©TheCanadian Journal ofUrology™: International Supplement, April 2014
inferioritywasmet and in fact testosteronesuppression
beyond the first 28 dayswas similar between all three
groups. A number of proposed theories to possibly
explain the difference is worthy of mention such as
initial rapid PSA suppression, lack of mini-flares of T
with each injection, and better FSH suppressionwith
degarelix. Thereareongoing trials inEuropeandNorth
Americawithrespecttothepossibleutilityofdegarelixin
intermittentADT. These trialsmayalsoshedmore light
onPSAsuppression,microsurgesandFSHsuppression.
Afinal difference comparing LHRH agonists and
degarelixhas recentlyemerged- cardiovascular event
rates. In thepooledglobal trialsof degarelix recently
presentedbyAlbertsenetal, therewasasubstantially
lower cardiovascular event rate in patients treated
by degarelix.
10
This phenomenon is likely to cause
significant controversy but also worthy of mention
giventhe largepatientpopulation(pooledglobal trials)
fromwhich thedata isobtained. Similar thefindings
of improvedPSAcontrol, suchafinding isdifficult to
explain on the surface given that in general, cardiac
events are felt to be exacerbated by the lowering of
testosteroneand in thecaseofdegarelix, thishappens
atan initially fasterbutnonetheless thereappears toa
50%decrease in cardiac events.
Clinical uses of degarelix
In theory if testosterone is lowered to castrate levels
more rapidly, a patientmight achieve clinical benefit
more rapidly. There are certain clinical situations
where degarelix is preferred or even mandated
over LHRH agonists. In patients who present with
metastaticprostatecancerand impendingspinal cord
compression, ureteral obstructiondue toadenopathy
or severebonepain, theuseofdegarelix isof obvious
utility as it avoids clinical testosterone surge or flare.
In fact,LHRHagonistsarespecificallycontraindicated
in these clinical situations and either immediate
orchiectomy, oral ketoconazoleordegarelixwouldbe
mandated. Most patients do not desire orchiectomy
andoralketoconazolemaynotbeproperlyabsorbed in
thisacutesettingmakingdegarelix thepreferredagent.
Beyond the above ideal use of degarelix, there are
other clinical scenarioswhere cliniciansmight prefer
degarelixover the traditional agonists. Since there is
no testosterone flare/surge, some physicians prefer
to start all patients on degarelix and then to switch
thepatient toa longeractingLHRHagonist after2-12
months. Garnick et al showed that this practicewas
safe for abarelix andmany clinicians extrapolate this
finding to switching with degarelix.
6,11
This clinical
switching isdonedueto themainclinicaldisadvantage
of degarelix: thedrug is currentlyonlyavailable as a
1monthdepot injection. It is likely that ifdegarelixor
another futureGnRHpureantagonistwasavailable in
a longeractingdepot (suchas3 to6monthdepot), the
switchingwouldbecomeunnecessary.
The long term followup of the original Klotz et al
clinicaltrialsuggestthatdegarelixmaybemoreeffective
thanmonthly leuprolideacetate.
7-9
However, thecancer
control outcome comparisons of degarelix versus
leuprolidewerenotpre-specifiedasprimaryendpoints
in the original Klotz et al pivotal trial so it is unclear
if degarelix truly offers a survival benefit compared
to LHRH agonists. If a clinician in practice feels that
degarelix ismore effective than LHRH agonists, then
itopensclinicaluse toany/allpatientswhoareplaced
on traditional ADT, such as high risk biochemical
recurrence, newly diagnosed men withM1 disease,
and in neoadjuvant/adjuvant settings. I believe it is
reasonable to educatemen about the option for long
termdegarelix noting the possible efficacy advantage
versustheconveniencedisadvantage. Inmyexperience,
somemenmaywant toavail themselvesof thepossible
improveddisease control andnot be concerned about
the monthly visits for injections. Other men choose
convenience and desire longer acting depot agonists
and forgo thepossibleefficacydifference.
In the specific setting of neoadjuvant hormonal
therapy(NHT)usepriortothestartofradiation,weknow
that degarelixprovidesmore rapidPSAreductionover
thefirst56daysofusecompared tomonthly leuprolide
in theKlotz et al clinical trial. Ifwebelieve that PSA is
ageneral surrogate forcanceractivityandprostatesize,
some cliniciansmaypreferdegarelixover anagonist in
thisearlyphase. Furthermore,thereissomeevidencethat
PSAnadirwhileonNHTbeforethestartofexternalbeam
radiotherapy(EBRT),predictsdisease-freeoutcome. This
would imply that usinganagentwith rapidity, suchas
degarelix,willhaveabetterchanceof lowering thePSA
morerobustlybeforeradiationandmightresult inbetter
long-term disease control. While speculative, there is
littledownsideof consideringdegarelix for thefirst few
monthsofNHT. Furthermore, inacaseof intermediate
riskdiseasewhere the totaldurationofNHT isgoing to
be 4-6months, there isminimal patient and physician
office inconvenience of using amonthlydepot for this
relativelybriefduration.
In addition, more rapiddownsizing facilitated by
themorerapidlyactingdegarelixmight facilitatemore
rapid surgical scheduling in selectedmenwith large
glandsprior tobrachytherapy. Likewise, in theradical
prostatectomypatient, theremaybeclinical situations
whereNHT isused for technicalreasons. Forexample,
NHTmayalsobeused forprostatesizeconsiderations
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