©TheCanadian Journal ofUrology™: International Supplement, April 2014
39
Al-AsaaedandWinquist
daily is oftenused as it is convenient and appears to
have thebest side effect profile in this class.
18
The response rate tofirst generationantiandrogens
is expected to be approximately 15%.
19,20
Switching
to other NSAA such as flutamide or nilutamide has
been proposed but is associated with a low and
idiosyncratic response rate and the potential for
exposingpatients to a greater riskof adverse effects.
21
Two new agents, enzalutamide and ARN-509, are
very potent antiandrogens referred to as “androgen
receptorsignaling inhibitors”.
3,22
Theynotonlypotently
bind to the androgen receptor, but also interfere
with its translocation into the nucleus andwith gene
transcription. Botharecurrentlyunderstudy inclinical
trials as SHM in men with CRPCwith and without
metastases.
Some SHM agents of historical interest include
estrogens (eg. diethylstilbestrol); the steroidal
antiandrogen, cyproterone acetate; and the steroidal
progestationaldrug,megestrolacetate. Diethylstilbestrol
(a synthetic non-steroidal estrogen) may induce
responses in CRPC and does not induce tumor flare
or vasomotor hot flashes but is associatedwith high
cardiovascularandthromboemboliccomplicationrates
andhas been largely abandoned.
23,24
Evidence for the
valueofotherestrogenformulations inCRPC issparse.
Megestrol acetatewas investigated byDawson et al
25
as a SHM inmenwithCRPCbut demonstrated a low
response rateof 14% (objective andPSAdecline rates)
andnodoseresponsewithhigherdoseswasobserved.
CyproteronehasalsobeenassociatedwithPSAresponse
in men with CRPC; however, both megestrol and
cyproterone have been associated with an increased
risk of cardiovascular side effects, andhave generally
beenabandoned inpractice.
26
The phenomenon of biochemical and clinical
response to discontinuation of antiandrogen
(“antiandrogenwithdrawal”--AAWD) has also been
observedwithanumberofotherSHMagents.
27,28
This
ispostulatedtobeduetoachange inandrogenreceptor
function in response tochronicantiandrogen therapy,
withparadoxical stimulationof theandrogenreceptor
due toreceptormutation.
29
Themedianantiandrogen
withdrawal response duration is approximately 4-6
months.
30
If clinically appropriate for the patient,
assessment for antiandrogenwithdrawal response is
generallyrecommendedparticularly inpatientstreated
withNSAAfora longduration. Patientswhoundergo
AAWD frombicalutamide shouldbeobserved forup
to 8weeks owing to thisdrug’s longer half-life.
CurrentlyafterNSAAandAAWD,anextreasonable
step is a trial of low corticosteroid with or without
ketoconazoleorabiraterone. Interestingly,prednisone
5mg twicedailywas associatedwithaPSAresponse
rate of 24%,medianPSAprogression-free survival of
5.6 months, and objective response rate of 16% in a
recently reported blinded placebo-controlled trial.
16
Abirateroneacetatemaybeconsideredat this juncture
in suitable patients with metastatic disease, but is
expensive, may not be funded or available for this
indication in all jurisdictions, and is associatedwith
incrementalmineralocorticoidsideeffects.
16
Inviewof
this, initiationof lowdoseprednisone alonewith the
additionofabirateroneatprogression in thesepatients
is alsoquite a reasonable strategy.
Historically, bilateral adrenalectomy to eliminate
adrenalandrogensasamethodofSHMwassuperseded
by use of aminoglutethemide and the imidazole
antifungal agent, ketoconazole. The activity of
ketoconazole in prostate cancer is thought to be due
to inhibitionof thecytochromep450enzymesCYP3A4
and CYP17 in the gonad and adrenal gland, with
possible additional effects due to androgen receptor
antagonism.
31
In a randomized trial of men with
CRPC, 27% of those receiving ketoconazole 400 mg
PO tid, hydrocortisone and AAWD had a PSA
response, and the objective response ratewas 20%.
32
Ketoconazole 200 mg PO tid was noted to elicit a
comparablePSAresponse rate ina singlearm study.
33
However, PSA response to ketoconazole should be
interpreted with caution as it is confounded by use
of lowdose corticosteroids; lowdoseprednisonehad
similarPSAandobjectiveresponserates in thecontrol
armofa recent randomized trial.
16
Ketoconazolemay
be cautiously considered as an alternative inpatients
who cannot afford or access abiraterone; however,
ketoconazole has been banned for systemic use in
the European Union due to serious hepatic toxicity,
and pretreatment with ketoconazolemay reduce the
efficacyof abiraterone.
34,35
Despite its limitations, ketoconazole provided
inspiration for pursuing the inhibition of
steroidogenesis as an additional therapeutic strategy
in CRPC. At the forefront of this approach is
abiraterone acetate which potently inhibits CYP17
mediated steroidogenesis in the testicle, adrenal,
and in intra- and peritumoral tissues resulting in
undetectable androgen levels.
36
ADT should be
continuedwithabiraterone, and lowdoseprednisone
isgiven tosuppressACTHproductionandmitigatethe
mineralocorticoidadverseeffectsdue toaccumulated
steroidprecursorsdue toCYP17blockade. Ryanetal
16
compared abiraterone acetate 1000mgPOdailyplus
prednisone10mgPOdaily toplaceboplusprednisone
in mainly asymptomatic chemotherapy-naive men
withmetastaticCRPC. Asignificant improvement in
