©TheCanadian Journal ofUrology™: International Supplement, April 2014
59
MostaghelANDLin
patients with a performance status (PS) of 2 had
worseoutcomes,withamediansurvivalof7.3months
versus 15.3months for thosewithPSof 0-1 receiving
abiraterone.
8
In exploratory analyses abiraterone significantly
increased the number of patients reporting an
improvement in fatigue intensity (58.1%versus40.3%,
p = 0.0001),
9
and the number of patients reporting
palliation of pain (45% versus 28.8%, p = 0.0005).
Median time to first skeletal-related event was also
significantly longer in abiraterone treated patients
(25months versus 20.3months, p = 0.0001).
10
While
visceral disease was associated with a poorer
prognosis, theabsolutebenefit inOS fromabiraterone
wassimilar in thosewithandwithoutvisceraldisease
(from8.3months to12.9months in thosewithvisceral
disease, and from12.3months to17.3months in those
without).
11
COU-AA-302
In the pre-chemotherapy setting, 1088 men with
asymptomatic or minimally symptomatic bone and
lymphnode (but not visceral)metastaticCRPCwere
randomized 1:1 to abiraterone/prednisone (n = 546)
or placebo/prednisone (n = 542), with co-primary
endpoints of rPFS and OS. The median PSAwas
approximately 40 ng/dL, about 30% of men were
≥ 75 years, and approximately 50% had bone-only
metastaticdisease.
At amedian followup of 22.2months abiraterone
doubledrPFS from8.3months to16.5months (HR0.53,
p < 0.001), accompanied by a trend for increasedOS
from27.3months in theplaceboarm tonot-reached in
theabirateronegroup (HR0.75, p=0.01whichdidnot
meettheprespecifiedpvalueof0.001),againprompting
the IDMC to recommend the studybe unblinded and
men on the placebo arm be offered abiraterone.
12
An
updated analysis of OS at a median survival of 27.1
months again trended toward favoring abiraterone at
30.1months in theplacebo armversus 35.3months in
theabirateronearm (HR0.79, p=0.015).
13
Allsecondaryendpointswerestatisticallysignificant
in favorofabiraterone, includingmedian time toopiate
use (not-reachedversus 23.7months), time to initiation
ofchemotherapy(25.2monthsversus16.8months),time
toperformance status decline (12.3months versus 10.9
months), time to PSAprogression (11.1months versus
5.6months),andproportionofpatientswith>50%PSA
response (62%versus 24%).
12
While this studydidnot
include patients with visceral disease or moderate to
severepain,exploratoryanalysesofthesesubpopulations
in the post-chemotherapy setting (discussed above)
suggest thesepatientsare likely tobenefit aswell.
Also of note, although ketoconazole-treated
patients were specifically excluded in the phase
III studies, phase I/II data suggest abiraterone has
activity in these patients. In a pre-chemotherapy
phase I studyPSAresponses>50%wereobserved in
64% of ketoconazole-naïve and 47% of ketoconazole
pre-treatedpatients.
14
In apost-docetaxel study, PSA
declines>50%occurred in45%ofketoconazole-naïve
and26%ofketoconazole-treatedpatients,withmedian
TTPof 28 and 14weeks, respectively.
15
Incidence andmanagement of side effects
Abiraterone isgenerallywell tolerated,with13%and
19% of abiraterone-treated patients in COU-AA-301
and COU-AA-302 (respectively) discontinuing
therapy for adverse effects versus 18% and 23% of
placebo-treatedpatients. Themost common adverse
events inbothgroupswere fatigue,backpain,nausea,
constipation,bonepainandarthralgia,all in therange
of 25%-30%, summarized in Table 1. The incidence
of urinary tract infection was statistically higher in
abiraterone treatedpatients (12%versus7% inplacebo,
p=0.02). Herewediscuss the incidence,management
andmonitoring of adverse events of special interest
specifically associatedwith abiraterone therapy.
Impact of food
Phase I studies demonstrated 5-7 fold higher drug
exposure when abiraterone is administered with a
low fatmeal (7% fat, 300 calories) as compared to the
fastedstate. Tominimize thevariability inabsorption,
abiraterone is administered as 1000mg (four 250mg
tablets)dailyonanempty stomach, definedas1hour
beforeor 2hours after ameal.
Mineralocorticoid and electrolyte effects
Adrenal inhibition of CYP17A results in blockade of
glucocorticoid aswell as adrenal androgen synthesis
leading to a compensatory rise in ACTH that can
lead to excess mineralocorticoid synthesis, Figure 1.
Phase I and II trials demonstrated symptoms of
mineralocorticoid excess occur in 50%-80% of
patients treated with single-agent abiraterone.
6
Mineralocorticoid-related symptoms in the phase
III studiesweremarkedly attenuated by inclusion of
prednisone 5 mg twice daily, andwere generally of
grade 1 or 2 inmagnitude, including fluid retention
(~33% versus 22%-24% in placebo), hypertension
(~10%versus8% inplacebo),andhypokalemia (~18%
versus 9% inplacebo).
14,16,17
Hypertensionandhypokalemiashouldbecorrected
before and during therapy and patients should be
