©TheCanadian Journal ofUrology™: International Supplement, April 2014
62
Practical guide to theuseof abiraterone in castration resistant prostate cancer
abiraterone,suggesting thatmutations in theARwhich
can allowAR activation by exogenous corticosteroids
mayplaya role.
31,32
These observations provide a strong rationale for
combiningabirateronewithpotentAR inhibitors such
as enzalutamide rather than sequential strategies of
singleagentswhichmayallowalternativepathwaysof
ARactivation toemerge. Moreover,earlyuseofpotent
combinedAR blockade may be particularly effective
inhormone naïve tumorswhichhave not yet had the
opportunity to develop resistance. In this respect,
neoadjuvant studies of multi-targetedAR blockade
using LHRH agonists combined with bicalutamide,
dutasteride and ketoconazole or LHRH agonists
combinedwithabirateronehavedemonstratedhigher
pathologic response rates thanpreviouslyobserved in
historic studiesofADTprior toprostatectomy.
33,34
Important clinical questions regarding the use
of abiraterone in different disease settings and in
combinationwith emerging novel agents remain to be
answered. Numerousstudiesevaluatingthesequencing
and combination of abirateronewith immunotherapy,
chemotherapyandotherAR targetedagents inmultiple
disease settings are underway. Rapid accrual and
completion of these studies will be imperative for
determiningrationaltreatmentstrategieswiththehighest
likelihoodofdurableefficacy.
Disclosure
Dr.ElaheA.MostaghelreceivedhonorariafromJanssen.
Dr.DanielW. Lin isa consultant forDendreon.
Support: DamonRunyonCancerResearchFoundation
(Damon Runyon-Genentech Clinical Investigator
Award CI-40-08 to EAM); National Institutes of
Health (Pacific Northwest Prostate Cancer SPORE
P50 CA97186 EAM, DWL); Department of Defense
CongressionallyDirectedMedical ResearchProgram
(EAM); ProstateCancer Foundation (EAM,DWL).
Unlabeled/unapproved use of drugs or devices:
Discussion of expanded indications in castration
sensitivedisease.
References
1. FortiG,SalernoR,MonetiGetal.Three-month treatmentwitha
long-actinggonadotropin-releasinghormoneagonistofpatients
with benign prostatic hyperplasia: effects on tissue androgen
concentration,5alpha-reductaseactivityandandrogenreceptor
content.
JClinEndocrinolMetab
1989;68(2):461-468.
2. Mohler JL,GregoryCW, FordOH3rdet al. Theandrogenaxis
in recurrentprostatecancer.
ClinCancerRes
2004;10(2):440-448.
3. Nishiyama T, Hashimoto Y, Takahashi K. The influence of
androgen deprivation therapy on dihydrotestosterone levels
in the prostatic tissue of patients with prostate cancer.
Clin
CancerRes
2004;10(21):7121-7126.
4. Geller J, Liu J,Albert J, FayW, BerryCC,Weis P. Relationship
betweenhumanprostatic epithelial cell protein synthesis and
tissue dihydrotestosterone level.
Clin Endocrinol (Oxf)
1987;
26(2):155-161.
5. ScherHI,SawyersCL.Biologyofprogressive,castration-resistant
prostate cancer: directed therapies targeting the androgen-
receptor signalingaxis.
JClinOncol
2005;23(32):8253-8261.
6. AttardG, ReidAH,Auchus RJ et al. Clinical and biochemical
consequences of CYP17A1 inhibition with abiraterone given
with andwithout exogenous glucocorticoids in castratemen
with advanced prostate cancer.
J Clin Endocrinol Metab
2012;
97(2):507-516.
7. deBono JS.Abirateroneacetate improvessurvival inmetastatic
castration-resistant prostate cancer: Phase III results. 2010
EuropeanSociety forMedicalOncology;Milan;2010.
8. Fizazi K, Scher HI, Molina A et al. Abiraterone acetate for
treatment of metastatic castration-resistant prostate cancer:
finaloverall survivalanalysisof theCOU-AA-301randomised,
double-blind, placebo-controlled phase 3 study.
Lancet Oncol
2012;13(10):983-992.
9. Sternberg CN, Molina A, North S et al. Effect of abiraterone
acetateon fatigue inpatientswithmetastaticcastration-resistant
prostate cancer afterdocetaxel chemotherapy.
AnnOncol
2013;
24(4):1017-1025.
10.Logothetis CJ, Basch E, Molina A et al. Effect of abiraterone
acetateandprednisonecomparedwithplaceboandprednisone
on pain control and skeletal-related events in patients with
metastatic castration-resistant prostate cancer: exploratory
analysisofdata from theCOU-AA-301randomised trial.
Lancet
Oncol
2012;13(12):1210-1217.
11.GoodmanO, FlaigT,MolinaAet al. Exploratoryanalysisof the
visceraldisease (VD)patient subset inCOU-AA-301, aphase III
studyofabirateroneacetate(AA)inmetastaticcastration-resistant
prostate cancer (mCRPC).ASCOGU2013. 2013;Abstract 14.
12.RyanCJ, SmithMR, deBono JSet al.Abiraterone inmetastatic
prostate cancerwithout previous chemotherapy.
NEngl JMed
2013;368(6):138-148.
13.RathkopfD,SmithM,DeBono Jetal.Updated interimanalysis
(55% OS) of COU-AA-302, a randomized phase 3 study of
abiraterone acetate in metastatic castration-resistant prostate
cancer patientswithout prior chemotherapy. ASCOGU 2013.
2013;Abstract 5.
14.RyanCJ,SmithMR,FongLetal.PhaseIclinicaltrialoftheCYP17
inhibitor abiraterone acetate demonstrating clinical activity in
patientswith castration-resistant prostate cancerwho received
priorketoconazole therapy.
JClinOncol
2010;28(9):1481-1488.
15.Danila DC, MorrisMJ, de Bono JS et al. Phase II multicenter
studyofabirateroneacetateplusprednisone therapy inpatients
withdocetaxel-treatedcastration-resistantprostatecancer.
JClin
Oncol
2010;28(9):1496-1501.
16.Ferraldeschi R, Sharifi N, Auchus RJ, Attard G. Molecular
pathways: Inhibiting steroid biosynthesis in prostate cancer.
ClinCancerRes
2013;19(13):3353-3359.
17.Attard G, Reid AH, Yap TA et al. Phase I clinical trial of a
selective inhibitorofCYP17, abirateroneacetate, confirms that
castration-resistantprostatecancercommonlyremainshormone
driven.
JClinOncol
2008;26(28):4563-4571.
18.PiaA,VignaniF,AttardGet al. Strategies formanagingACTH
dependent mineralocorticoid excess induced by abiraterone.
CancerTreat Rev
2013;39(8):966-973.
19.TolcherAW,ChiKN,ShoreNDetal.Effectofabirateroneacetate
plusprednisoneon theQT interval inpatientswithmetastatic
castration-resistantprostatecancer.
CancerChemotherPharmacol
2012;70(2):305-313.
