Comparative Cardiovascular Safety of Gonadotropin-releasing Hormone Antagonists and Agonists Among Patients Diagnosed with Prostate Cancer: A Systematic Review and Meta-analysis of Real-world Evidence Studies.

BACKGROUND AND OBJECTIVE: Gonadotropin-releasing hormone (GnRH) antagonists and agonists are cornerstone treatments in prostate cancer. However, evidence regarding the comparative cardiovascular safety of these drugs from clinical trials is inconclusive. The objective of this study was to systematically assess the risk of adverse cardiovascular events of GnRH antagonists compared with GnRH agonists across real-world evidence studies. METHODS: We conducted a systematic search of PubMed, Embase, Cochrane Library, Scopus, and Web of Science (2008-2023). We included real-world evidence studies comparing the risk of cardiovascular outcomes of GnRH antagonists with those of GnRH agonists among patients with prostate cancer. We conducted a meta-analysis of effect estimates across studies at a low or moderate risk of bias, assessed via the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool, using random-effect models. KEY FINDINGS AND LIMITATIONS: Among ten included studies, four were classified as having a moderate and six as having a serious risk of bias. Across three studies at a moderate risk of bias in the primary analysis, degarelix was associated with an increased risk (pooled relative risk [RR]: 1.31, 95% confidence interval [CI]: 1.14-1.51) of major adverse cardiovascular events (MACEs). An augmented risk was observed in two studies among patients with a history of cardiovascular disease (pooled RR: 1.31, 95% CI: 1.11-1.56) compared with one study among patients without a history of cardiovascular disease (RR: 1.15, 95% CI: 0.83-1.59). CONCLUSIONS AND CLINICAL IMPLICATIONS: Real-world evidence studies indicate that degarelix, compared with GnRH agonists, is associated with a modest increased risk of MACEs, particularly among patients with a history of cardiovascular disease. However, residual confounding due to the treatment of high-risk patients with degarelix may account for these findings. Additional large studies with detailed data on tumor characteristics and cardiovascular risk factors are needed to confirm these findings. PATIENT SUMMARY: In this systematic evaluation of evidence among patients diagnosed with prostate cancer in routine care, degarelix was associated with higher cardiovascular adverse outcomes than gonadotropin-releasing hormone agonists.

A review of phase II and III drugs for the treatment and management of endometriosis.

INTRODUCTION: Endometriosis is an estrogen-dependent disease that gives rise to pelvic pain and infertility. Although estroprogestins and progestins currently stand as the first-line treatments for this condition, demonstrating efficacy in two-thirds of patients, a significant portion of individuals experience only partial relief or symptom recurrence following the cessation of these therapies. The coexistence of superficial, deep endometriosis, and ovarian endometriomas, as three distinct phenotypes with unique pathogenetic and molecular characteristics, may elucidate the current heterogeneous biological response to available therapy. AREAS COVERED: The objective of this review is to furnish the reader with a comprehensive summary pertaining to phase II-III hormonal treatments for endometriosis. EXPERT OPINION: Ongoing research endeavors are directed toward the development of novel hormonal options for this benign yet debilitating disease. Among them, oral GnRH antagonists emerge as a noteworthy option, furnishing rapid therapeutic onset without an initial flare-up; these drugs facilitate partial or complete estrogen suppression, and promote prompt ovarian function recovery upon discontinuation, effectively surmounting the limitations associated with previously employed GnRH agonists. Limited evidence supports the use of selective estrogen and progesterone receptor modulators. Consequently, further extensive clinical research is imperative to garner a more profound understanding of innovative targets for novel hormonal options.

Safety, pharmacokinetics, and pharmacodynamics of SHR7280, an oral gonadotropin-releasing hormone receptor antagonist, in healthy men: a randomized, double-blind, placebo-controlled phase 1 study.

BACKGROUND: Gonadotropin-releasing hormone (GnRH) antagonists are a promising therapeutic approach for treating hormone-dependent prostate cancer. Currently, the mainstream GnRH antagonists are polypeptide agents administered through subcutaneous injection. In this study, we evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR7280, an oral small molecule GnRH antagonist, in healthy men. METHODS: This phase 1 trial was a randomized, double-blind, placebo-controlled, and dose-ascending study. Eligible healthy men were randomized in a 4:1 ratio to receive either oral SHR7280 tablets or placebo twice daily (BID) for 14 consecutive days. The SHR7280 dose was initiated at 100 mg BID and then sequentially increased to 200, 350, 500, 600, 800, and 1000 mg BID. Safety, PK, and PD parameters were assessed. RESULTS: A total of 70 subjects were enrolled and received the assigned drug, including 56 with SHR7280 and 14 with placebo. SHR7280 was well-tolerated. The incidence of adverse events (AEs, 76.8% vs 85.7%) and treatment-related AEs (75.0% vs 85.7%), as well as the severity of AEs (moderate AEs, 1.8% vs 7.1%) were similar between the SHR7280 group and placebo group. SHR7280 was rapidly absorbed in a dose-dependent manner, with a median Tmax of each dose group ranging from 0.8 to 1.0 h on day 14 and a mean t1/2 ranging from 2.8 to 3.4 h. The PD results demonstrated that SHR7280 exhibited a rapid and dose-proportional suppression of hormones, including LH, FSH, and testosterone, with maximum suppression achieved at doses of 800 and 1000 mg BID. CONCLUSIONS: SHR7280 showed an acceptable safety profile, as well as favorable PK and PD profiles within a dose range of 100 to 1000 mg BID. This study proposes a rationale for further investigation of SHR7280 as a potential androgen deprivation therapy. TRIAL REGISTRATION: Clinical trials.gov NCT04554043; registered September 18, 2020.

Oral gonadotropin-releasing hormone antagonists for treating endometriosis-associated pain: a systematic review and network meta-analysis.

OBJECTIVE: To review the use of oral gonadotropin-releasing hormone (GnRH) antagonists and synthesize their efficacy and safety parameters for the treatment of endometriosis-associated pain. DESIGN: Systematic review and network meta-analysis. SETTING: Not applicable. PATIENT(S): Premenopausal women with endometriosis who had experienced moderate or severe pain. INTERVENTION(S): The Web of Science, Embase, Scopus, and MEDLINE were searched until April 10, 2022. Only randomized controlled trials were included. The risk of bias in the included studies was assessed using the Cochrane Risk of Bias tool 2. A Bayesian random-effects network meta-analysis was used to perform indirect comparisons. I2 was used to assess the global heterogeneity. Relative treatment estimates were performed. Treatment ranking was performed through the surface under the cumulative ranking curve. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation framework. MAIN OUTCOME MEASURE(S): Endometriosis-associated pain, dysmenorrhea, dyspareunia, and noncyclic pelvic pain reduction. RESULT: (s): Five studies and 6 randomized controlled trials, including a total of 2,796 women and 10 different doses of oral GnRH antagonist treatments, were eligible for inclusion. All studies were considered to have a low risk of bias. Almost all efficacy- and safety-related outcomes showed a dose-response relationship. Regarding endometriosis-associated pain, the top 3 treatments were elagolix 400 mg, linzagolix 75 mg, and linzagolix 200 mg, with mean differences of -1.26 (95% credible interval [CrI], -1.70 to -0.79), -0.98 (95% CrI, -1.84 to -0.15), and -0.98 (95% CrI, -1.90 to -0.064), respectively. The top 3 treatments to decrease dysmenorrhea were relugolix 40 mg, elagolix 400 mg, and relugolix 20 mg, with mean differences of -1.60 (95% CrI, -2.07 to -1.14), -1.25 (95% CrI, -1.56 to -0.95), and -1.10 (95% CrI, -1.59 to -0.62), respectively. However, only high-dose treatments were significantly associated with most quality of life- and adverse effect-related outcomes. Relugolix 40 and 20 mg and elagolix 400 mg, with odds ratios of 6.88 (95% CrI, 2.18-24.58), 1.60 (95% CrI, 0.62-4.13), and 1.85 (95% CrI, 1.05-3.30), had a significantly increased incidence of adverse events. CONCLUSION: (s): Oral GnRH antagonists are effective for endometriosis-associated pain and dysmenorrhea and the patient global impression. The incidence of ovarian hypoestrogenic effects in a short-term duration was significant in a dose-effect response, particularly the highest dose. CLINICAL TRIAL REGISTRATION NUMBER: International Prospective Register of Systematic Reviews registration number CRD42022332904.

The Efficacy and Safety of Relugolix Compared with Degarelix in Advanced Prostate Cancer Patients: A Network Meta-analysis of Randomized Trials.

CONTEXT: Degarelix is associated with high rates of injection site reaction. The US Food and Drug Administration approved relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, for the treatment of advanced prostate cancer patients. OBJECTIVE: This systematic review and network meta-analysis aimed to compare the efficacy and safety of relugolix versus degarelix. EVIDENCE ACQUISITION: A systematic search was performed using major web databases for studies published before January 30, 2021, according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) extension statement for a network meta-analysis. Studies that compared the efficacy (12-mo castration rate with testosterone ≤50 ng/dl) and safety (adverse events [AEs]) of relugolix or degarelix and of the control group (GnRH agonists) were included. We used the Bayesian approach in the network meta-analysis. EVIDENCE SYNTHESIS: Four studies (n = 2059) met our eligibility criteria. The main efficacy analysis was conducted for two different treatments (relugolix and all doses of degarelix vs GnRH agonists); relugolix (risk ratio [RR] 1.09, 95% credible interval [CrI]: 0.95-1.23) and degarelix (RR 0.98, 95% CrI: 0.91-1.06) were not associated with different 12-mo castration rates. In the subgroup analysis, degarelix 480 mg was significantly associated with a lower castration rate (RR 0.46, 95% CrI: 0.07-0.92). In all efficacy ranking analyses, relugolix achieved the best rank. The safety analyses showed that relugolix (RR 0.99, 95% CrI: 0.6-1.6 and RR 0.72, 95% CrI: 0.4-1.3, respectively) and degarelix (RR 1.1, 95% CrI: 0.75-1.35 and RR 1.05, 95% CrI: 0.42-2.6, respectively) were not associated with either all AE or serious AE rates. In the ranking analyses, degarelix achieved the worst rank of all AEs and the best rank of serious AEs. Relugolix (RR 0.44, 95% CrI: 0.16-1.2) and degarelix (RR 0.74, 95% CrI: 0.37-1.52) were not associated with different cardiovascular event (CVE) rates; both were associated with lower CVE rates than GnRH agonists in the ranking analyses. CONCLUSIONS: We found that the efficacy and safety of relugolix are comparable with those of degarelix, albeit with no injection site reaction. Such data should be interpreted with caution until large-scale direct comparison studies with a longer follow-up are available. PATIENT SUMMARY: We found that relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, has comparable efficacy and safety with degarelix, a parenteral GnRH antagonist, for the treatment of advanced prostate cancer patients.

Fixed versus flexible antagonist protocol in women with predicted high ovarian response except PCOS: a randomized controlled trial.

BACKGROUND: No previous study directly compares the fixed day-5 initiation versus the flexible initiation of GnRH antagonist administration in IVF/ICSI for those patients who are predicted as high ovarian responders without PCOS. To evaluate whether the number of oocytes retrieved is different by using the two GnRH antagonist protocols in Chinese women with predicted high ovarian response except PCOS. METHODS: A randomized controlled trial of 201 infertile women with predicted high ovarian response except PCOS undergoing in vitro fertilization. Ovary stimulation was performed using recombinant FSH and GnRH antagonists. GnRH antagonist ganirelix (0.25 mg/d) was started either on day 5 of stimulation (fixed group) or when LH was > 10 IU/L, and/or a follicle with mean diameter > 12 mm was present, and/or serum E2 was > 600 pg/ml. Patient monitoring was initiated on day 3 of stimulation in flexible group. RESULT(S): No significant difference was observed between the fixed and flexible groups regarding the number of oocytes retrieved (16.72 ± 7.25 vs. 17.47 ± 5.88, P = 0.421), the Gonadotropin treatment duration (9.53 ± 1.07 vs. 9.67 ± 1.03, P = 0.346) and total Gonadotropin dose (1427.75 ± 210.6 vs. 1455.94 ± 243.44, P = 0.381). GnRH antagonist treatment duration in fixed protocol was statistically longer than the flexible protocol (6.57 ± 1.17 vs 6.04 ± 1.03, P = 0.001). There was no premature LH surge in either protocol. CONCLUSION(S): Fixed GnRH antagonist administration on day 5 of stimulation appear to achieve a comparable oocyte retrieved compared with flexible antagonist administration. TRIAL REGISTRATION: NCT02635607 posted on December 16, 2015 in clinicaltrials.gov.

HORMONAL THERAPY IN WOMEN OF REPRODUCTIVE AGE WITH ENDOMETRIOSIS: AN UPDATE.

Medical therapy of endometriosis is under continuous reevaluation. Hereby we updated the drugs currently available or under investigation for the hormonal treatment of endometriosis.

A comprehensive review of hormonal and biological therapies for endometriosis: latest developments.

INTRODUCTION: Endometriosis is a chronic benign estrogen-dependent disease characterized by the presence of endometriotic glands and stroma outside the uterine cavity. Although combined hormonal contraceptives and progestins, currently available first-line treatments for endometriosis, are efficacious and well tolerated for treating disease-related pain, some women experience partial or no improvement of pain or its recurrence is frequent after discontinuation of the therapies. For these reasons, new drugs are under investigation for the treatment of endometriosis. AREAS COVERED: This review aims to give to the reader a complete and updated overview of hormonal and biological therapies for the treatment of endometriosis, underlining the latest developments in this field of research. EXPERT OPINION: Among the new drugs investigated, late clinical trials on gonadotropin-releasing hormone (GnRH) antagonists and aromatase inhibitors (AIs) have demonstrated the most promising results. For this reason, elagolix, a new GnRH-antagonist, recently received the approval by the Food and Drug Administration (FDA) for treating pain associated to endometriosis. Other drugs with innovative targets have been identified, but the majority of these compounds have only been evaluated in pre-clinical studies or early clinical trials. Thus, a further extensive clinical research is necessary to better elucidate their pharmacologic characteristics, their efficacy, and safety for the treatment of this benign chronic disease.

A change from gonadotropin releasing hormone antagonist to gonadotropin releasing hormone agonist therapy does not affect the oncological outcomes in hormone sensitive prostate cancer.

BACKGROUND: The aim of our retrospective study was to evaluate the 5-year survival and time to castration resistant prostate cancer in patients with hormone sensitive prostate cancer treated with the gonadotropin releasing hormone antagonist, degarelix. Another aim was to evaluate the effects of changing the treatment from degarelix to a gonadotropin releasing hormone agonist after achieving stable disease control, on the clinical and oncological outcomes. RESULTS: Our analysis was based on the data of 108 patients with prostate cancer who were treated with degarelix. Of these, the treatment was changed from degarelix to a gonadotropin releasing hormone agonist in 57 patients (changed group), and the treatment with degarelix was continued in the other 51 (continued group). The overall 5-year survival was statistically superior in the changed (96.6%) group than that in the continued (74.1%) group (p = 0.006). The 5-year cancer-specific survival was also superior in the changed (100%) group than that in the continued (84.6%) group (p = 0.027). The average time to castration resistant prostate cancer was comparable in both the changed (43.3 months) and continued (35.2 months) groups (p = 0.117). Lower serum levels of prostate specific antigen and alkaline phosphatase were maintained after changing the therapy from degarelix to a gonadotropin releasing hormone agonist. CONCLUSIONS: Degarelix is effective in the treatment of prostate cancer. Degarelix therapy can also be safely changed to a gonadotropin releasing hormone agonist without any adverse clinical or oncological effects.

CONTEXTE: L'objectif de notre étude rétrospective était d'évaluer la survie à 5 ans et le délai de transition du cancer de la prostate hormono-sensible au cancer de la prostate résistant à la castration chez des patients porteurs d'un cancer de la prostate hormono-sensible qui étaient traités par un antagoniste de la gonadolibérine, le dégarélix. Un autre objectif était d'évaluer les effets sur les résultats cliniques et oncologiques du remplacement du dégarélix par un agoniste de la gonadolibérine après obtention d'un état stable et contrôlé. RÉSULTATS: Notre analyse repose sur les données de 108 patients atteints d'un cancer de la prostate traités par dégarélix. Parmi ceux-ci, le traitement par dégarélix a été remplacé par un agoniste de la gonadolibérine chez 57 (groupe modifié), et le traitement par dégarélix a été poursuivi chez les autres patients (groupe inchangé). La survie globale à 5 ans était statistiquement plus élevée pour le groupe modifié (96.6%) que pour le groupe inchangé (74,1%; p = 0.006). Les chances de survie cancer-spécifiques à 5 ans était également plus élevées pour le groupe modifié (100%) que pour le groupe inchangé (84,6%; p = 0.027). Le délai moyen de transition du cancer de la prostate hormono-sensible au cancer de la prostate résistant à la castration était comparable dans le groupe modifié (43,3 mois) et dans le groupe inchangé (35,2 mois). Des taux sériques plus bas d'antigène spécifique de la prostate et de phosphatase alcaline ont été maintenus après le remplacement du dégarélix par un agoniste de la gonadolibérine. CONCLUSIONS: Le dégarélix est. efficace dans le traitement du cancer de la prostate. Le traitement par dégarélix peut aussi être remplacé en toute sécurité par un agoniste de la gonadolibérine sans aucun effet clinique ou oncologique indésirable. MOTS-CLÉS: Antagonistes et inhibiteurs de la gonadolibérine, Agoniste de la gonadolibérine, Cancer de la prostate, Dégarélix, Résistant à la castration.

GnRH Antagonist: a New and an Effective Way of Treatment of Advanced Prostate Cancer.

Castration remains the mainstay of treatment in the management of metastatic prostate cancer. Medical castration plays an important role in a majority of these patients. Gonadotropin releasing hormone (GnRH) agonists have been commonly used hitherto to achieve medical castration. Arrival of GnRH antagonists have opened a new approach in the management of these patients with distinct drug-related and cancer-related benefits including prevention of microsurges and reduction in cardiovascular complications. This article elucidates the mechanism of action of GnRH antagonists along with its clinical advantages and demerits.