©TheCanadian Journal ofUrology™: International Supplement, April 2014
treatedwithdocetaxel [NCT00974311].
18
Enzalutamide
doesnot requireconcomitantsteroidadministration. At
thedosageof160mgperdayseizureswereencountered
in 0.9% of patients receiving enzalutamide.
19
Based on
thedata from theAFFIRM trial, enzalutamide received
FDAapproval for administration in the post-docetaxel
setting. A second phase III study (PREVAIL) was
developed to investigate the utility of enzalutamide in
a docetaxel naïve setting [NCT01212991]. The study
showed a 29% reduction in risk of death (HR = 0.706,
p<0.0001)andan81%reductionintheriskofradiographic
progression(HR=0.186,p<0.0001)whenenzalutamide
was compared to placebo. Enzalutamide also delayed
time to chemotherapy by 17 months (HR = 0.35,
p < 0.0001) when compared to placebo.
20
Currently,
enzalutamide is awaiting FDA approval for the pre-
docetaxel setting.
ARN-509
Like enzalutamide, ARN-509 is an oral competitive
androgen receptor antagonist that impairs androgen
receptorbinding toDNAandandrogenreceptor target
genemodulation,and inducescellapoptosis. ARN-509
hasa slightlyhigher affinity for theandrogen receptor
than enzalutamide
21
and showed a greater efficacy
than enzalutamide in a murine xenograft model of
humanCRPC.
16
In a phase I clinical study, ARN-509
was safeandwell-toleratedacrossalldose levels,with
aminimumeffectivedoseprojectedtobe>180mg/day.
Unlikeenzalutamide, no seizureswerenoted. Dosage
of 240mg/daywas selected for phase II studies,with
aprimary endpoint of PSA response at 12weeks, and
secondaryendpoints evaluatingantitumor effects and
changesincirculatingtumorcells(CTC)[NCT01171898].
Thethreetreatmentarms inthephaseIIstudy included:
1) non-metastatic CRPC which is chemotherapy
and abiraterone naïve; 2) metastatic CRPCwhich is
chemotherapy and abiraterone naïve; 3) metastatic
CRPC recurrent after abiraterone treatment. Asecond
phase II clinical trial is underway with an estimated
primary completion date in 2015 [NCT01790126] that
will evaluate theutilityofARN-509dosedat 240mg/
day in thesettingofhormone sensitiveprostatecancer
with theprimaryquality-of-lifeendpointmeasures.
Androgenbiosynthesis inhibitors
Abiraterone
Abiraterone-acetate, a prodrug for abiraterone, is
a cytochrome P450 c17 (CYP17) inhibitor, blocking
androgen synthesis by the adrenal glands, testes,
andwithin theprostate tumor in a ligand-dependent
fashion.
22
In the initial phase III clinical trial [Cou-
301, NCT00638690], abiraterone in combination
with prednisone showed an improvement in overall
survivalby3.9monthsoverplacebo-matchedcontrols
in a post-docetaxel setting (14.8 months versus 10.9
months, p < 0.001) and all secondary endpoints
confirmed superiority.
23
Abiraterone required
concomitantadministrationofsteroids. Thesedata led
toFDAapproval forabiraterone for thepost-docetaxel
setting. A followupphase III clinical trial [Cou-302:
NCT00887198] inthepre-docetaxelsettingalsoshowed
that abiraterone improved radiographicprogression-
freesurvival (16.5monthsversus8.3months,p<0.001),
showed a trend toward improved overall survival
(mediannotreached,versus27.2months,hazardratio,
0.75; 95%CI, 0.61 to 0.93; p = 0.01) and significantly
delayed initiation of chemotherapy in patients with
metastatic CRPC.
24
Currently, abiraterone is FDA
approved in thepre-docetaxel setting.
TAK-700
TAK-700selectively inhibits the17,20-lyaseactivityof
CYP17A1, and generally does not lead to secondary
mineralcorticoid excess that is seen in abiraterone-
acetate,andmaypermitsteroid-freedosing. Inaphase
I/IIstudy [NCT00569153], 96patientswithmetastatic
CRPC in a chemo-naïve setting received TAK-700 at
variousdosing intervalswithandwithoutprednisone
supplementation. The studywas limited by a large
percentage of patients (50%) due to either adverse
events (AEs) or disease progression. In decreasing
orderof frequency, themostcommonAEswere fatigue
(72%), nausea (44%), and constipation (31%).
25
PSA
response rates (≥ 50% decrease) at 12 weeks were
significantwith63% (300mgBID), 52% (400mgBID+
prednisone), 41%(600mgBID+prednisone), and62%
(600mgQD) in their respectivegroups.
26
Ina July2013pressrelease,TakedaPharmaceuticals
announced that the ELM-PC 5 phase 3 study
[NCT01193257] was unblinded based on the
recommendationof the IndependentDataMonitoring
Committee (IDMC). Overallsurvivalwould likelynot
be significant in theOrteronel plus prednisonewhen
compared to the control arm (HR 0.894, p = 0.23).
There was, however, a significant improvement in
radiographic progression-free survival (rPFS) in the
Orteronel plus prednisone arm over the control arm
(HR0.755,p=0.0003).
27
Currently, thereare fouractive
phase III clinical trials investigatingTAK-700.
TOK-001
TOK-001, formerly known as VN/124-1, inhibits
prostate cancer growth by 17A-hydroxylase/17,20-
lyase (CYP17) inhibition and down-regulation of
101
ThoresonETAL.
