Ever since Dr. Andrew Schally discovered the structure of GnRH, many investigative teams have identified both agonists and antagonists of the GnRH receptor. Extensive work performed in the late 1970Тs and early 1980Тs demonstrated the utility of LHRH superagonists in a variety of medical conditions requiring the cessation of production of both male and female sex steroids. The introduction of leuprolide acetate for the management of metastatic prostate cancer, followed by goserelin acetate marked the beginning of the use of LHRH analogues in the management of prostate cancer in the United States. More recently, additional sixth amino acid substitutions of native LHRH have been introduced and include triptorelin and other longer acting formulations of leuprolide. Additional clinical indications have followed with regulatory approvals, and represent the expected physiological approach induced by the action of LHRH agonists. These indications include endometriosis, uterine fibroids, and precocious puberty. Multiple other indications are currently under investigation and will likely expand in future years. Ongoing work with GnRH antagonists did not proceed as smoothly and rapidly during this time. Based on limited water solubility, localized and systemic histamine release and difficult in formulation for long term adminstration, and the requirement for larger doses of antagonist to suppress the LHRH receptor (when compared to agonists), the commercialization of GnRH antagonists lagged behind their agonist counterparts. However, ongoing work clearly demonstrated the improved utility of GnRH antagonists in circumstances in which acute suppresion of the hypothalamic-pituitary-gonadal axis was required. The development of GnRH antagonists was highlighted just recently with the regulatory approval of two such peptides, cetrorelix and ganorelix, for the short term management of in vitro reproduction indications. The development of abarelix depot represents one of the more advanced programs in which a GnRH anatagonist has been utilized for the chronic usage in the management of prostate cancer. Abarelix has been formulated into a long term depot suspension which allows every 4 week dosing. Randomized, prospective sponsor blinded studies have been conducted that has compared abarelix monotherapy to either leuprolide depot alone as monotherapy (Study 149-98-02) or abarelix depot monotherapy to the
combination of leuprolide depot plus the oral administration of bicalutamide (Study 149-98-03). Both of these studies evaluated the avoidance of testosterone surge and rapidity of achieving medical castration within the first week of treatment in prostate cancer patients requiring the benefits of initial hormonal therapy. Abarelix depot universally (100% of patients) avoided the testosterone surge, compared to avoidance of surge by either leuprolide (18%, p<0.001) or the combination of leuprolide plus bicalutamide (14%, p<0.001). In addition, aproximately 70% of patients receiving abarelix were medically castrate within the first week of therapy compared to 0% of patients receiving ether leuprolide or leuprolide plus bicalutamide. In both studies, the ability to achieve and maintain castration levels of testosterone were equivalent from days 29 through day 85 of treatment. Safety evaluations were comparable between abarelix and leuprolide. More patients receiving bicalutamide withdrew because of adverse events. One surprising finding of these studies demonstrated a differential effect on follicle stimulating hormone levels. The use of abarelix caused an immediate suppression of FSH values, which were sustained. In contrast, LHRH agonists caused the expected surge, followed by a nadir, and then a return to near baseline levels. Given the potential importance of FSH in prostate cancer biology, the differential role of GnRH antagonists with LHRH agonists is worthy of further study. Other studies have evaluated the use of GnRH antagonists in other clinical stages of prostate cancer as well as other hormonally mediated disorders. Preliminary evaluations suggest that prostate gland volume reduction can be rapidly effected by GnRH antagonists. There may be more rapid resolution of pain associated with endometriosis following administration of GnRH antagonists. Earlier anecdotal studies using daily administration of cetrorelix had demonstrated rapid resolution of painful symptoms associated with advanced metastatic prostate cancer. Studies of larger patient populations have now shown that abarelix, administered on a Day 1, 15, 29, 57 and every 28 days thereafter can induce meaningful remissions in patients with advanced, symptomatic prostate cancer in whom LHRH agonists are relatively or absolutely contraindicated. Thus, the availability of GnRH antagonists have come full circle. Future studies will undoubtedly fully evaluate the potential of GnRH antagonists in a multitude of medical conditions which are exacerbated or induced by androgens and estrogens.