©TheCanadian Journal ofUrology™: International Supplement, April 2014
Address correspondence to Dr. Judd W. Moul, Division
of Urologic Surgery,
DUMC 3707-Room 1562, Duke
South,
DukeUniversityMedicalCenter,
Durham,NC27710
USA
Utilityof LHRHantagonists for advanced
prostate cancer
JuddW.Moul,MD
DivisionofUrologic Surgery,Department of Surgery andDukeCancer Institute,DukeUniversity,Durham,NorthCaroline,USA
MOULJW.UtilityofLHRHantagonistsforadvanced
prostate cancer.
Can JUrol
2014;21(Suppl 1):22-27.
Introduction:
Androgendeprivation therapy (ADT) is
the lynchpin of treatment for advanced prostate cancer.
Prescribingphysiciansandpatientshaveachoicebetween
orchiectomy, luteinizing hormone releasing hormone
(LHRH)agonists, combinedandrogendeprivation (CAD)
or LHRH antagonists.
Materialsandmethods:
Literaturerelating to theuseof
LHRH antagonists in themanagement of prostate cancer
was reviewed.
Results:
Abarelix was the first-in-class LHRH pure
antagonist that was Food and Drug Administration
(FDA) approved in 2003. Due to a variety of concerns
including hypersensitivity reactions it was withdrawn
from theUnitedStates (U.S.)market in2005. The only
currently commercially available LHRH antagonist in
the U.S. is degarelix available as a once-a-month depot
injection. The potential clinical advantage of degarelix
compared to the LHRH agonists is the very rapid and
sustained testosterone suppression with no identifiable
physiological or clinical testosterone surge or flare. The
main disadvantage of degarelix compared to the LHRH
agonists is the monthly dosing and the inconvenience
for some patients and practices. Recent studies tout
improved disease control for degarelix compared to
monthly leuprolideacetate;however, theseresultsremain
controversial.
Conclusions:
The rapid T-suppression achieved with
degarelixmayprovideaclinicalbenefit forvariousgroups
ofmenwith advanced or locally advanced disease.
KeyWords:
degarelix,LHRH, abarelix, antagonists,
prostate cancer, hormonal therapy, androgen
deprivation
benefit does not outweigh thepotential for increased
side-effects from using two hormonal medications
rather thanone.
The challenge with LHRH agonists, even when
administered as CAB in combination with an
antiandrogen, is thepossibilityofperiodic testosterone
surges, flares and micro-surges. Gonadotropin
releasing hormone (GnRH) receptor antagonism
withagents suchas abarelix (no longer commercially
available) or degarelix represents a class of treatment
that acts via immediate and competitive blockade
of pituitary GnRH receptors, directly blocking
release of both LH and follicle stimulating hormone
(FSH).
3-6
The LHRH agonists work primarily by
the competitive blockade of LHwhile degarelix can
be classified as a GnRH antagonist since it blocks
both LH and FSH. However it is recognized that
the primary clinical application in prostate cancer
is the LHRH antagonism. With no LH available to
stimulateproductionof testosterone, theresult israpid
testosteronesuppressionwithoutan initialstimulation
of the hypothalamic–pituitary–gonadal axis and the
testosterone surge associated with LHRH agonists,
Introduction
Formostof the last25years,hormone therapy (HT)or
androgendeprivation therapy (ADT) for treatmentof
advancedprostatecancerhasbeenbasedon luteinizing
hormone releasing hormone (LHRH) agonists,
such as leuprolide acetate or goserelin acetate.
1
LHRH agonists traditionally have been considered
equivalent tobilateralorchiectomy in termsofreported
testosteronesuppression. Since the late1980’sanother
ADT strategy is combination of the LHRH agonist
with an oral non-steroidal antiandrogen. Called
“combined androgen blockade” (CAB) or “maximal
androgen blockade” (MAB) the oral agents used
include bicalutamide, flutamide, or nilutamide.
2
This combined treatment has remained controversial
since its inceptionwith some clinicians endorsing it’s
use and others concluding that the modest survival
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