©TheCanadian Journal ofUrology™: International Supplement, April 2014
Address correspondence to Dr. Elahe A. Mostaghel, Fred
HutchinsonCancerResearchCenter, 1100FairviewAvenue
N,MSD5-100, Seattle,WA98109USA
Practical guide to theuseof abiraterone in
castration resistant prostate cancer
ElaheA.Mostaghel,MD,
1,2
DanielW. Lin,MD
3
1
DivisionofClinical Research, FredHutchinsonCancerResearchCenter, Seattle,Washington,USA
2
DivisionofMedicalOncology,UniversityofWashington, SeattleWashington,USA
3
Department ofUrology,UniversityofWashington, Seattle,Washington,USA
MOSTAGHELEA, LINDW. Practical guide to the
use of abiraterone in castration resistant prostate
cancer.
Can JUrol
2014;21(Suppl 1):57-63.
Introduction:
While androgen deprivation therapy
remains the primary treatmentmodality for patientswith
metastaticprostate cancer, treatment isuniformlymarked
by progression to castration resistant prostate cancer
(CRPC). Abiraterone is thefirstnewdrug toenterclinical
practice in a series of novel agents designed to potently
target adrenal and tumor androgenproduction.
Materials and methods:
Herein, we review the
mechanism of action of abiraterone and the phase III
data supporting its approval for patientswithmetastatic
CRPC. We discuss practical treatment considerations,
including the incidence and management of side effect
andmonitoringrequirements,andconcludebydiscussing
future directions in the use of abiraterone, including
early data supporting an expanded role for abiraterone
in castration sensitive disease.
Results:
Accumulating data emphasize that ‘androgen
independent’ or ‘hormone refractory’ tumors remain
sensitive to hormonal activation and suggest that despite
suppressionof circulating testosterone (T), residual tumor
androgens play a prominent role in mediating CRPC
progression.
Conclusions:
Accordingly, therapeutic strategies such
abiraterone that more effectively target production of
intratumoral androgens arenecessary.
Key Words:
castration resistant prostate cancer,
intratumoral androgen, CYP17A, abiraterone
activation and suggest that despite suppression of
circulating testosterone (T), residual tumor androgens
playaprominentrole inmediatingCRPCprogression.
5
Emergingdatasuggestresidual intratumoralandrogens
areproducedvia theuptakeandconversionofadrenal
androgens, andpotentiallyviadenovosynthesis from
cholesterolorprogesteroneprecursorswithinthetumor.
Thecriticalenzymerequiredforandrogensynthesis
from cholesterol is cytochrome P450 17 alpha-
hydroxylase (CYP17A). Adrenal expression of this
enzymeaccounts forproductionofcirculatingadrenal
androgens, including dehydroepiandrosterone
(DHEA,whichprimarilycirculates in itssulfated form,
DHEA-S),andandrostenedione (AED),andanumber
ofstudieshavedemonstratedexpressionofCYP17Ain
castration resistantprostate tumors. Given its central
Introduction
Theefficacyofandrogendeprivation therapy (ADT) is
routinelybasedonachievingcastrate levelsofserumT,
arbitrarily defined as T ≤ 20 or 50 ng/dL. However,
tissue androgen measurements in men with either
locally recurrent or metastatic castration resistant
prostate cancer (CRPC) clearly demonstrate that
prostate and tumor androgen concentrations remain
wellwithin the range capableactivating theandrogen
receptor (AR).
1-4
Clinical and pre-clinical findings
demonstrate that tumorsremainsensitive tohormonal
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