BACKGROUND: Relugolix has been used to treat advanced prostate cancer. This study assessed adverse events (AEs) associated with relugolix from the US Food and Drug Administration Adverse Event Reporting System (FAERS).
METHODS: Disproportionality analysis, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed to quantify the signals of relugolix-associated AEs.
RESULTS: A total of 5,059,213 reports of AEs were collected from the FAERS database, of which 5,662 reports were identified with relugolix as the \"primary suspect (PS)\". A total of 70 significant disproportionality PTs conforming to the four algorithms were simultaneously retained. Unexpected new AEs, such as erectile dysfunction, gynaecomastia, testicular atrophy, male genital atrophy, libido decreased might also occur.
CONCLUSIONS: This study found potential new AEs signals and might provide important support for clinical monitoring and risk identification of relugolix.

Relugolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, has been well studied in the treatment of endometriosis symptomatic. It is mainly metabolized by the CYP3A subfamily of P450 enzymes, while minorly metabolized by CYP2C8. Daidzein in different dose groups exhibited a certain induction on the mRNA expression level of CYP3A4 and resulted in the potent induction of CYP3A4. However, it is still unknown whether daidzein and relugolix interact. We developed an effective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to study the effect of daidzein on the pharmacokinetics of relugolix in rats after oral administration of 12 mg/kg relugolix in a single or mixed of 50 mg/kg daidzein. The results showed that the method had respectable linearity (r 2 > 0.999) on the scale of 0.7-1000 ng/mL. The intra-day precision was between 3.0% and 8.4% in this assay, and the inter-day was between 4.0% and 11.7%. The intra-day accuracy was from -4.3% to 6.1%, and the inter-day was 2.9% to 12.1%. Another three key indicators, including the stability, the recovery rate of extraction and the new technique\'s matrix effect, were perfectly in accord with the test verification rule in the biological medium by the United States Food and Drug Administration. Meanwhile, treatment with daidzein led to a decrease in Cmax and AUC0-t of relugolix by about 15.56% and 21.36%, respectively. Although there was no statistical difference in pharmacokinetic parameters, it reflected the induction trend of daidzein on relugolix metabolism for food-drug interaction. It would provide reference and improvement value for subsequent experiments.

Prostate cancer (PC) is a rapidly increasing ailment worldwide. The previous decade has observed a rapid advancement in PC therapies that was evident from the number of FDA approvals during this phase. Androgen deprivation therapies (ADT) have traditionally remained a mainstay for the management of PCs, but the past decade has experienced the emergence of newer classes of drugs that can be used with or without the administration of ADT. FDA approved poly (ADP-ribose) polymerase inhibitors (PARPi), such as olaparib and rucaparib, after successful clinical trials against gene-mutated metastatic castration-resistant prostate cancer. Furthermore, drugs like apalutamide, darolutamide, and enzalutamide with an androgen-targeted mechanism of action have manifested superior results in non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-sensitive prostate cancer (mCSPC), and metastatic castration-resistant prostate cancer (mCRPC), respectively, with or without previously administered docetaxel. Relugolix, an oral gonadotropin-releasing hormone antagonist, and a combination of abiraterone acetate plus prednisone were also approved by FDA after a successful trial in advanced PC and mCRPC, respectively. This review aims to analyze the FDA-approved agents in PC during the last decade and provide a summary of their clinical trials. It also presents an overview of the ongoing progress of prospective molecules still under trial.

Gonadotropin-releasing hormone (GnRH) receptor agonists are still the most commonly used androgen deprivation treatment (ADT) drugs for prostate cancer in clinical practice. Currently, the GnRH receptor antagonists used for endocrine therapy for prostate cancer primarily include degarelix and relugolix (TAK-385). The former is administered by subcutaneous injection, while the latter is an oral drug. Compared to GnRH agonists, GnRH antagonists reduce serum testosterone levels more rapidly without an initial testosterone surge or subsequent microsurges. This review focuses on the mechanism of action of GnRH antagonists and agonists, the developmental history of GnRH antagonists, and emerging data from clinical studies of the two antagonists used as endocrine therapy for prostate cancer.