Oral Gonadotropin-releasing Hormone Antagonist Research Articles

The effectiveness of relugolix compared with leuprorelin for preoperative therapy before laparoscopic myomectomy in premenopausal women, diagnosed with uterine fibroids: protocol for a randomized controlled study (MyLacR study)

BackgroundThe oral gonadotropin-releasing hormone antagonist relugolix, which temporarily stops menstruation, is used to treat heavy menstrual bleeding, pelvic pressure, and low back pain in women with uterine fibroids. Treatment can also help women recover from low hemoglobin levels and possibly shrink the fibroids. However, evidence of preoperative use of relugolix before laparoscopic myomectomy is limited. Nevertheless, the treatment could reduce interoperative blood loss, decrease the risk of developing postoperative anemia, and shorten the operative time. Thus, we aim to test whether 12-week preoperative treatment with relugolix (40 mg orally, once daily) is similar to or not worse than leuprorelin (one injection every 4 weeks) to reduce intraoperative blood loss.MethodsEfficacy and safety of preoperative administration of drugs will be studied in a multi-center, randomized, open-label, parallel-group, noninferiority trial enrolling premenopausal women ≥ 20 years of age, diagnosed with uterine fibroids and scheduled for laparoscopic myomectomy. Participants (n = 80) will be recruited in the clinical setting of participating institutions. The minimization method (predefined factors: presence or absence of fibroids ≥ 9 cm and the International Federation of Gynecology and Obstetrics [FIGO] type 1–5 fibroids) with randomization is used in a 1:1 allocation. Relugolix is a 40-mg oral tablet taken once a day before a meal, for 12 weeks, up to the day before surgery. Leuprorelin is a 1.88 mg, or 3.75 mg subcutaneous injection, given in three 4-week intervals during patient visits before the surgery. For the primary outcome measure of intraoperative bleeding, the blood flow is collected from the body cavity, surgical sponges, and collection bag and measured in milliliters. Secondary outcome measures are hemoglobin levels, myoma size, other surgical outcomes, and quality-of-life questionnaire responses (Kupperman Konenki Shogai Index and Uterine Fibroid Symptoms—Quality of Life).DiscussionReal-world evidence will be collected in a clinical setting to use pre-treatment with an oral gonadotropin-releasing hormone antagonist to reduce intraoperative bleeding in women who undergo laparoscopic myomectomy.Trial registrationjRCTs031210564 was registered on 19 January 2022 in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp).

Efficacy and Safety of Radiotherapy Plus Relugolix in Men With Localized or Advanced Prostate Cancer

Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer. To assess the efficacy and safety of the oral gonadotropin-releasing hormone antagonist relugolix with radiotherapy for treating prostate cancer. This multicenter post hoc analysis of patients with localized and advanced prostate cancer receiving radiotherapy in 2 randomized clinical trials (a phase 2 trial of relugolix vs degarelix, and a subset of the phase 3 HERO trial of relugolix vs leuprolide acetate) included men who were receiving radiotherapy and short-term (24 weeks) ADT (n = 103) from 2014 to 2015 and men receiving radiotherapy and longer-term (48 weeks) ADT (n = 157) from 2017 to 2019. The data were analyzed in November 2022. Patients receiving short-term ADT received relugolix, 120 mg, orally once daily (320-mg loading dose) or degarelix, 80 mg, 4-week depot (240-mg loading dose) for 24 weeks with 12 weeks of follow-up. Patients receiving longer-term ADT received relugolix, 120 mg, orally once daily (360-mg loading dose) or leuprolide acetate injections every 12 weeks for 48 weeks, with up to 90 days of follow-up. Castration rate (testosterone level <50 ng/dL [to convert to nmol/L, multiply by 0.0347) at all scheduled visits between weeks 5 and 25 for patients receiving short-term ADT and weeks 5 and 49 for patients receiving longer-term ADT. Of 260 patients (38 Asian [14.6%], 23 Black or African American [8.8%], 21 Hispanic [8.1%], and 188 White [72.3%] individuals), 164 (63.1%) received relugolix. Relugolix achieved castration rates of 95% (95% CI, 87.1%-99.0%) and 97% (95% CI, 90.6%-99.0%) among patients receiving short-term and longer-term ADT, respectively. Twelve weeks post-short-term relugolix, 34 (52%) achieved testosterone levels to baseline or more than 280 ng/dL. Ninety days post longer-term ADT, mean (SD) testosterone levels were 310.5 (122.4) (106.7) ng/dL (relugolix; n = 15) vs 53.0 ng/dL (leuprolide acetate; n = 8) among the subset assessed for testosterone recovery. Castration resistance-free survival was not statistically different between the relugolix and leuprolide acetate cohorts (hazard ratio, 0.97; 95% CI, 0.35-2.72; P = .62). Adverse events grade 3 or greater for short-term or longer-term relugolix (headache, hypertension, and atrial fibrillation) were uncommon (less than 5%). The results of these 2 randomized clinical trials suggest that relugolix rapidly achieves sustained castration in patients with localized and advanced prostate cancer receiving radiotherapy. No new safety concerns were identified when relugolix was used with radiotherapy.

Relugolix versus leuprolide in combination with radiotherapy for localized prostate cancer (REVELUTION trial): An initial analysis of patient treatment preferences and quality of life.

301 Background: Relugolix, an oral gonadotropin releasing hormone (GnRH) antagonist, has superior testosterone suppression and may lower cardiovascular (CV) toxicity compared with more commonly used injectable GnRH agonists, such as leuprolide. The Relugolix Versus Leuprolide Trial (REVELUTION, NCT 05320406) is an ongoing, investigator-initiated, randomized trial comparing radiotherapy (XRT) plus relugolix versus XRT plus leuprolide for men with localized prostate cancer (PCa). Primary endpoint is change in coronary plaque on cardiac computed tomography from baseline to 12 months following treatment. Secondary endpoints include patient-reported outcomes (PRO). Herein, we report patient-specific treatment preferences prior to randomization and acute treatment-associated toxicity. Methods: Men with non-metastatic intact or biochemically recurrent PCa pursuing pelvic XRT (1.8-2.5 Gy per fraction) with ≥ 6 months of androgen deprivation therapy (ADT) were enrolled and randomized 1:1 to leuprolide (IM/SC 45 mg q6mo) or relugolix (PO 360 mg day 1, 120 mg daily thereafter). Prior to randomization, each patient completed an ADT preference questionnaire after reviewing an education brochure describing both drugs’ administration, testosterone kinetics, and common toxicities. PROs were assessed by International Prostate Symptom Score (IPSS) and Expanded Prostate Index Composite (EPIC-CP) at baseline and 3-/6-months after XRT initiation, with higher scores indicating more severe toxicity. Scores were compared using linear mixed-effects models accounting for within-subject correlations. Results: Between 06/2022 and 07/2023, 65 men were randomized (34 leuprolide, 31 relugolix). Median follow-up was 5 months (IQR 4-8). Prior to randomization, 61 (94%) preferred relugolix over leuprolide, due to faster testosterone recovery (n=36, 59%), lower CV risk (n=23, 38%), or oral administration (n=2, 3%); the four patients who preferred leuprolide all had compliance concerns with a daily oral pill. Compared with XRT+leuprolide, XRT+relugolix was associated with less impact on IPSS urinary score (mean difference [MD] -3.68, p=0.04). There was no difference in EPIC-CP incontinence (MD +0.07, p=0.91), bowel (MD +0.39, p=0.44), sexual (MD -0.74, p=0.43), or vitality (MD +0.17, p=0.80). Conclusions: In this trial of men with localized PCa treated with XRT plus ADT, most preferred relugolix over leuprolide. Relugolix, compared with leuprolide, mitigated acute urinary toxicity from XRT, perhaps due to superior castration resulting in greater prostate gland downsizing and less obstructive uropathy. Longer-term follow up is ongoing, and primary CV toxicity endpoint is expected to be complete in 2024. Clinical trial information: NCT05320406 .

Management of Advanced Prostate Cancer With Relugolix: Illustrative Case Scenarios From an Advanced Practice Provider Perspective

Prostate cancer is the second most common cause of cancer-related mortality among men in the United States, with an estimated 34,700 deaths annually. Androgen deprivation therapy (ADT) is the cornerstone of advanced prostate cancer therapy, and injectable luteinizing hormone-releasing hormone (LHRH) agonists have served as the most commonly used ADT for over 30 years. Relugolix, a first-in-class, once-daily, oral gonadotropin-releasing hormone (GnRH) antagonist, was developed to address some of the limitations of available ADT therapies. Herein, we present two hypothetical case reports via an advanced practice provider (APP) perspective that reflect prototypical examples of patients with advanced localized disease not suitable for surgery or newly diagnosed hormone-sensitive metastatic disease treated with relugolix. The cases presented are meant to be instructional and within the scope of the current approved prescribing information for all medications mentioned. Best practices from an APP perspective are shared.

Maintenance of castration with concomitant relugolix and apalutamide (Apa) in patients with high-risk localized prostate cancer (HR-LPC): 1 year update.

e17094 Background: Androgen deprivation therapy (ADT) is a mainstay in the management of prostate cancer (PC). We assessed the efficacy of achieving and maintaining castrate testosterone (T) levels when combining relugolix, an oral gonadotropin-releasing hormone antagonist, concomitantly with Apa, an androgen receptor inhibitor. The single-arm, open-label, multicenter, phase 2 Apa-RP study evaluates the biochemical recurrence-free rate in patients with HR-LPC following radical prostatectomy (RP) who received 12 months of adjuvant Apa and ADT (main study). A substudy was added to assess whether the approved maintenance dose of relugolix with concomitant Apa maintained castration. Study results of the 28-day coadministration of relugolix + Apa showed that all evaluable patients achieved and maintained castration at standard relugolix dose and were transitioned into the main study (Brown et al. Target Oncol. 2022). Herein, we report longer term data of T levels and safety findings in the substudy patients who received relugolix + Apa for 1 year. Methods: Patients (n = 12) with HR-LPC (PSA ≥20 ng/mL or Gleason score ≥8) received a loading dose of relugolix (360 mg) at substudy initiation (Day -14) followed by the standard, approved relugolix dose (120 mg/d) for 13 days. Starting on Day 1, patients received relugolix + Apa (240 mg/d) for 28 days, with substudy completion on Day 28. These patients transitioned to the main study and received relugolix + Apa for a total of 1 year. T levels (castrate level defined as &lt; 50 ng/dL) were measured at baseline (Day -14), Day 1, Day 28, and then every 3 months. Results: Of the 12 patients who continued onto the main study, 1 withdrew and another was noncompliant with therapy and subsequently withdrew but maintained castration while on therapy. Of the 10 patients who successfully completed therapy, 100% maintained castration during 1 year of concomitant therapy with relugolix + Apa . No patient required dose modification of relugolix. Median T level was 10.0 ng/dL after 1 year of treatment. One month after treatment discontinuation, 8/10 (80%) patients saw recovery of their T (T ≥50 ng/dL). Treatment-emergent adverse events (TEAEs) occurred in all 12 patients (100%). TEAEs were consistent with known safety profiles for each drug administered separately. Conclusions: During the 12 months of concomitant relugolix + Apa administration, all patients who completed therapy maintained castrate T levels without relugolix dose modification. All but 2 patients had T recovery within 30 days of therapy discontinuation. These data support long-term T suppression with relugolix + Apa at standard doses. Subsequent T levels will be reported upon final analysis of the main study. Clinical trial information: NCT04523207 .

Clinical development of the oral gonadotropin-releasing hormone antagonist elagolix

Elagolix is the first oral gonadotropin-releasing hormone antagonist that entered clinical development and received regulatory approval for the management of women with endometriosis and heavy menstrual bleeding associated with uterine fibroids in combination with a hormonal add-back therapy. This mini review aims to summarize the key clinical studies that led to its regulatory approval.

Safety, pharmacokinetics, and pharmacodynamics of SHR7280, an oral gonadotropin-releasing hormone antagonist in healthy premenopausal women.

Background: Treatment with gonadotropin-releasing hormone (GnRH) antagonists is a powerful strategy to suppress gonadotropin activity in women with sex hormone-dependent disorders. Herein, we provide the safety, pharmacokinetics (PK), and pharmacodynamics (PD) profiles of SHR7280, an oral non-peptide GnRH antagonist in healthy premenopausal women. Methods: In this randomized, double-blinded, placebo-controlled, dose-ascending, phase 1 trial, healthy premenopausal women were randomized to receive SHR7280 or placebo orally. Four doses of SHR7280 (200, 300, 400, and 500mg BID) were planned. Safety, PK, and PD parameters were evaluated. Results: SHR7280 presented tolerable toxicity and most adverse events were mild in severity. SHR7280 showed rapid onset of action (median Tmax ranged from 1.0 to 1.2h for each dose), and plasma exposure was dose-dependent. PD results showed that SHR7280 300mg BID and above suppressed estrogen concentration within the estradiol (E2) treatment window for endometriosis (20-50pg/ml), inhibited the emergence of the peak of luteinizing hormone (LH) and the concentration of follicle stimulating hormone (FSH), and maintained the concentration of progesterone (P) in an anovulatory state (2nmol/L). Conclusion: SHR7280 showed favorable safety, PK, and PD profiles in the dose range of 200-500mg BID in healthy premenopausal women. This study supports the continued clinical development of SHR7280 as a GnRH antagonist for sex hormone-dependent disorders in women. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04554043, Identifier NCT04554043.

Development of relugolix combination therapy as a medical treatment option for women with uterine fibroids or endometriosis

Treatment of uterine fibroids (UF) and endometriosis (EM) has relied on the surgical skills of gynecologists to improve symptoms and potentially alter the course of these debilitating diseases. Medical management of symptoms for both diseases leverages combined hormonal contraceptives used off label as a first-line treatment, with nonsteroid anti-inflammatory drugs and opioids to manage pain as needed. Gonadotropin-releasing hormone (GnRH) receptor agonists (peptide analogs) have been used as short-term therapy to manage severe symptoms of UF or EM, treat anemia, and reduce fibroid size before surgery. The introduction of oral GnRH receptor antagonists opened the door for the development of new treatment options for UF, EM, and other estrogen-driven diseases. Relugolix is an orally active, nonpeptide, GnRH receptor antagonist that competitively binds to GnRH receptors, preventing the release of follicle-stimulating hormone and luteinizing hormone (LH) into the systemic circulation. In women, the reduction in follicle-stimulating hormone concentrations prevents natural follicular development, suppressing ovarian production of estrogen, and together with reductions in LH concentrations, prevent ovulation, corpus luteum formation, and, thereby, the production of progesterone (P). By reducing circulating concentrations of estradiol (E2) and P, relugolix improves heavy menstrual bleeding and other symptoms associated with UF and moderate to severe pain associated with EM, including dysmenorrhea, nonmenstrual pelvic pain (NMPP) and dyspareunia. However, as monotherapy, the use of relugolix is associated with signs and symptoms of a hypoestrogenic state, including bone mineral density loss and vasomotor symptoms. The clinical development of relugolix incorporated the addition of a 1 mg dose of E2 and a 0.5-mg dose of norethindrone acetate (NETA) to achieve systemic E2 concentrations that remain in a therapeutic range while mitigating the risk for bone mineral density loss and vasomotor symptoms, enabling the longer-term treatment and reducing the impact of symptoms on quality of life, and potentially delaying or preventing the need for surgery. Relugolix 40 mg in combination with estradiol (E2) 1 mg and NETA 0.5 mg as a single fixed-dose combination tablet (relugolix combination therapy [relugolix-CT]) approved in the United States as MYFEMBREE is the first and only once daily oral GnRH antagonist combination therapy indicated for the management of heavy menstrual bleeding associated with UF and moderate to severe pain associated with EM. In the European Union (EU) and the United Kingdom (UK), relugolix-CT is approved as RYEQO for the management of symptoms associated with UF. In Japan, relugolix 40 mg, as monotherapy, was the first GnRH receptor antagonist approved to improve symptoms associated with UF or pain associated with EM under the brand name RELUMINA. In men, relugolix suppresses testosterone production. Relugolix 120 mg (ORGOVYX) was developed by Myovant Sciences and is approved in the United States, EU, and UK as the first and only oral androgen-deprivation therapy for the treatment of advanced prostate cancer. This review is focused on the development of relugolix and relugolix-CT in women's health indications.

Pre-IVF treatment with a GnRH antagonist in women with endometriosis (PREGNANT): study protocol for a prospective, double-blind, placebo-controlled trial

IntroductionInfertility is a common complication of endometriosis. While in vitro fertilisation-embryo transfer (IVF) successfully treats endometriosis-associated infertility, there is some evidence that pregnancy rates may be diminished in women seeing...

Oral Gonadotropin-Releasing Hormone Antagonist Relugolix Has the Same Effect as Gonadotropin-Releasing Hormone Agonist Injections in Terms of Preparation for Transcervical Resection Myomectomy.

For preparing the optimal condition in transcervical resection (TCR) surgery, gonadotropin-releasing hormone (GnRH) agonist has been utilized. Recently, an oral GnRH antagonist (relugolix) is available and acts directly on GnRH receptor, avoiding flare up and reducing blood E2 levels rapidly. We retrospectively compared the oral GnRH antagonist (n = 14) effect to that of subcutaneous GnRH agonist (n = 19) for the pretreatment of endometrium in TCR myomectomy. Endometrial thickening was determined by intraoperative videos. The color tone of the endometrium in the normal part was assessed by digital image processing. The median duration of the first GnRH agonist injection and the surgery was 67 days (21-136 days), which is significantly longer than that of the oral GnRH antagonist group, 18.5 days (7-157 days P < 0.01). Both the GnRH agonist and antagonist groups did not exhibit prominence in the endometrium. The GnRH antagonist group showed the same degree of whiteness in the normal endometrium as the GnRH agonist group. The oral GnRH antagonist administration could rapidly atrophy the endometrium and create an optimal surgical field for TCR in a short period.

The novel oral gonadotropin‐releasing hormone receptor antagonist relugolix is a new option for controlled ovarian stimulation cycles

PurposeRelugolix is an oral gonadotropin‐releasing hormone antagonist (GnRHant), which was first introduced in 2019. This study investigated the effects of the conventional injectable GnRHant formulation and this new oral GnRHant formulation on controlled ovarian stimulation (COS) cycles.MethodsRelugolix was administered in 126 cycles and conventional GnRHant injection was administered in 658 cycles (controls). The follicle stimulation was performed by an antagonist method, and for final oocyte maturation, recombinant human chorionic gonadotropin (rHCG), or gonadotropin‐releasing hormone agonist (GnRHa), or both (dual trigger) were selected. The number of retrieved oocytes was counted and then they were evaluated for subsequent development up to cleavage stage.ResultsThe number of retrieved oocytes which was the primary outcome of this research was affected by the combination of GnRHant type and the final oocyte maturation agent. The combination of relugolix and a GnRHa trigger showed a significantly lower number of retrieved oocytes (p < 0.001) than the other combinations.ConclusionsRelugolix is a new option for COS cycles, but should be carefully combined with the final maturation agent.Clinical trial approvalThis study was conducted after approval by the Medical Corporation Sankeikai Institutional Ethics Committee (approval number: 2019‐34).

Uterine Adenomyosis Treated by Linzagolix, an Oral Gonadotropin-Releasing Hormone Receptor Antagonist: A Pilot Study with a New ’Hit Hard First and then Maintain’ Regimen of Administration

(1) Background: The aim of the present pilot study was to study the effect of a new oral gonadotropin-releasing hormone antagonist on adenomyosis. (2) Methods: Eight premenopausal women, aged between 37 and 45 years, presenting with heavy menstrual bleeding, pelvic pain, and dysmenorrhea due to diffuse and disseminated uterine adenomyosis, confirmed by magnetic resonance imaging (MRI), received 200 mg linzagolix once daily for a period of 12 weeks, after which they were switched to 100 mg linzagolix once daily for another 12 weeks. The primary efficacy endpoint was the change in volume of the adenomyotic uterus from baseline to 24 weeks, evaluated by MRI. Secondary efficacy endpoints included the change in uterine volume from baseline to 12 and 36 weeks by MRI, and also weeks 12, 24, and 36 assessed by transvaginal ultrasound (TVUS). Other endpoints were overall pelvic pain, dysmenorrhea, non-menstrual pelvic pain, dyspareunia, amenorrhea, quality of life measures, bone mineral density (BMD), junctional zone thickness, and serum estradiol values. (3) Results: Median serum estradiol was suppressed below 20 pg/mL during the 12 weeks on linzagolix 200 mg, and maintained below 60 pg/mL during the second 12 weeks on linzagolix 100 mg. At baseline, the mean ± SD uterine volume was 333 ± 250 cm3. After 24 weeks of treatment, it was 204 ± 126 cm3, a reduction of 32% (p = 0.0057). After 12 weeks, the mean uterine volume was 159 ± 95 cm3, a reduction of 55% from baseline (p = 0.0001). A similar pattern was observed when uterine volume was assessed by TVUS. Improvements in overall pelvic pain, dysmenorrhea, non-menstrual pelvic pain, dyspareunia, and dyschezia, as well as quality of life measured using the EHP-30 were also observed. Mean percentage BMD loss at 24 weeks was, respectively, −2.4%, −1.3%, and −4.1% for the spine, femoral neck, and total hip. The most common adverse events were hot flushes, which occurred in 6/8 women during the first 12 weeks, and 1/8 women between 12 and 24 weeks. (4) Conclusions: Linzagolix at a dose of 200 mg/day reduced uterine volume, and improved clinically relevant symptoms. Treatment with 100 mg thereafter retains the therapeutic benefits of the starting dose while minimizing side effects. This ‘hit hard first and then maintain’ approach may be the optimal way to treat women with symptomatic adenomyosis.

A novel orally active gonadotropin‐releasing hormone antagonist, relugolix, is a potential substitute for injectable GnRH antagonists in controlled ovarian stimulation in assisted reproductive technology

PurposeTo evaluate the efficacy of an oral gonadotropin‐releasing hormone antagonist (GnRH Ant), relugolix (R), for assisted reproductive technology (ART).MethodsWe enrolled women undergoing ART using a GnRH Ant for controlled ovarian stimulation. We compared R; 20 mg/day with cetrorelix acetate (C); 0.125 mg. C was administered to 88 women in 2019, and R to 93 women in 2020. Clinical outcomes associated with ART were assessed in both groups.ResultsThe luteinizing hormone levels on the day of human chorionic gonadotropin injection in the R group (1.26 ± 0.93 IU/L) were significantly lower than those in the C group (2.85 ± 3.02 IU/L). There were no cases in which egg retrieval was canceled in both groups. The total doses of gonadotropins administered were greater in the R group compared with the C group. The number of days of GnRH Ant administration in the R group (1.71 ± 0.57 days) was significantly longer compared with the C group (1.48 ± 0.58 days). The number of oocytes collected, fertilization rates, and pregnancy rates (R; 47.1% vs C; 45.8%) did not differ between the two groups.ConclusionAn orally active GnRH Ant, relugolix, when used in controlled ovarian stimulation for ART, showed comparable clinical outcomes with cetrorelix.

Relugolix, an oral gonadotropin-releasing hormone antagonist for the treatment of prostate cancer.

Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) analogues is standard treatment for intermediate and advanced prostate cancer. GnRH agonist therapy results in an initial testosterone flare, and increased metabolic and cardiovascular risks. The GnRH antagonist relugolix is able to reduce serum testosterone levels in men with prostate cancer without inducing testosterone flare. In the HERO Phase III trial, relugolix was superior to leuprolide acetate at rapidly reducing testosterone and continuously suppressing testosterone, with faster post-treatment recovery of testosterone levels. Relugolix was associated with a 54% lower incidence of major adverse cardiovascular events than leuprolide acetate. As the first oral GnRH antagonist approved for the treatment of advanced prostate cancer, relugolix offers a new treatment option.

Linzagolix: a new GnRH-antagonist under investigation for the treatment of endometriosis and uterine myomas

ABSTRACT Introduction Uterine myomas and endometriosis are benign hormone-dependent diseases affecting women of reproductive age. Substantial efforts have been made to develop innovative medical options for treating these gynecologic diseases. Elagolix and relugolix have been approved in some countries for treating endometriosis and myomas, respectively; however, linzagolix (OBE 2109, KLH 2109) is a new oral gonadotropin-releasing hormone (GnRH) antagonist in phase II–III trials. Treatment options for women with contraindications for hormonal therapies or who refuse particular options, are the driving force behind the development of new drugs in this area. Area covered This drug evaluation highlights definitive and preliminary results from previous and ongoing studies of linzagolix for the treatment of endometriosis and myomas. Expert opinion Linzagolix showed a dose-dependent and rapidly reversible action on the pituitary-gonadal axis. In a recent phase II trial (EDELWEISS), linzagolix significantly reduced pain related to endometriosis and improved quality of life at single daily doses of 75–200 mg. The preliminary results of international, double-blind phase III trials (PRIMROSE 1 and 2) reported its efficacy in treating heavy menstrual bleeding related to myomas with a good safety profile. Further studies will determine the necessity of add-back therapy during long-term use of linzagolix.

Recognizing and treating endometriosis.

Endometriosis, defined as endometrium-like tissue located outside the uterine cavity, is a chronic and frequently painful disease that affects about 10% of reproductive-aged women worldwide. The ectopic endometrial tissue, which is still hormonally responsive, generates a chronic inflammatory state resulting in an array of sometimes debilitating symptoms as well as subfertility. Despite its prevalence and significant effect on a woman's health and quality of life, receiving a diagnosis of endometriosis often takes years. This article reviews the epidemiology, pathophysiology, clinical presentation, and treatment options for managing endometriosis in women who do not desire pregnancy and in those who do, and includes information on the newest treatment option, the oral gonadotropin-releasing hormone (GnRH) antagonist elagolix.

Efficacy and safety of elagolix with add-back therapy in women with uterine fibroids and coexisting adenomyosis

ObjectiveTo determine if coexisting adenomyosis limits the efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy in reducing heavy menstrual bleeding in women with uterine fibroids.DesignPooled analysis of two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids [UF]-1 and UF-2).SettingA total of 153 gynecological clinical care settings in the United States and Canada.Patient(s)Premenopausal women (18–51 years) with >80 mL of menstrual blood loss (MBL)/cycle and uterine fibroids with and without coexisting adenomyosis diagnosed by ultrasound and/or magnetic resonance imaging at baseline.Intervention(s)Participants were randomized 1:1:2 to placebo, elagolix 300 mg twice daily alone, or elagolix 300 mg twice daily with estradiol 1 mg/norethindrone acetate 0.5 mg once daily.Main Outcome Measure(s)The primary endpoint was the proportion of women who had <80 mL of MBL during the final month and ≥50% reduction in MBL from baseline to the final month. Adverse events were monitored.Result(s)Of 786 women treated across the two trials, 16% (126 women) had coexisting adenomyosis. Among this subset, a significantly greater proportion of women who received elagolix with add-back therapy (77.1% [95% confidence interval, 66.2, 88.0]) met both primary endpoint criteria compared with women who received placebo (12.2% [95% confidence interval, 1.0, 23.4]). Adverse events most frequently reported in the elagolix with add-back adenomyosis subset were hot flushes (18.3%), nausea (11.7%), and night sweats (8.3%).Conclusion(s)Elagolix with add-back therapy significantly reduced heavy menstrual bleeding in women with uterine fibroids and coexisting adenomyosis, suggesting that elagolix efficacy was not adversely affected by the presence of adenomyosis (Elaris UF-1 and UF-2 Clinical-Trials.gov numbers, NCT02654054 and NCT02691494).

Endometriosis and Medical Therapy: From Progestogens to Progesterone Resistance to GnRH Antagonists: A Review

Background: The first objective of this review was to present, based on recent literature, the most frequently applied medical options (oral contraceptive pills (OCPs) and progestogens) for the management of symptomatic endometriosis, and evaluate their effectiveness in treating premenopausal women with endometriosis-associated pelvic pain, dysmenorrhea, non-menstrual pelvic pain and dyspareunia. The second objective was to review the concept of progesterone resistance and newly available treatment options. Methods: We reviewed the most relevant papers (n = 73) on the efficacy of OCPs and progestogens as medical therapy for endometriosis, as well as those on progesterone resistance and new medical alternatives (oral gonadotropin-releasing hormone (GnRH) antagonist). Eleven papers, essentially reviews, were selected and scrutinized from among 94 papers discussing the concept of progesterone resistance. Results: Having reviewed the most significant papers, we can confirm that OCPs and progestogens are effective in two-thirds of women suffering from endometriosis, but that other options are required in case of failure (in one-third of women due to progesterone resistance) or intolerance to these compounds. It is clear that there is a need for effective long-term oral treatment capable of managing endometriosis symptoms, while mitigating the impact of side effects. Biochemical, histological and clinical evidence show that estrogens play a critical role in the pathogenesis of endometriosis, so lowering levels of circulating estrogens should be considered an effective medical approach. The efficacy of three oral GnRH antagonists is discussed on the basis of published studies. Conclusion: There is a place for GnRH antagonists in the management of symptomatic endometriosis and clinical trials should be conducted, taking into account the different phenotypes in order to propose novel algorithms.

Relugolix: a novel androgen deprivation therapy for management of patients with advanced prostate cancer.

Androgen deprivation therapy (ADT) is the foundation of treatment for patients with locally advanced, recurrent and metastatic prostate cancer, most commonly using luteinizing releasing hormone (LHRH) agonists. More recently, a new approach to ADT has emerged with the development of gonadotropin-releasing hormone (GnRH) antagonists, which aim to overcome some of the potential adverse physiologic effects of LHRH agonists. This article focuses on the newest GnRH antagonist, relugolix – a once-daily treatment and the only oral GnRH antagonist that has now been approved for the treatment of advanced prostate cancer. In phase II and III studies, relugolix achieved rapid and sustained castration without the testosterone surge associated with LHRH agonists, thus avoiding the potential clinical consequences of tumor flare and the necessity for concomitant anti-androgen therapy. Relugolix also achieved rapid testosterone recovery, which may potentially reduce ADT-related adverse events and offer opportunities for combination and intermittent therapy strategies. Cardiovascular safety is a particular concern in men with prostate cancer and ADT further increases cardiovascular risk: indeed, LHRH agonists are required to have a drug label warning about an increased risk of cardiovascular disease. Data from the phase III HERO study demonstrate an improved cardiac safety profile for the GnRH antagonist relugolix compared with the LHRH agonist leuprolide, including a significantly reduced risk for a major adverse cardiovascular event. Taken together, the data indicate that relugolix may mitigate some of the cardiovascular concerns surrounding ADT and has the potential to become a new standard of care for men with prostate cancer. In summary, relugolix represents a novel and recently available prostate cancer management strategy, incorporating the mechanistic advantages of GnRH antagonists and the potential benefits of oral administration.

Real-World Characterization of Women with Diagnosed Endometriosis Initiating Therapy with Elagolix Using a US Claims Database.

PurposeElagolix is an oral gonadotropin-releasing hormone antagonist approved in the United States for the management of moderate to severe pain associated with endometriosis. We performed a real-world evaluation of the demographic and clinical characteristics of women diagnosed with endometriosis who were initiating elagolix therapy in the United States.Patients and MethodsThis retrospective cohort database analysis included women 18–49 years of age with ≥1 pharmacy claim for elagolix between August 2018 and December 2019 from the Copyright © 2020 Truven Health Analytics LLC. All Rights Reserved. Women had continuous medical and pharmacy health plan enrollment during the baseline period (year immediately preceding the index date [date of earliest elagolix claim]) and had ≥1 medical claim with endometriosis (International Classification of Diseases [ICD]-9/10 code [617.x and N80.x]) on or before the index date. Baseline demographics, comorbidities, ICD code-based endometriosis anatomic site, endometriosis-related treatments, and pain symptoms were summarized descriptively.ResultsThe study included 2083 patients with mean age at baseline of 33.2 ± 8.1 years. Comorbidities most commonly recorded were non-cancer, non-endometriosis pain (59.5%), including arthritis/joint pain (43.7%) and back/neck pain (31.7%), and mental disorder (40.7%), including anxiety (32.7%). The majority of endometriosis diagnosis codes recorded referred to unspecified location (52.3%) and pelvic peritoneum (23.0%); 61.0% of patients received a medical endometriosis-related treatment in the baseline period, with the most common treatments being contraceptives (various routes of administration, 40.2%) and progestins (31.7%). Additionally, 35.4% of the patients received an endometriosis-related surgery during baseline, with the most common being laparoscopy (33.2% of all patients). Opioids were used during the baseline period by 57.3% of the patients. For pain symptoms, 71.5%, 30.4%, and 19.3% of the patients had claims for pelvic pain, dysmenorrhea, and dyspareunia, respectively.ConclusionEndometriosis therapies were used by a significant proportion of patients with endometriosis in the year immediately preceding elagolix initiation.