©TheCanadian Journal ofUrology™: International Supplement, April 2014
not induce a flare phenomenon through initial
agonisticactivity likeLHRHagonists. Thefirstdrug to
beclinicallyapproved foruse,aberelix,wasultimately
pulled from the market in the U.S. due to systemic
allergic reactions secondary to histamine release and
testosterone escapes. A next-generation compound,
degarelix,wasdevelopedandtested invitroand invivo
and does not have such histamine-releasing activity.
As expected, degarelix abolishes gonadotropin and
testosterone flare on initial administration and does
not experiencemicrosurgeson repeat administration,
while It suppresses PSAand testosterone faster than
LHRH agonists (p < 0.001).
41
Further, because co-
administration of an antiandrogen is not required
to block flare, it avoids side effects from this class
of medications. With respect to clinical outcomes,
patients receivingdegarelixexperience fewerurinary
tract infections (5% versus 8%). Biochemical control
in patientswith high risk disease (baseline PSA> 50
ng/mL)hadbetterprogression-freesurvival at 1year
versusagonist therapy(66%versus54.7%,p=0.0245).
56
Nochange in theratesofcardiovascularevents, stroke,
or thromoembolic eventswerenotedbeforeandafter
starting degarelix, implying an improvement over
other forms ofADT.
57
Effects onFSH
While most focus of LHRH agonist and antagonist
activityhas focusedon theability todownregulateor
block the releaseof LH,many forget that physiologic
LHRH also results in FSH release.
58,59
With LHRH
agonists, FSH production is downregulated but
recovers generally with time (mean levels declines
54.8% over baseline). LHRH antagonists, on the
other hand, appear to have amore pronounced and
persistent suppression of FSH (mean levels declines
88.5%over baseline).
41,60,61
FSH,whilenot strictlygermane to the testosterone
axis that drives prostate cancer growth, has been
shown to interact with receptors on prostate cancer
cells andact as a stimulant for cellulargrowth.
62
FSH
receptors are differentially expressed on prostate
cancer cellsandareexpressedwithinbloodvesselsof
various tumors.
63-66
Combined androgenblockade
Greatersuppressionofandrogenicactivity isachieved
whencombininganLHRHagonistwithanon-steroidal
antiandrogen that blocks AR activity. There have
been multiple studies examining clinical outcomes
from CAB versus LHRH agonist monotherapy in
various populations. Crawford et al compared two
such populations (leuprolide versus leuprolide plus
flutamide)inalargerandomizedcontrolledtrialreported
in 1989 with a median length in survival favoring
CAB (16.5 months versus 13.9 months, p = 0.039).
67
Afewyears later,Eisenbergerandcolleaguesreported
asimilar largerandomizedstudy,butwithorchiectomy
with and without flutamide showing no significant
difference between the two arms.
68
Ameta-analysis
of trials comparingCAB (LHRH agonist plus one of
the following: nilutamide, flutamide, or cyproterone
acetate) to LHRH therapy alone showed a 2%-3%
improvement in 5 year overall survival, but thiswas
not statistically significant.
12
When examining just
non-steroidalantiandrogens (nilutamideorflutamide
plus LHRH agonist), there was a 2.9% statistically-
significantadvantage toCAB (p=0.005). Thenumber
needed to treatwithCAB is 35 toprovide additional
benefit inoverall survival tooneperson.
Survival benefits offeredbyCAB are likely offset
by increased rates of adverse events and reduced
quality-of-life.
10
The conflicting results translate
into guidelines. The American Society of Clinical
Oncology (ASCO) recommends CAB for the initial
management ofmetastatic, recurrent, orprogressive
prostatecancer, yet currentNationalComprehensive
CancerNetwork (NCCN) guidelines state that CAB
provides no proven additional benefit over LHRH
agonist therapy alone.
13,69
Certainly, these authors
feel strongly that thosepatientswhoexperienceflare,
microsurges or testosterone breakthroughs should
undergosecondaryhormonalmanipulation,perhaps
with the addition of an antiandrogen if one is not
currentlybeingused.
Roleof testosterone levels inprostate cancer
management
Measuring testosterone
Oneof thegreatdifficulties inevaluating testosterone
as amarker for prostate cancer remains our relative
inability toaccuratelyandpreciselymeasure itsvalue.
Asmentionedearlier,older techniquessuchasdouble-
isotope dilution assay, radioimmunoassays, and
chemiluminescenceassaysare impreciseat low levels
of testosterone, such as those in children, women,
and castrate men. These assays have coefficients
of variability (CV) up to 40%. Large commercial
laboratories have adoptedmore precise LC/MS-MS
as the standard formeasuring serum testosterone in
hypogonadalmen. CV still range from2.7% to25.6%
on the same equipment and between equipment
when measuring a single sample.
70
This variability
18
Traditional androgen ablation approaches to advancedprostate cancer: new insights
