©TheCanadian Journal ofUrology™: International Supplement, April 2014
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failurewashigher in theabirateronegroup (2.1%versus
0.7% inplacebo). Themost frequently reported cardiac
eventswere grade 1 and 2 tachycardia and grade 3 or
loweratrialfibrillation. Aspatientswith leftventricular
ejection fraction<50%wereexcluded from thephase III
studies,pre-treatmentassessmentofcardiacstatuswith
electrocardiogram and echocardiographymaywarrant
consideration in elderly patients with reduced cardiac
function. Asignificant effect of abirateroneon theQT/
QTc interval inpatientswithCRPCwasnotobserved.
19
Potential drug interactions
Abiraterone is a strong inhibitor of severalmicrosomal
drug metabolizing enzymes, including CYP1A2 and
CYP2D6.
20
Abiraterone increased systemic exposure
of dextromethorphan (metabolized by CYP2D6)
approximately 2-3 fold, while the pharmacokinetics
of theophylline (metabolized by CYP1A2) were
unaffected. This suggests cautionmay be warranted
when abiraterone is co-administered with known
CYPD26 substrates (including beta blockers, serotonin
reuptake inhibitors, anti-arrhythmics, neuroleptics, as
well as codeine, tramadol, andof relevance tourologic
patients, tolterodine).
21
Practical treatment considerations
Whiletheintroductionofabirateronehasheraldedanew
era in the hormonal treatment ofmenwithmetastatic
CRPC, there remain important questions regarding its
optimalplace incontinuumofprostatecancer therapy.
These include issuesof sequencingof abirateronewith
immunotherapy, chemotherapy and enzalutamide in
menwithmetastaticCRPC, the efficacyof abiraterone
in castration sensitive disease, the role of abiraterone
as part of therapy in men with localized disease or
biochemical relapse, whether co-administration of
prednisone can be safely decreased to 5mg/day, and
whethersequentialorcombinatorialtreatmentstrategies
will yield themostdurable responses.
Inmenwithasymptomaticorminimallysymptomatic
metastatic CRPC, abiraterone is an attractive first line
optiongivenitseaseofadministrationandrelativelylow
toxicityprofile. Similarly,thecombinationofabiraterone
andsipuleucelTwouldlikelybeawell-toleratedregimen
inthissettingandiscurrentlyunderclinicalinvestigation.
Theefficacyofabiraterone inmenwithsymptomatic
diseaseprior tochemotherapyhasnotbeen specifically
demonstratedduetoexclusionofthesepatientsfromthe
phaseIIItrial;however,datafromthepost-chemotherapy
trial suggest thesepatients are likely tobenefit aswell.
The pace of diseasemay be the best guide to therapy
in this setting. PatientswithhighGleason scores, poor
response to initialADT, rapidlyprogressivedisease, or
poorlycontrolledsymptomsmayderivegreaterbenefit
fromimmediatechemotherapy,whileatrialofabiraterone
maybereasonableinpatientswithlessextensiveormore
slowly progressing disease.
22
In this regard it should
be noted that treatment with abiraterone in the phase
III studieswas continueduntil clinical or radiographic
evidenceofprogression, thus it isreasonabletocontinue
therapyinpatientswithPSAprogressionaslongasthere
isevidenceofongoingclinicalbenefit.
While both abiraterone and enzalutamide are
supported by phase III data demonstrating an
OS benefit in the post-chemotherapy setting, the
optimal approach to sequencing them is unknown.
Retrospective evaluations of patients receiving
abirateroneafterenzalutamideorviceversahaveshown
modestresponserateswithmediantimestoprogression
of3-4months.
23-25
Untilbiomarkerstostratifypatientsor
clinical trialdata tosupportcombinationorsequencing
strategies are available, the sequencing of abiraterone
and enzalutamide is likely tobedictatedby insurance
andregulatoryapprovals. Fromapracticalperspective
enzalutamideavoidstheneedforprednisone,although
this may become less important if studies show
abiraterone canbegivenwitha lower 5mgdose.
An emerging consideration is whether therapy
with abiraterone (or enzalutamide)may influence the
efficacyofsubsequentchemotherapy.
22
Taxanes inhibit
AR transcriptional activity by various mechanisms
including induction of transcriptional corepressors
and prevention of microtubule-mediated transit of
AR to the nucleus, suggesting amechanismbywhich
development of resistance to hormonal AR pathway
inhibitorsmayleadtocross-resistancewithtaxanes.
23,26,27
Notably,asmallretrospectiveanalysisofdocetaxelafter
progression on the phase I/II studies of abiraterone
showed > 50% PSAdeclines in only 26% of patients,
compared to 45% in the TAX327 study.
28
At present
theseobservations remainhypothesis-generating.
Conclusions and futuredirections
While clinical responses to abiraterone have been
remarkable, not all patients respond and themajority
ultimately progress with a rising PSA indicating
reactivation of AR signaling. Emerging clinical
and pre-clinical data similarly suggest resistance is
associatedwithreactivationofARsignaling, including
increased expression of CYP17A and induction of
ligand-independentARsplicevariants.
29,30
Interestingly,
recentcasereportsdescribe instancesofan ‘abiraterone
withdrawal syndrome,’ inwhich (generally transient)
PSA declines occur following discontinuation of
