©TheCanadian Journal ofUrology™: International Supplement, April 2014
Does the advantage of enzalutamide oral therapy
justify its use before docetaxel?
In an open label single arm phase II study of
enzalutamide 160mgdaily in 67hormone naïve non-
castratemenwithprostate cancer at any stage, 39%of
whomhad radiographicmetastasis,PSAresponse rate
of > 80%was 93% atweek 25.
11
Themediandecrease
in PSA level was -99%, withmaintenance or increase
in levels of testosterone. Gynecomastia, fatigue and
hot flushes were the most common toxicities. These
data arepromising, but activity and toxicityprofile of
enzalutamideinlargestudiesofdocetaxelnaïvemenare
notcompletelyreported,andthususepriortodocetaxel
is not currently endorsed. Completed andmaturing,
aswell asongoing studieswill provide theseanswers.
Preliminary results from the PREVAIL study, a
phase 3 trial in 1700 chemotherapy naïve men with
mCRPC administered enzalutamide 160 mg daily
compared to placebo have recently been completed
andresultsupdated (NCT01212991). An independent
data safety monitoring board recommended the
current protocol be stopped to allow all patients on
theplaceboarm tobe treatedwithenzalutamidesince
the interim analysis showed a 30% reduction in risk
ofdeathandan81% reduction in riskof radiographic
progression or death in favor of the enzalutamide
arm.
12
Abiraterone and prednisone, studied in the
same mCRPC chemotherapy naïve population, was
FDA endorsed based upon significant improvement
inradiographicPFSand trend towardoverall survival
(overall survival abiraterone-prednisone not reached
versus 27.2months for prednisone alone, HR 0.75;
95%CI 0.61 to 0.93, p= 0.01). The survival benefit of
enzalutamide compared to placebo is more robust,
despite a smaller absolute difference in overall
survival in the enzalutamidegroup (overall survival:
enzalutamidearm: 32.4months [range31.5months to
limitNR] versus placebo arm: 30.2months [range 28
months to limitNR]). The trend toward longermedian
survivaleven in thecomparatorarms (30.2months for
placebo on enzalutamide study versus 27.2 months
for prednisone as abiraterone comparitor) is possibly
explained by the increasing array of agents available
formCRPCwhich continue to improve upon overall
survival in thepostdocetaxelsetting. Full reportof the
data fromPREVAILaswellasanFDAendorsement for
use of enzalutamideprior todocetaxel is expected in
2014. Decisionsregardingbestsequenceofabiraterone
andenzalutamide in thepreandpostdocetaxelsetting
will require further study.
Ongoingstudiesareunderway toassess toxicityof
abirateroneandenzalutamidewhencombined. Phase
II studiesof enzalutamidecompared tobicalutamide,
the US STRIVE study which is enrolling men with
mCRPC with biochemical as well as those with
radiographicprogression,and theEuropeanTERRAIN
trial, enrolling mCRPC patients only, are ongoing
(NCT01664923). Enzalutamide is being evaluated in
smaller studies in the post-prostatectomy setting for
menwithhigh risk features, in thepre-prostatectomy
space, in the localized hormone naïve space, as well
as in novel combinations. Aphase I combination of
docetaxel every 21 days with enzalutamide 160 mg
daily appearedwell toleratedwithout demonstrable
effect upon docetaxel pharmacokinetics.
13
Ongoing
and planned studies of enzalutamide combinations
and sequences include studies with PSA-Tricom,
abirateroneacetatewithprednisone (AAP), tivozanib,
and sipuleucel-T.
Howshouldenzalutamidebesequencedwith
other agents?
Enzalutamide following abiraterone acetatewith
prednisone
Though studiesareongoing,weknow littleabout the
toxicity and efficacy of novel prostate cancer agents
given in sequences not previously studied. Reports
from compassionate use programs for enzalutamide
and abiraterone provide some insight. In Germany,
35 patients withmCRPC and progression following
docetaxel andAAP received enzalutamide.
14
Rate of
PSA response to enzalutamide > 50%was 28%, less
than the54% in theAFFIRMstudy. Thosewho initially
responded toAAP had higher PSA response rate to
enzalutamide (43% abiraterone responders versus
15%non-responders), though thenumbersweresmall.
In Britain 46 patientswithmCRPCwith progression
followingdocetaxel andAAPhadmean time to PSA
progressiononenzalutamideof15weeks, less than the
8.3months in theAFFIRMstudy.
15
Cautionshouldbe
taken for any comparison toAFFIRMhowever, given
early reporting and small numbers, with 30 patients
stillonezalutamideat the timeofdatabasepublication.
Rates of toxicity were similar to those reported in
AFFIRM, though the authors cited an increased rate
of psychiatric side effects thanpreviously reported.
Abiraterone acetate with prednisone following
enzalutamide
Thirty-eight patients from two European sites with
mCRPC with disease progression on enzalutamide
following AFFIRM unblinding were prospectively
followedandsubsequentlytreatedwithAAP.
16
Ofthese
men,45%didnotdemonstrateaPSAresponseof>50%
duringenzalutamidetreatment. OnAAP,PSAresponse
67
Hoffman-CensitsandKelly
