurrent endometriosis-related pain following surgery can be as high as 40–50% by 5 years, and persistent “chronic post-surgical pain” occurs in up to 15–20% of patients at 3–6 months postoperatively. 5 , 6 Despite these risks, repeat surgery is common; in a retrospective study evaluating the occurrence of surgery after laparoscopic treatment for endometriosis, only 53.3% of patients remained surgery-free at 5 years. 7 Recommended medical interventions for symptom management include combined hormonal contraceptives and progestogens. 8 In case of insufficient pain reduction, gonadotropin-releasing hormone (GnRH) agonist therapy has been shown to be effective in treating endometriosis and gonadal steroid-driven disorders; however, long-term use beyond 6 months 9 may be limited due to risk of bone mineral density (BMD) loss from hypoestrogenism. 10 Elagolix, an oral GnRH antagonist, is limited to a 6-month treatment duration due to risk of BMD loss for the high dose (300 mg once every 2 days). 11 A longer treatment duration of 2 years is only approved with a lower dose (150 mg once daily), but with qualitatively lower dysmenorrhea and non-menstrual pelvic pain (NMPP) response rates compared with the higher dose. 12 Thus, there is a need for an effective medical treatment that can be used long-term (>6 months) for management of endometriosis-associated pain. This is particularly important because the physical symptoms and stigma associated with endometriosis can adversely affect many aspects of daily life, including social activities, sexual functioning, work productivity, and mental health. 13 Relugolix is an oral, non-peptide GnRH receptor antagonist and part of a once-daily combination therapy (relugolix-CT; 40 mg relugolix, 1 mg estradiol, 0.5 mg norethindrone acetate) designed to maintain estradiol concentrations within a therapeutic range (20–50 pg/mL) to reduce endometriosis and uterine fibroid symptoms while minimizing BMD loss and vasomotor symptoms associated with a hypoestrogenic state. 14 , 15 It is approved in the United States and Canada to treat moderate-to-severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids, with a maximum recommended treatment duration of 24 months. 16 , 17 It is also approved in the European Union and several other jurisdictions and administrative districts for treatment of symptomatic endometriosis in women with a history of previous medical or surgical treatment for endometriosis, and to treat moderate-to-severe symptoms of uterine fibroids. 18 In the European Union, no maximum treatment duration is specified; however, a dual-energy X-ray absorptiometry scan is recommended after the first 52 weeks of treatment and thereafter as clinically appropriate. 18 In the pivotal SPIRIT 1 and SPIRIT 2 studies of women with endometriosis-associated pain, relugolix-CT significantly reduced dysmenorrhea, NMPP, and dyspareunia, and was well tolerated with <1% BMD loss through 24 weeks. 14 In women who continued to receive relugolix-CT for up to an additional 80 weeks in the SPIRIT Long-Term Extension (LTE) study, relugolix-CT demonstrated a sustained reduction in endometriosis-associated pain (dysmenorrhea, NMPP, and dyspareunia), improvements in daily activities and functioning, reduced need for analgesics, and no evidence of progressive BMD loss during long-term treatment. 19 As part of the evaluation of up to 104 weeks of treatment with relugolix-CT, an analysis was conducted to evaluate the time to minimal-to-no pain for one of the dual co-primary endpoints of NMPP and dysmenorrhea. 19 This post hoc analysis expands on these observations to assess the effect of relugolix-CT on time course to reduction in endometriosis-associated pain, achievement of amenorrhea, and cessation of analgesic use over 104 weeks in the SPIRIT LTE study. This analysis similarly used a specific Numerical Rating Scale (NRS) threshold (NRS ≤1), described as minimal-to-no pain, which is distinct from the prespecified thresholds used to assess the co-primary endpoints in the SPIRIT trials. 14 , 19 This approach may provide an easier way to communicate the effect of relugolix-CT to healthcare practitioners and patients.

Study design of the SPIRIT 1, 2, and LTE studies was described previously. 14 , 19 Briefly, SPIRIT 1 ( NCT03204318 ) and SPIRIT 2 ( NCT03204331 ) were replicate, 24-week, Phase 3, randomized, double-blind, placebo-controlled, multinational studies designed to evaluate the efficacy and safety of once-daily oral relugolix-CT. Women with endometriosis-associated pain were randomized 1:1:1 to receive relugolix-CT or placebo for 24 weeks, or delayed relugolix-CT (relugolix 40 mg monotherapy for 12 weeks followed by relugolix-CT for 12 weeks; Figure 1 ). Figure 1 SPIRIT 1, SPIRIT 2, and SPIRIT Long-Term Extension study design. a SPIRIT 1 ( NCT03204318 ) and SPIRIT 2 ( NCT03204331 ), respectively. b Relugolix-CT = relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg. c Delayed relugolix-CT = relugolix monotherapy 40 mg for 12 weeks and then relugolix-CT for 12 weeks. d SPIRIT LTE ( NCT03654274 ). The flowchart outlines a clinical trial process for women with endometriosis-associated pain. Initially, 638 participants from SPIRIT 1 and 623 from SPIRIT 2 were randomized in a 1:1:1 ratio. The trials involved a randomized, double-blind treatment phase (the pivotal trials) with three groups: Placebo, Relugolix-CT QD and Delayed Relugolix-CT, which received Relugolix QD for 12 weeks followed by Relugolix-CT QD for 12 weeks. After 24 weeks, 1044 participants completed the pivotal trials. Of these, 802 entered the open-label Long-Term Extension period, in which all women received Relugolix-CT. There were 501 participants who completed Week 104. The flowchart details the progression from initial randomization through to the completion of the long-term extension period. A flowchart showing the study design and patient disposition within this clinical trial for endometriosis-associated pain. Abbreviations : CT, combination therapy; LTE, Long-Term Extension; QD, once daily. SPIRIT 1, SPIRIT 2, and SPIRIT Long-Term Extension study design. a SPIRIT 1 ( NCT03204318 ) and SPIRIT 2 ( NCT03204331 ), respectively. b Relugolix-CT = relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg. c Delayed relugolix-CT = relugolix monotherapy 40 mg for 12 weeks and then relugolix-CT for 12 weeks. d SPIRIT LTE ( NCT03654274 ). Participants were premenopausal women (18–50 years of age) with endometriosis and moderate-to-severe dysmenorrhea and NMPP (women who demonstrated a dysmenorrhea NRS score ≥4.0 at least 2 days and mean NMPP NRS score ≥2.5, or mean NMPP NRS score ≥1.25 and NMPP NRS score ≥5.0 on ≥4 days). Full eligibility criteria and results of SPIRIT 1 and 2 were previously published. 14 Eligible women who completed 24 weeks of blinded treatment in SPIRIT 1 or 2 were invited to participate in the 80-week, open-label, multinational SPIRIT LTE study ( NCT03654274 ), representing a cumulative treatment period of 104 weeks. During the LTE study, all participants received once-daily relugolix-CT, independent of treatment received during the pivotal studies. Participants in the LTE were categorized according to the randomized treatment received during the pivotal studies: continuous relugolix-CT (women who received relugolix-CT from week 0 of the double-blind treatment period); delayed relugolix-CT (women who received relugolix monotherapy until week 24 of the double-blind treatment period and then switched to relugolix-CT); and placebo → relugolix-CT (women who received placebo during the double-blind treatment period and subsequently received relugolix-CT during the LTE). Study visits occurred every 4 weeks from pivotal study baseline through Week 104. Data were analyzed according to pivotal study baseline treatment assignment groups. The SPIRIT 1 and 2 study protocols were approved by local institutional review boards (a full list of approving institutional review boards and independent ethics committees can be found in the Supplementary Information ), and the studies were conducted in accordance with International Conference on Harmonisation guidelines and ethical principles of the Declaration of Helsinki. All women provided written informed consent. 14 The co-primary endpoints of the SPIRIT LTE study were the proportion of dysmenorrhea and NMPP responders at Week 52 and Week 104/end of treatment, for which results were previously published. 19 Responders were defined as those achieving a mean reduction in NRS scores of ≥2.8 points for dysmenorrhea or ≥2.1 points for NMPP and no increase in analgesic use. Secondary efficacy endpoints included the proportion of women not using analgesics (including opioids) at Week 52 and Week 104. To investigate the temporal aspects of treatment response in this post hoc analysis, data from the pooled patient population of SPIRIT 1, SPIRIT 2, and SPIRIT LTE trials were assessed using a new, stricter threshold for pain scores. Kaplan–Meier plots were developed using median time-to-event analysis for the time until women reached specified endpoints, including minimal-to-no pain defined as an NRS score of ≤1 for dysmenorrhea or NMPP, the achievement of 28 days of amenorrhea, and analgesic-free status (ie, proportion of patients not using analgesics for endometriosis-associated pain). Analgesic medication tiers and record-keeping were defined in pivotal study protocols. 14 Median time to reach the reported outcomes was summarized and reported for each treatment group of SPIRIT 1 and SPIRIT 2. Kaplan–Meier estimates were calculated for the temporal trends in treatment response, as well as cumulative probability of reaching these endpoints over the pivotal and extension study periods at Weeks 24, 52, and 104. These analyses were exploratory and descriptive in nature and not intended to support formal statistical comparisons.

Baseline characteristics were balanced among treatment groups. 14 Of 1261 women who were randomized 1:1:1 to relugolix-CT, delayed relugolix-CT, or placebo, there were 802 (77%) women enrolled in the extension study (at Week 24), comprising 278, 247, and 277 in the relugolix-CT, delayed relugolix-CT, and placebo→relugolix-CT groups, respectively. The size of the analyzed cohort was 799: 681 (85%) and 501 (62%) women completed 52 and 104 weeks of treatment, respectively. Among women completing 104 weeks of treatment, 172 (61.9%) were in the relugolix-CT group, 155 (62.8%) in the delayed relugolix-CT group, and 174 (62.8%) in the placebo→relugolix-CT group. 19 Treatment was discontinued in 300/802 (37.4%) participants. Discontinuation rates were balanced between treatment groups, with the main reason being withdrawal by participant in 104/802 (13.0%) participants. 19 Discontinuation due to adverse events occurred in 66/802 (8.2%) participants, most of these adverse events were non-serious and were reported for only one patient each. 19 Demographics and baseline characteristics of the LTE study population were balanced among groups and similar to pivotal studies baselines. 19 Median time for women to achieve minimal-to-no dysmenorrhea (NRS ≤1) was 8 weeks (approximately two menstrual cycles) for women in the relugolix-CT group and for women in the delayed relugolix-CT group ( Figure 2 ). Median time to minimal-to-no dysmenorrhea was not reached in the placebo→relugolix-CT group during the initial 24 weeks of placebo; women in this group reached median time to minimal-to-no dysmenorrhea at Week 32, following the transition to relugolix-CT. Figure 2 Median time to minimal-to-no pain (NRS ≤1) for dysmenorrhea. Selected timepoints for cumulative probability to minimal-to-no dysmenorrhea up to Week 104. Grey shading highlights the randomized treatment period. Relugolix-CT = relugolix-CT from Week 0. Delayed relugolix-CT = relugolix monotherapy 40 mg for 12 weeks and then relugolix-CT for 12 weeks. Placebo→relugolix-CT = placebo for 24 weeks, relugolix-CT following transfer to the extension period. Kaplan–Meier plot for all timepoints were previously published in Becker et al, 2024 ( Supplement ). 19 A grouped bar graph showing cumulative probability (%) of experiencing minimal-to-no pain over time since first dose (weeks). Weeks 0 to 24 have a gray background, and are labeled “Randomized Treatment”, while Weeks 36 to 104 have white background and are labeled “Extension Period: All Women Received Relugolix-CT”. The Y-axis shows cumulative probability and ranges from 0% to 100%. The X-axis, labeled “Time Since Date of First Dose of Randomized Study Drug (Weeks)”, marks Weeks 0, 4, 8, 12, 24, 36, 52, 78, 104. A dashed horizontal line indicates a cumulative probability of 50%. Three groups are compared at each timepoint: Placebo to Relugolix-CT, Relugolix-CT and Delayed Relugolix-CT. Week 4: 6.6%, 9.4%, 17.1%. Week 8: 12.1%, 56.3%, 75.7%. Week 12: 17.0%, 69.8%, 81.8%. Week 24: 22.4%, 82.5%, 86.4%. Week 36: 74.4%, 91.4%, 94.4%. Week 52: 90.3%, 94.5%, 95.9%. Week 78: 92.9%, 95.3%, 95.9%. Week 104: 94.9%, 95.3%, 95.9%. Numbers of patients at risk at Weeks 0 and 104: Relugolix-CT: 418 to 5; Delayed Relugolix-CT: 417 to 5; Placebo to Relugolix-CT: 416 to 9. Legend: Placebo to Relugolix-CT (Gray bars), Relugolix-CT (Orange bars), Delayed Relugolix-CT (Teal bars). A grouped bar graph showing cumulative probability of experiencing minimal-to-no pain for dysmenorrhea over time by treatment group. Abbreviations : CT, combination therapy; NRS, Numerical Rating Scale. Median time to minimal-to-no pain (NRS ≤1) for dysmenorrhea. Selected timepoints for cumulative probability to minimal-to-no dysmenorrhea up to Week 104. Grey shading highlights the randomized treatment period. Relugolix-CT = relugolix-CT from Week 0. Delayed relugolix-CT = relugolix monotherapy 40 mg for 12 weeks and then relugolix-CT for 12 weeks. Placebo→relugolix-CT = placebo for 24 weeks, relugolix-CT following transfer to the extension period. Kaplan–Meier plot for all timepoints were previously published in Becker et al, 2024 ( Supplement ). 19 The cumulative probability of women in the relugolix-CT group achieving minimal-to-no dysmenorrhea at Weeks 24, 52, and 104 was 82.5%, 94.5%, and 95.3%, respectively ( Supplementary Table 1 ). Similar cumulative probabilities were observed with delayed relugolix-CT (86.4%, 95.9%, and 95.9%, respectively). Of women initially receiving placebo, 22.4% achieved minimal-to-no dysmenorrhea at Week 24; following transition to relugolix-CT, this cumulative probability increased to 90.3% and 94.9% at Weeks 52 and 104, respectively. Median time to amenorrhea was approximately 8 weeks in women treated with relugolix-CT or delayed relugolix-CT and was not reached in the placebo→relugolix-CT group within the 24-week placebo-only treatment (median = 32 weeks) ( Figure 3 ). Figure 3 Median time to 28-day amenorrhea. The red vertical dashed lines represent the timepoints at Weeks 24/52/104. Grey shading highlights the randomized treatment period. Relugolix-CT = relugolix-CT from Week 0. Delayed relugolix-CT = relugolix monotherapy 40 mg for 12 weeks and then relugolix-CT for 12 weeks. Placebo→relugolix-CT = placebo for 24 weeks, relugolix-CT following transfer to the extension period. Kaplan–Meier curves are presented for descriptive purposes only and are not intended to support formal statistical comparisons. A Kaplan–Meier curve that compares three treatment groups: Placebo to Relugolix-CT, Relugolix-CT, and Delayed Relugolix-CT in achieving 28-day amenorrhea. The Y-axis shows cumulative probability (0–100%), and the X-axis shows time since first dose (0-104 weeks). A dashed horizontal line indicates a cumulative probability of 50%, while vertical dashed lines highlight Weeks 24, 52, and 104. Relugolix-CT and Delayed Relugolix-CT rise quickly early on, reaching high cumulative probabilities within 8–12 weeks, then plateau in the mid-to-high 90% range. Placebo to Relugolix-CT increases more slowly, reaching 50% by Week 32, but approaches the upper range by study end. During the extension period, all women received Relugolix-CT, and the curves converged. Numbers of patients at risk at Weeks 0 and 104: Relugolix-CT: 418 to 7; Delayed Relugolix-CT: 417 to 3; Placebo to Relugolix-CT: 416 to 11. A Kaplan–Meier curve showing cumulative probability of 28-day amenorrhea for three treatment groups. Abbreviation: CT, combination therapy. Median time to 28-day amenorrhea. The red vertical dashed lines represent the timepoints at Weeks 24/52/104. Grey shading highlights the randomized treatment period. Relugolix-CT = relugolix-CT from Week 0. Delayed relugolix-CT = relugolix monotherapy 40 mg for 12 weeks and then relugolix-CT for 12 weeks. Placebo→relugolix-CT = placebo for 24 weeks, relugolix-CT following transfer to the extension period. Kaplan–Meier curves are presented for descriptive purposes only and are not intended to support formal statistical comparisons. The cumulative probability of women who reported amenorrhea in the relugolix-CT group at Weeks 24, 52, and 104 was 82.2%, 93.6%, and 95.8%, respectively ( Supplementary Table 2 ). Similar cumulative probabilities were observed with delayed relugolix-CT (89.6%, 96.1%, and 96.8%, respectively). The cumulative probability of women who reported amenorrhea in the placebo→relugolix-CT group increased from 20.2% at Week 24 (duration of placebo-only treatment) to 85.3% and 93.2% at Weeks 52 and 104, respectively, following the initiation of relugolix-CT. Median time to achieve minimal-to-no NMPP (NRS ≤1) for women in the relugolix-CT group was 32 weeks, compared with 28 weeks in the delayed relugolix-CT group and 40 weeks for women treated with placebo→relugolix-CT ( Figure 4 ). Figure 4 Median time to minimal-to-no pain (NRS ≤1) for NMPP. Selected timepoints for cumulative probability to minimal-to-no NMPP up to Week 104. Grey shading highlights the randomized treatment period. Relugolix-CT = relugolix-CT from Week 0. Delayed relugolix-CT = relugolix monotherapy 40 mg for 12 weeks and then relugolix-CT for 12 weeks. Placebo→relugolix-CT = placebo for 24 weeks, relugolix-CT following transfer to the extension period. Kaplan–Meier plot for all timepoints were previously published in Becker et al, 2024 ( Supplement ). 19 A grouped bar graph showing cumulative probability (%) of experiencing minimal-to-no pain over time since first dose (weeks). Weeks 0 to 24 have a gray background, and are labeled “Randomized Treatment”, while Weeks 36 to 104 have white background and are labeled “Extension Period: All Women Received Relugolix-CT”. The Y-axis shows cumulative probability and ranges from 0 to 100. The X-axis, labeled “Time Since Date of First Dose of Randomized Study Drug (Weeks)”, marks Weeks 0, 4, 8, 12, 24, 36, 52, 78, 104. A dashed horizontal line indicates a cumulative probability of 50%. Three groups are compared at each timepoint: Placebo to Relugolix-CT, Relugolix-CT and Delayed Relugolix-CT. Week 4: 4.9%, 7.3%, 10.1%. Week 8: 10.7%, 16.8%, 19.0%. Week 12: 17.2%, 26.5%, 28.4%. Week 24: 28.9%, 42.6%, 42.2%. Week 36: 49.7%, 53.7%, 54.2%. Week 52: 62.1%, 59.9%, 61.3%. Week 78: 70.4%, 65.1%, 69.4%. Week 104: 74.3%, 70.5%, 74.7%. Numbers of patients at risk at Weeks 0 and 104: Relugolix-CT: 418 to 51; Delayed Relugolix-CT: 417 to 36; Placebo to Relugolix-CT: 416 to 48. Legend: Placebo to Relugolix-CT (Gray bars), Relugolix-CT (Orange bars), Delayed Relugolix-CT (Teal bars). A grouped bar graph showing cumulative probability of minimal-to-no pain for NMPP over time by treatment group. Abbreviations: CT, combination therapy; NMPP, non-menstrual pelvic pain; NRS, Numerical Rating Scale. Median time to minimal-to-no pain (NRS ≤1) for NMPP. Selected timepoints for cumulative probability to minimal-to-no NMPP up to Week 104. Grey shading highlights the randomized treatment period. Relugolix-CT = relugolix-CT from Week 0. Delayed relugolix-CT = relugolix monotherapy 40 mg for 12 weeks and then relugolix-CT for 12 weeks. Placebo→relugolix-CT = placebo for 24 weeks, relugolix-CT following transfer to the extension period. Kaplan–Meier plot for all timepoints were previously published in Becker et al, 2024 ( Supplement ). 19 The cumulative probability of women in the relugolix-CT group achieving minimal-to-no NMPP was 42.6%, 59.9%, and 70.5% at Weeks 24, 52, and 104, respectively ( Supplementary Table 3 ). Women treated with delayed relugolix-CT had similar results to the continuous relugolix-CT group: 42.2%, 61.3%, and 74.7%, respectively. In the placebo→relugolix-CT group, cumulative probabilities were 28.9%, 62.1%, and 74.3%, respectively. Median time to becoming analgesic (including opioid)-free was 16 weeks for women in the relugolix-CT group, 12 weeks for women treated with delayed relugolix-CT, and 28 weeks for women treated with placebo→relugolix-CT ( Figure 5 ). Figure 5 Median time to becoming analgesic-free. The red vertical dashed lines represent the timepoints at Weeks 24/52/104. Grey shading highlights the randomized treatment period. Relugolix-CT = relugolix-CT from Week 0. Delayed relugolix-CT = relugolix monotherapy 40 mg for 12 weeks and then relugolix-CT for 12 weeks. Placebo→relugolix-CT = placebo for 24 weeks, relugolix-CT following transfer to the extension period. Kaplan–Meier curves are presented for descriptive purposes only and are not intended to support formal statistical comparisons. A Kaplan–Meier curve that compares three treatment groups: Placebo to Relugolix-CT, Relugolix-CT, and Delayed Relugolix-CT in becoming analgesic-free. The Y-axis shows cumulative probability (0–100%), and the X-axis shows time since first dose (0–104 weeks). A dashed horizontal line indicates a cumulative probability of 50%, while vertical dashed lines highlight Weeks 24, 52, and 104. Relugolix-CT and Delayed Relugolix-CT rise more quickly than Placebo to Relugolix-CT early on, exceeding a cumulative probability of 50% by Week 16 and Week 12, respectively, while Placebo to Relugolix-CT exceeds a cumulative probability of 50% by Week 28, following the switch from Placebo to Relugolix-CT at Week 24. During the extension period, all women received Relugolix-CT, and the curves converged and plateaued, with all treatment groups exceeding a cumulative probability of 87% by Week 52. Numbers of patients at risk at Weeks 0 and 104: Relugolix-CT: 418 to 13; Delayed Relugolix-CT: 417 to 9; Placebo to Relugolix-CT: 416 to 9. A Kaplan–Meier curve showing cumulative probability of becoming analgesic free for three treatment groups. Abbreviation: CT, combination therapy. Median time to becoming analgesic-free. The red vertical dashed lines represent the timepoints at Weeks 24/52/104. Grey shading highlights the randomized treatment period. Relugolix-CT = relugolix-CT from Week 0. Delayed relugolix-CT = relugolix monotherapy 40 mg for 12 weeks and then relugolix-CT for 12 weeks. Placebo→relugolix-CT = placebo for 24 weeks, relugolix-CT following transfer to the extension period. Kaplan–Meier curves are presented for descriptive purposes only and are not intended to support formal statistical comparisons. At Weeks 24, 52, and 104, the cumulative probability of women not using analgesics in the relugolix-CT group was 68.8%, 88.6%, and 94.9%, respectively, similar to the delayed relugolix-CT group (75.2%, 90.1%, and 94.6%, respectively) ( Supplementary Table 4 ). For women in the placebo→relugolix-CT group, cumulative probabilities were 42.2%, 87.6%, and 93.6%, respectively. The cumulative probability of women who became opioid-free in the relugolix-CT group was 87.9%, 97.2%, and 98.4% at Weeks 24, 52, and 104, respectively. Similar cumulative probabilities were observed in women treated with delayed relugolix-CT: 92.1%, 96.6%, and 96.6%, respectively. For women treated with placebo→relugolix-CT, cumulative probabilities were 83.0%, 95.1%, and 98.0%, respectively.

In this analysis, median time to achieving minimal-to-no pain associated with dysmenorrhea was observed within approximately two menstrual cycles (8 weeks) from treatment initiation for women who received continuous relugolix-CT, with nearly all women (95.3%) reporting resolution at the end of the 2-year period across treatment groups. Median time to achieving these outcomes in the women who were randomized to placebo in the SPIRIT 1 and 2 studies was not reached until after they entered the SPIRIT LTE study and initiated open-label relugolix-CT, which is expected given the negligible effect of placebo on symptoms. 14 Consistent with minimal-to-no dysmenorrhea, reporting patterns for amenorrhea were achieved within similar time periods and by the majority of women. Unlike dysmenorrhea, which is improved with the achievement of amenorrhea, NMPP may have a more complicated etiology, including fibrosis and neuropathic pain that necessitates a longer course of treatment. Median time to minimal-to-no NMPP was achieved in approximately 8 months in the relugolix-CT group. Over half (59.9%) of women had NMPP at Week 52 and more than two-thirds (70.5%) of women at the conclusion of the SPIRIT LTE study. The increasing cumulative probability of women experiencing resolution of endometriosis-associated pain following treatment with relugolix-CT was in tandem with a decrease in analgesic use. Nearly all women were analgesic- and opioid-free at the end of the 2-year study period across treatment groups. The current analysis used a specific NRS score (NRS ≤1 on a Likert scale of 0 to 10) to define minimal-to-no pain. This threshold provided a strict approach to the evaluation of pain and is consistent with the evaluation of the effects of relugolix-CT in the pivotal Phase 3 program for uterine fibroids (LIBERTY). 20 In the LIBERTY program, the decision to choose a benchmark of NRS ≤1 was based on the expectation that minimal-to-no pain would be associated with less need for analgesics, improved quality-of-life indices, and exceed the standard threshold of 30% improvement in pain that patients consider clinically meaningful. 21 Evaluating pain resolution may help simplify patient counseling about therapeutic options by describing “absence of pain,” rather than “reduction of pain,” which may be more subjective. The majority of women in the SPIRIT LTE study demonstrated improvement in both dysmenorrhea and NMPP using a predefined threshold of meaningful change (a decrease in NRS score of 2.8 points and 2.1 points, respectively) without an increased use of analgesics. 19 Additionally, high rates of amenorrhea were achieved through 104 weeks among women treated with relugolix-CT. 19 Therapy for up to 104 weeks was also associated with sustained and clinically meaningful reductions in dyspareunia and clinically meaningful improvements in function. 19 While there was no control in the SPIRIT LTE, and therefore no means to conclusively state that continued improvements in clinical outcomes were due to treatment, data from the current analysis—which provide more details about the time to effect by reporting the proportion of women who have improvement or resolution of endometriosis-associated pain while receiving continuous treatment with relugolix-CT—indicate improvements in symptoms are experienced as early as 8 weeks from initiation of treatment. While resolution of menstrual pain may be consistent with the mechanism of action of GnRH receptor antagonism and external hormone therapy to suppress ovulation, the resolution of NMPP is more complex. 22 Mechanisms underlying NMPP may include inflammation, intracrine metabolism, and fibrosis, while central sensitization of pain may contribute to NMPP perception. 23 , 24 The processes triggered by the change in hormonal environment with relugolix-CT may take longer to achieve a substantial NMPP reduction. Therefore, it is important to maintain treatment over a long period of time (>1 year) to reduce NMPP. Questions remain about whether there is a differential benefit of GnRH monotherapy compared with combination therapy using estrogen/progestin, the latter could theoretically diminish treatment response because endometriosis is an estrogen-dependent disorder. 25 Higher estrogen and progesterone concentrations would continue to support growth of endometriosis implants and continuation of symptoms. 26 Estrogen-mediated proliferative effects are not expected during treatment with relugolix-CT, and data from the ovulation inhibition study show that estrogen concentrations are consistently maintained at concentrations corresponding to those observed in the early follicular phase of a natural menstrual cycle. 27 , 28 The SPIRIT 1 and 2 trials showed a numerically greater reduction in dysmenorrhea from baseline to Week 12 in women treated with delayed relugolix-CT compared with relugolix-CT, though not for NMPP scores, which became comparable between treatment groups once women treated with delayed relugolix-CT transitioned to relugolix-CT. 14 In the current analysis, cumulative probability of achieving minimal-to-no pain for dysmenorrhea and NMPP showed a similar pattern. The risk profile for relugolix monotherapy for endometriosis in Phase 2 and Phase 3 studies showed a high level of BMD loss compared with relugolix-CT, which was much lower and stabilized over treatment duration. 14 , 29 Furthermore, in SPIRIT 1 and 2, the incidence of vasomotor symptoms (including preferred terms of hyperhidrosis, feeling hot, hot flush, night sweats, and flushing) was lower in women treated with relugolix-CT compared with relugolix monotherapy. 14 These data suggest that hypoestrogenic risks associated with relugolix monotherapy outweigh potential benefit and highlight the therapeutic advantage of initiating treatment with relugolix-CT. In the Elaris EM-III and Elaris EM-IV endometriosis studies, after 12 months of treatment with the GnRH antagonist elagolix, amenorrhea was experienced by 27% and 20% of women, respectively, with the 150 mg once-daily dose; and 63% and 61% of women, respectively, with the 200 mg twice-daily dose. 30 While not head-to-head studies, the SPIRIT LTE study demonstrated the overall incidence of amenorrhea in women treated with continuous relugolix-CT over a similar time period (52 weeks) to be 79.6%. 19 The current analysis provides further understanding of the effects of relugolix-CT on the proportion of women achieving resolution of menses during treatment. These data showed that nearly all women (93.6% at Week 52, and 95.8% at Week 104) developed amenorrhea, consistent with the near elimination of dysmenorrhea. Several factors should be considered when planning surgery for endometriosis, including ovarian reserve, patient intentions and priorities, age, infertility duration, associated infertility factors, previous surgery, pelvic pain, ovarian endometrioma, and associated adenomyosis. 25 For women who choose surgical intervention, laparoscopic management of endometriosis may be associated with short- and long-term complications, including intraoperative injury to the bowel and bladder, major infections, 31 and denervation injury, which can lead to severe constipation, urinary retention, and loss of bowel or bladder function. 32 Additionally, the lack of benefit or sustained effect of surgery may prompt a need for repeated operation; as many as 20% of patients reported no improvement in symptoms. 33 Post-surgery, the incidence of recurrence of endometriosis-related pain is 40–50% within 5 years, and the incidence of persistent chronic postsurgical pain is up to 15–20%, 3–6 months postoperatively. 5 , 6 Despite these risks, repeat surgery is common; with one study finding that only 53.3% of patients remained surgery-free at 5 years. 24 Scientific societies advise that endometriosis should be viewed as a chronic disease, requiring a long-term management plan, aiming to use available medical treatment and avoiding repeated surgeries, 24 and advocate for a “shared decision-making” between healthcare providers and patients. 8 Results of this analysis demonstrate that treatment with relugolix-CT for 104 weeks was associated with a median time to minimal-to-no dysmenorrhea (NRS score ≤1) of two menstrual cycles. The vast majority of women (95.3%) had minimal-to-no pain (dysmenorrhea) at the end of the SPIRIT LTE study and high rates of amenorrhea. Median time to minimal-to-no NMPP was approximately 8 months. Over half of women had minimal-to-no NMPP at Week 52, increasing to 70.5% at the end of the SPIRIT LTE study. Although the cumulative probability of achieving minimal-to-no NMPP increased over time, ~29.5% of women had not achieved this threshold by Week 104, and it is unknown whether this proportion would have continued to decrease with longer follow-up. This is an alternative method to assess the impact of medical treatment on pain symptoms and other features associated with endometriosis. Additionally, real-world evidence that evaluates the heterogeneity of the patient experience, as opposed to the homogeneity of the clinical trial setting, would contribute to better understanding of relugolix-CT. This post hoc analysis benefited from a long-term follow-up of up to 2 years, in a large cohort of women with moderate-to-severe endometriosis-associated pain at baseline. The NRS threshold (NRS ≤1) for pain response used in this study was rigorous and the outcomes were confirmatory of previously published data, 14 , 19 potentially simplifying the communication on treatment effects of relugolix-CT. However, the NRS ≤1 threshold was selected for this post hoc analysis and was not statistically compared with, or intended to replace, the prespecified responder definitions used in SPIRIT 1 and 2 (mean reduction in NRS score of ≥2.8 points for dysmenorrhea and ≥2.1 points for NMPP, with no increase in analgesic use). Therefore, results should be interpreted descriptively and with caution. The LTE portion of this study was open-label and, therefore, subject to potential performance and detection bias, and was also limited by the absence of comparator groups. In addition, the original studies were not initially designed for the endpoints of this post hoc analysis (temporal aspects of treatment response); therefore, the results of this analysis are presented descriptively without inference of statistical significance for treatment differences. Additionally, the high dropout rate may have resulted in censoring that is not independent of outcomes (ie, potentially informative censoring), which should be considered when interpreting the Kaplan–Meier curves.

This post hoc analysis demonstrated the possibility of improvement or resolution of menstrual and non-menstrual pain over time in women with endometriosis-associated pain. Relugolix-CT may help expand treatment options for longer-term management of women who wish to minimize the need for initial or repeat surgical procedures.