©TheCanadian Journal ofUrology™: International Supplement, April 2014
Translational research discoveries redefine
advancedprostate cancer
Drs. Tilki andEvanshave reviewed the latest scientific
discoveries that have resulted in critical changes in
our understanding of the development and clinical
management of advanced prostate cancer.
1
While
seeminglyminor to the casual observer, the change in
terminologyfrom“hormonerefractoryprostatecancer”
totheuseoftheterm“castrationresistantprostatecancer”
(CRPC) representsan importantparadigmshift inhow
we manage prostate cancer that is progressing in the
settingofcastratelevelsoftestosterone. CRPCisdefined
by disease progression despite androgen deprivation
therapyandmaypresent as either a continuous rise in
serumPSAlevels,theprogressionofpre-existingdisease,
and/ortheappearanceofnewmetastases. Thisisdeeply
rooted in therecent translationaldiscoveries in thefield
ofbasicprostatecancerresearchwiththeseobservations
havingadirect impact onmenwithadvanceddisease.
Some of the more critical observations concerning
biologyofandrogensand theandrogenreceptoraxis in
thedevelopmentofCRPChave led to thedevelopment
of many new therapeutic targets and agents. Several
newmedications such as the androgen biosynthesis
inhibitorabirateroneandtheandrogenreceptorpathway
blocker enzalutamide have already found their place
as Food and Drug Administration (FDA) approved
medications in the United States and several other
countriesaround theworld.
2
Androgendeprivation in advancedprostate
cancer
Reducing serum testosterone to low levels or so called
“castrate” levels has been the mainstay of advanced
prostatecancer fordecades. Theutilityof thisandrogen
ablation approach in metastatic disease is clearly
established. In addition, the androgen deprivation
strategieshavebeenrefinedandadaptedinotherclinical
settings. These include applications in adjuvant and
neoadjuvant settings for radiation therapyand surgery
and expanded interest and use of the intermittent
hormonal therapy for advanceddisease. Critical in the
application of androgen deprivation is the importance
of periodic measurement of serum testosterone levels
toverifyeffective castration, generally considered tobe
<50ng/dL.
3
Lastly,whilethestandardandrogenablation
relies primarily upon luteinizing hormone releasing
hormone (LHRH) analogues, Rove and Crawford
provide insightson theuseofbothLHRHagonistsand
antagonists forandrogenablationwhileMouldiscusses
the practical applications of LHRH antagonists in the
spectrumof advancedprostate cancer.
4,5
Dr.Moul also
referencesarecentglobalpooled trialanalysisof therisk
of cardiac events within 1 year of initiating androgen
deprivation. Cardiaceventswerenotedtobesignificantly
lower among men treated with a GnRH antagonist
comparedwithGnRH agonists, an observation that is
likely tocontinue to fuel thedebateovercardiovascular
riskandandrogendeprivationstrategies.
6,7
Intermittent androgendeprivation therapy (IADT)
involvescyclesofADTthatare interruptedby injection-
free intervalswhere testosterone levelsarepermitted to
rise above castrate levels. It has proposed that IADT
potentiallyreducessomeoftheboneandcardiovascular
health sequelae of ADT andmay improve oncologic
outcomes,althoughthisisnotwithoutsomecontroversy.
Dasonandassociates reviewhow theapproachworks
andmost importantly summarize the major clinical
trials that have been performed in this area.
8
The
authorsalsoprovideuseful summariesof thepotential
long termADT complications such as the metabolic
syndromeandbonehealth issues.
Secondaryhormonalmanipulationinadvanced
prostatecancer
Manynew agents have been approved for advanced
CRPCover the last fewyears. Prior to2010,docetaxel
remained the only agent approved when androgen
deprivation failed. Secondaryhormonalmanipulation
inCRPCwas commonlyperformedwith the concept
firstwidelypromotedbySmall andVogelzang.
9
Drs.
Al-AsaaedandWinquist reviewcurrentmanagement
guidelines and discuss what the role of secondary
hormonalmanipulation is in thecurrentCRPCspace.
10
Table 1 summarizes some of themore common and
traditional secondary hormonal manipulations used
before the introduction of newer agents such as
abiraterone that someconsiderasa formof secondary
hormonalmanipulation.
2
Currentmanagement of advanced and castration resistant prostate cancer
TABLE1.
Traditionalsecondaryhormonalmanipulations
in thesettingofcastrationresistantprostatecancer
9,10
Typeof therapy
Response rate
(rarelydurable)
Steroids
10%-20%
Ketoconazole
30%-60%
Estrogens
40%-60%
Antiandrogens
20%
Antiandrogenwithdrawal
20%
