©TheCanadian Journal ofUrology™: International Supplement, April 2014
role in the production of either adrenal or tumor-
derived extragonadal androgen synthesis, CYP17A
hasemergedasaprimary targetofnovel therapeutics.
Mechanismof action
CYP17Aisasingleenzymethatcatalyzesthesequential
hydroxylase (required forcortisol synthesis)and lyase
(required for adrenal androgen synthesis) steps that
are required for conversionofC21pregnenolone and
progesteroneprecursors to theC19adrenalandrogens,
DHEA and AED, Figure 1. Abiraterone acetate,
an orally administered, rationally designed small
moleculederived from thestructureofpregnenolone,
irreversibly inhibits both the hydroxylase and lyase
activityofCYP17Awithapproximately10-foldgreater
potency thanketoconazole.
Because adrenal inhibition of CYP17A results
in blockade of glucocorticoid as well as adrenal
androgen synthesis, abiraterone is co-administered
with prednisone to ameliorate the secondary rise in
adrenocorticotropichormone (ACTH) thatcan lead to
excessmineralocorticoid synthesis (discussed further
below).
6
Efficacy data and FDA approved treatment
indications
AnumberofphaseIandIIstudiesinitiallydemonstrated
thatabirateronesuppressesserumandrogen levelsand
achieves prostate-specific antigen (PSA) and clinical
responses inchemotherapynaïveanddocetaxel-treated
CRPC patients. Phase III studies in chemotherapy
naïve (COU-AA-302) and post-docetaxel treated
men (COU-AA-301) have confirmed these findings,
resulting inFDAapproval of abiraterone formenwith
metastaticCRPC either before or after treatmentwith
chemotherapy.
COU-AA-301
In the post chemotherapy setting, 1195 men with
metastaticCRPCwererandomized2:1 toabiraterone/
prednisone (n=797) orplacebo/prednisone (n=398)
with a primary endpoint of overall survival (OS).
Median PSAwas approximately 130 ng/dL, 90% of
patients had an ECOG score of 0-1, median agewas
70, and 28%were ≥ 75 years. Bone, lymphnode and
visceral metastases were present in approximately
90%, 40% and 10% of patients respectively, and
30% of patients had received more than one prior
58
Practical guide to theuseof abiraterone in castration resistant prostate cancer
Figure1.
Steroidhormonepathways in theadrenal gland.
chemotherapy regimen. Treatment was
continued until clinical or radiographic
evidenceof progression.
Thefirst interimanalysisdemonstrated
a 3.9monthOS benefit formen receiving
abiraterone, prompting the independent
data monitoring committee (IDMC) to
recommendthestudybeunblindedandmen
on theplaceboarmbeofferedabiraterone.
7
Anupdated analysis at amedian survival
of20.2monthsdemonstratedamedianOS
of 15.8months for abiraterone versus 11.2
monthsforprednisone(HR0.74,p<0.0001),
extending theOSbenefit to4.6months.
All secondary endpoints were
statistically significant in favor of
abiraterone, including median time to
PSA progression (8.5 months versus 6.6
months),median radiologicprogression-
free survival (rPFS, 5.6 months versus
3.6 months), and proportion of patients
with > 50% PSA response (29.5% versus
5.5%). The impact of abiraterone on
OS was observed across all subgroups,
including patients who had received
one (15.4months versus 11.5months) or
two prior chemotherapy regimens (14.0
months versus 10.3 months). Notably,
