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
1970�s and early 1980�s 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.
