©TheCanadian Journal ofUrology™: International Supplement, April 2014
AddresscorrespondencetoDr.Wm.KevinKelly,Department
of Medical Oncology, Kimmel Cancer Center, Jefferson
MedicalCollegeofThomas JeffersonUniversity,1025Walnut
Street, Suite 700, Philadelphia, PA19107USA
Practical guide to theuseof enzalutamide
JeanHoffman-Censits,MD,Wm. KevinKelly,DO
DepartmentofMedicalOncology,KimmelCancerCenter,JeffersonMedicalCollegeofThomasJeffersonUniversity,Philadelphia,Pennsylvania,USA
HOFFMAN-CENSITS J, KELLY WK. Practical
guide to the use of enzalutamide.
Can J Urol
2014;
21(Suppl 1):64-69.
Introduction:
Wesummarizethedevelopment,definitive
trials, and practical use of enzalutamide for practicing
urologists andmedical oncologists.
The care paradigm for patientswithmetastatic castration
resistantprostatecancer(mCRPC) isachanging landscape,
withtheongoingdiscoveryofdriversofcancerprogression
yielding actionable targets for drug development.
Since 2010, sipuleucel-T, cabazitaxel, abiraterone with
prednisone, radium 223 and enzalutamide have been
Food and Drug Administration approved based upon
improvement in overall survival inmenwithmCRPC.
Materials and methods:
AMEDLINE search for
“enzalutamide or MDV3100” yielded 258 results.
Prospective trialswere reviewed. Abstracts fromASCO
(American Society of Clinical Oncology) meetings and
pressrelease informationwere includedwhereapplicable.
Results:
Enzalutamide, anoral inhibitor of the androgen
receptor pathway, was approved in 2012 based upon
improvement inoverallsurvivalof4.8months inmenwith
mCRPC followingdocetaxel versus placebo. Measures of
prostate-specificantigen(PSA)andradiographicresponse,
and clinically significant endpoints such as quality of life
improvementandtoxicityparametersfavoredenzalutamide.
Toxicity is modest with asthenia and fatigue beingmost
common,with a1% incidence of seizure reported, though
patients canbe selected todecrease this risk.
Conclusion:
Enzalutamide is an effective oral therapy
for mCRPC, with an overall survival benefit before and
followingchemotherapy. Toxicity ismild, andseizurerisk
can be mitigated by careful patient selection. Ongoing
studies will help determine the best sequence of novel
agents for prostate cancer, along with safe and effective
combinationsof therapies. Betterunderstandingof tumor
characteristics, particularly reliance on the androgen
receptorpathway,will lead topersonalizedapproaches to
prostate cancer therapy.
Key Words:
enzalutamide, androgen receptor,
metastatic prostate cancer, castration resistant,
docetaxel refractory
enzalutamide (formerlyMDV3100)doserangewas30
mg to 600mgdaily,withketoconazole anddocetaxel
naïve men experiencing the most robust responses.
2
Seizureswere confirmed or suspected in one patient
eachat600mg,480mg,and360mgcohorts,suggesting
dosedependencyof this toxicity.
Phase IIIAFFIRMstudy:efficacyand toxicity
Based upon data from the phase I/II trial, 160 mg
dailywas the dose selected for the pivotal phase III
AFFIRM trial, inwhichmenwithmetastaticcastration
resistant prostate cancer (mCRPC) and disease
progression followingdocetaxelwere randomized to
receive enzalutamideversusplacebo.
3
Enzalutamide
treatment led to a median overall survival of 18.4
months (95% CI, 17.3 months to not yet reached)
Introduction
Enzalutamide is an oral potent inhibitor of the
androgen receptor (AR) signaling pathway, with
actions including inhibition of ligand/receptor
binding, nuclear translocation of activated androgen
receptor, and inhibition of AR regulated nuclear
transcription.
1
This inhibition of the AR signaling
pathway by enzalutamide is dramatically more
potent than bicalutamide, and is without potential
agonist properties that are sometimes acquiredwith
bicalutamide treatment. In the phase I/II trial, the
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