european urology 51 (2007) 306–314

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Review – Prostate Cancer

Antiandrogens in the Treatment of Prostate Cancer

Manfred P. Wirth *, Oliver W. Hakenberg, Michael Froehner

Department of Urology, University Hospital ‘‘Carl Gustav Carus’’, Technical University of Dresden, Fetscherstrasse 74,
D-01307 Dresden, Germany

Article info Abstract

Article history: Objectives: To give an overview on the contemporary role of antiandro-

Accepted August 22, 2006 gens in prostate cancer treatment.
Published online ahead of Methods: A review of the literature was performed concerning pharma-
print on September 11, 2006 cologic properties, possible indications and side effects of antiandrogens
in the treatment of early and advanced prostate cancer.
Keywords: Results: One steroidal and three non-steroidal antiandrogens are in
Prostate cancer common use for the treatment of prostate cancer. Monotherapy with
Hormonal treatment non-steroidal antiandrogens may prevent osteoporosis, loss of muscu-
Antiandrogens lature and may preserve sexual activity in a proportion of patients and
Bicalutamide therefore has advantages in quality of life compared to castration. In
Flutamide patients with localized disease managed by watchful waiting or in an
Nilutamide adjuvant setting, there are no studies showing an advantage in early
Cyproterone acetate versus delayed treatment with antiandrogens regarding clinical progres-
sion. In locally advanced non-metastatic prostate cancer, antiandrogen
monotherapy seems to be an alternative to castration treatment if
treatment is required. In patients with metastatic disease and a high
tumor burden, antiandrogen monotherapy is inferior to castration. In
advanced disease, combined androgen blockade can provide a small
survival advantage, which, however, has to be balanced against
increased side effects and costs.
Conclusions: Antiandrogens are a treatment option in some patients
with prostate cancer. However, it has to be taken into account that
the hormonal effect is inferior to castration.
# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Tel. +49 351 4582447; Fax: +49 351 4584333.
E-mail address: Manfred.Wirth@uniklinikum-dresden.de (M.P. Wirth).

1. Introduction tion have not been further improved [1,2]. Regard-

less of the obvious symptomatic benefit in advanced
Since the discovery of the beneficial effect of disease, definite evidence for any prolongation of
androgen deprivation by orchiectomy on prostate survival by endocrine treatment not combined with
cancer disease, the stage-corrected survival rates of curative local treatment (radical prostatectomy or
prostate cancer patients treated by androgen abla- external beam radiotherapy) is still lacking. Early
0302-2838/$ – see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2006.08.043
 european urology 51 (2007) 306–314 307

Table 1 – Pros and cons of different modalities of hormonal treatment for prostate cancer

Treatment modality Pro Con

Orchiectomy  low long-term costs  high short-term costs

 definitive androgen ablation
 no problems with compliance
 surgical complications possible
 psychological side effects, cognitive decline
 long term side effects (anaemia and osteoporosis)
 loss of libido and potency
 loss of physical activity
 loss of muscle mass, weight gain
 hot flushes
 irreversible measure

LHRH analogues  preservation of body integrity  side effects comparable with surgical castration
 temporary treatment possible  ‘‘flare-up’’ phenomenon
 treatment reversible  high long-term costs
 regular contact with physician

LHRH antagonists  no ‘‘flare-up’’ phenomenon  anaphylaxis

Nonsteroidal antiandrogens  temporary adjuvant or  high long-term costs (bicalutamide)

intermittent therapy possible
 preservation of sexual function possible  gynecomastia and breast pain frequent
 oral applicability, partially once daily  hepatotoxicity and diarrhoea
(especially flutamide)
 favourable tolerability profile  non-compliance
 osteoporosis probably less frequent  less effective in high tumor burden
(metastatic disease)
 step-up treatment possible  limited approval
 treatment reversible

Steroidal antiandrogens
 temporary adjuvant or  side effects comparable with surgical castration
intermittent therapy possible
 oral applicability  inferior to castration in terms of
time to progression
 step-up treatment possible  hepatotoxicity with long term use
 treatment reversible  limited approval

Maximal (combined) androgen  blockade of both testicular  combined side effects of castration
blockade and adrenal androgens and oral antiandrogens
 possible small survival advantage  high long-term costs
 treatment reversible

Estrogens  treatment reversible  cardiovascular toxicity

 low costs
 oral applicability

studies demonstrated a survival advantage, but
these studies do not meet contemporary require-
ments for comparative clinical trials any more and
can therefore not be regarded as conclusive [1].
Surgical or chemical castration is accompanied by
adverse effects and results in a decrease in quality of
life if undertaken early in the course of the disease
(Table 1). Most patients with metastatic prostate
cancer will develop hormone-refractory disease
within 12 to 18 months. Longer response periods
may be expected when hormonal treatment is started
at earlier stages [3,4]. Long-term androgen depriva-
tion, however, increases the risk of adverse effects
such as osteoporosis and pathologic fractures [5].
Prostate cancer today is diagnosed with increas-
ing frequency in physically and sexually active
younger men and although prostate cancer is
increasingly detected in localized and potentially
curable tumor stages [6], a considerable proportion
of patients will experience treatment failure and will
become candidates for hormonal treatment [1].
Therefore, considerable effort has been undertaken
to assess the effect of early, adjuvant or neoadjuvant
hormonal manipulations and to decrease the side
effects of this treatment modality [3]. This article
summarizes the current role of antiandrogens in the
treatment of prostate cancer.
2. Properties and side effects of currently
available antiandrogens
Nonsteroidal antiandrogens (bicalutamide, fluta-
mide, nilutamide) competitively inhibit the binding
of androgens to the androgen receptor. As a
consequence, the serum testosterone levels are
308 european urology 51 (2007) 306–314
Table 2 – Properties and side effects of the currently available antiandrogens
Bicalutamide Flutamide
Half-life: 7 days 5–6 hours
Dosage: 150 mg daily* 3  250 mg daily
Side effects:  hepatotoxicity  diarrhoea
(rarely)  hepatotoxicity
 hot flushes (more frequent than
 breast tenderness other antiandrogens,
 gynaecomastia (70%) may be fatal)
 nausea  impotence (20%)
 diarrhoea  gynaecomastia
 impotence (20%)
*
Monotherapy, 50 mg daily when combined with LHRH agonists.
y
Not licenced for monotherapy.
z
Not seen with other non-steroidal antiandrogens.
§
Hypotension, tachycardia, heart failure, syncope, myocardial infarct, haemorrhage, cerebrovascular accident, cardiovascular disorder, retinal
vascular disorder, embolus, pulmonary embolism, superficial and deep thrombophlebitis, thrombosis, retinal vein thrombosis, phlebitis,
vascular headache, shock.
not suppressed and may even increase. In contrast,
the only available steroidal antiandrogen cyproter-
one acetate in addition to antiandrogenic also has
progestational and antigonadotrophic properties. Its
application via a feedback suppression of pituitary
LHRH release thus leads to a reduction of serum
testosterone levels. Cyproterone aceteate medica-
tion in contrast to the use of non-steroidal anti-
androgens, thus results in the suppression of libido
and erectile function and causes side effects similar
to castration [7].
Bicalutamide is the most extensively studied
nonsteroidal antiandrogen [7]. Compared to LHRH
agonist treatment bicalutamide monotherapy results
in reduced fat accumulation, increased bone density
and fewer bothersome adverse effects both in animal
studies [8] as well as clinically [9,10]. However,
gynecomastia and breast pain are frequent side
effects of bicalutamide monotherapy and occur in
70–80% of patients [11–13]. This can partially be
prevented by local radiotherapy or tamoxifen treat-
ment. In randomised studies, tamoxifen prevented
gynecomastia effectively (odds ratio 0.1, p = 0.0009),
whereas prophylactic breast irradiation reduced the
incidence of gynecomastia by about 50% (odds ratio
0.51, p = 0.008), [14,15]. Tamoxifen did not add mean-
ingful toxicity to bicalutamide monotherapy [15]. It is,
however, still unclear what effect the estrogen-
antagonist tamoxifen has on prostate cancer. There-
fore, the routine use of tamoxifen to prevent gyne-
comastia cannot be recommended at present while
the use of prophylactic or therapeutic breast irradia-
tion is established. After the development of bicalu-
tamide-induced gynecomastia and/or breast pain,
about one third of patients may be expected to benefit
from breast irradiation (two fractions of 6 Gy) [16].
Nilutamide Cyproterone acetate
2 days 30–40 hours
3  100 mg dailyy 3  100 mg daily
 visual disturbances  lower testosterone levels
(delayed adaptation to  loss of libido
darkness, 33%)z  impotence (80%)
 alcohol intolerance (20%)z  rarely gynaecomastia
 nausea  cardiovascular toxicity (4–40%§)
 hepatotoxicity  hepatotoxicity (may be fatal)
(rarely, may be fatal)
 interstitial pneumonitis8
 impotence (50%),
Another problem of non-steroidal antiandrogens
is the interaction with other drugs due to inter-
ference with plasma protein binding. The use of
antiandrogens in patients taking drugs with high
plasma protein binding such as warfarin, phenytoin
or theophylline will increase the free drug serum
concentration of these substances which may result
in increased effects or side effects of these drugs [17].
Table 2 summarizes the properties and side effects
of the four antiandrogens in clinical use. There are
relatively few data available for nilutamide.
Although direct comparisons are not available,
compared to the other antiandrogens bicalutamide
seems to have some advantages in terms of the side
effect profile. Hepatotoxicity, the most serious side
effect of nilutamide, flutamide and cyproterone
acetate is relatively uncommon with bicalutamide.
This relative advantage of bicalutamide is partially
outweighed by the high rate of gynecomastia. Taken
together, the side effect profile of non-steroidal
antiandrogens compares favourably with castra-
tion, nevertheless, uncritical long-term use is
inappropriate and harbours the risk of adverse
events and even decreased survival [18]. Intermit-
tent LHRH analogue treatment is an alternative to
antiandrogens to reduce side effects caused by
castration. Osteoporosis can also be prevented by
bisphosphonate treatment.
3. Antiandrogen monotherapy
3.1. Locally advanced or metastatic disease
In two combined randomised trials involving 480
patients with locally advanced non-metastatic
 european urology 51 (2007) 306–314
disease (clinical stages T3-T4N0M0), bicalutamide
monotherapy (150 mg daily) was compared with
castration. After a median follow-up of 6.3 years,
there was no detectable difference concerning time
to progression or overall survival [19]. This study,
however, was not able to demonstrate equivalence
between both treatments since the upper 1-sided
95% confidence interval was greater than the value
of 1.25 needed to reject the hypothesis that
bicalutamide was at least 25% inferior to castration
[19]. Thus, there was no unequivocal proof in this
trial that bicalutamide monotherapy was equally
effective as castration treatment. Advantages for
bicalutamide monotherapy, however, were
observed concerning sexual interest and physical
capacity although detailed data on sexual potency
were not reported [19]. Other studies suggest that
approximately one third of patients receiving
150 mg bicalutamide daily maintain sexual func-
tion during long term treatment [20].
In a prospective randomised study including 220
patients with stage C or D prostate cancer, bicalu-
tamide monotherapy (150 mg daily) was compared
to combined androgen blockade. Patients in the
bicalutamide arm underwent castration at disease
progression. Again, there were no detectable differ-
ences concerning disease-specific or overall survival
[21] while subgroup analysis suggested an unex-
plained increased overall mortality in patients
with high-grade disease treated with bicalutamide
only [21].
Tyrrell and co-workers compared bicalutamide
monotherapy (150 mg daily) with castration as
treatment for locally advanced non-metastatic or
metastatic prostate cancer (n = 1453). Bicalutamide
monotherapy was as effective as castration in non-
metastatic patients, but there was a small survival
advantage for castration in the M1 subgroup. This
difference was perhaps partially outweighed by a
better tolerability profile and a higher quality of life
in patients treated with bicalutamide monotherapy
[22].
Thus, after adequate patient information, bica-
lutamide monotherapy is an option for younger and
sexually active patients with locally advanced
disease and in selected patients with metastatic
prostate cancer. In men with a high disease burden
(PSA values >400 ng/ml), castration definitely
remains superior to antiandrogen monotherapy
[23,24].
Schröder and co-workers reported the final
results of a randomised EORTC trial comparing
flutamide versus cyproterone acetate monothera-
pies in men with metastatic prostate cancer and
favourable prognostic factors [25]. They found no
309
significant difference between the two treatment
arms concerning time to progression, disease-
specific or overall survival. The side effect analysis
favoured cyproterone acetate regarding gynecomas-
tia, diarrhoea and nausea [25]. In a phase III study of
metastatic prostate cancer treatment with com-
bined androgen blockade (goserelin acetate plus
cyproterone acetate) versus goserelin acetate alone
or cyproterone acetate alone with 525 patients,
monotherapy with the antiandrogen cyproterone
acetate was inferior to LHRH monotherapy in
delaying time to progression (difference in the
median delay of time to progression was 3 months,
p < 0.02) [26]. Current recommendations of the
American Society of Clinical Oncology therefore
do not recommend the use of cyproterone acetate
for monotherapy [27,28].
The supplementation of antiandrogen monother-
apy with a 5a-reductase inhibitors is possible. It has
been suggested that such a combination treatment
may increase the antiandrogenic activity with low
additional toxicity. About one third of patients
treated in this way may be expected to maintain
spontaneous erections [29]. No data on the long-
term efficacy of such treatment regimens has been
reported and this combination increases treatment
costs considerably.
3.2. Adjuvant and primary antiandrogenic treatment in
early prostate cancer
Again, bicalutamide is the most extensively studied
drug for this application. In the ongoing Early
Prostate Cancer Program (EPC) bicalutamide is
being evaluated as an adjuvant treatment for early
prostate cancer (stages T1b-4N0-1M0), whereby
antiandrogenic monotherapy together with ‘watch-
ful waiting’ as a primary treatment strategy is also
defined as ‘adjuvant’. The program consists of three
double-blind, parallel-group, placebo-controlled
trials (North America, (trial 23, n = 3292), Europe/
rest of world (trial 24, n = 3603), Scandinavia (trial 25,
n = 1218) [11,30]. While in the North American trial,
all patients underwent curative treatment prior to
study entry, watchful waiting was allowed as
‘primary treatment’ besides radical prostatectomy
or radiotherapy in trials 24 and 25 and in the
Scandinavian trial comprised 82% of patients
[11,30]. The study treatment was given for two
years or until disease progression in trial 23 and
until disease progression in trials 24 and 25. A
maximum treatment duration of five years was
recommended for patients receiving treatment
adjuvant to curative measures [18,31]. Because of
these differences in treatment schedules and in
310 european urology 51 (2007) 306–314
patient selection, the results of a combined analysis
of the three studies have to be interpreted with
caution. Time to objective clinical progression and
survival were the primary study end points, time to
treatment failure, PSA progression and toxicity as
secondary end points. Side effects (gynecomastia/
breast pain) were the most common reason for
discontinuation of treatment in the bicalutamide
group and disease progression in the placebo group
[11]. At the time of the most recently published
analysis, at a median follow-up of 7.4 years, there
was no benefit in progression-free survival for the
bicalutamide group in the entire study population
[18]. There was even a trend towards decreased
overall survival for localized prostate cancer under
watchful waiting when treated with bicalutamide
(hazard ratio 1.16, 95% confidence interval 0.99–
1.37, p = 0.07). In all patients with locally advanced
disease, however, bicalutamide significantly
improved progression-free survival irrespective of
the primary treatment applied. Overall survival in
patients with locally advanced disease was
improved in the bicalutamide group only in patients
treated by radiotherapy (hazard ratio 0.65, 95%
confidence interval 0.44–0.95, p = 0.03) and these
patients had a lower risk of prostate cancer-related
mortality. In the bicalutamide group of patients
with locally advanced disease under watchful
waiting overall survival was not significantly
improved (hazard ratio 0.81, 95% confidence inter-
val 0.66–1.01, p = 0.06) nor was any survival differ-
ence seen in the radical prostatectomy subgroup
[18].
Overall, the currently available data from the
ongoing EPC studies suggest that early or adjuvant
hormonal therapy is not beneficial in patients with
localized disease while it seems of proven benefit in
prolonging progression-free survival in patients
with locally advanced disease irrespective of the
primary treatment and in prolonging overall survi-
val in patients undergoing primary radiotherapy
[18,31].
4. Combined androgen blockade
The superiority of combined (‘‘complete’’) androgen
blockade (i.e. the combination of an antiandrogen
with orchiectomy or medical castration) as the
primary treatment for advanced prostate cancer
has not been proven conclusively up to date despite
a large number of randomised trials [32,33]. A meta-
analysis of 20 trials found no differences between
combined androgen blockade and castration when
2-year overall survival was evaluated. Based on the
10 trials with available 5-year survival data, this
same meta-analysis, however, did show a signifi-
cant survival advantage for combined androgen
blockade [32]. No evidence is available supporting a
greater benefit of combined treatment in patients
with favorable prognostic factors.
Combined androgen blockade using a non-ste-
roidal antiandrogen tends to be superior to those
using cyproterone acetate in delaying progression
[26,32,33]. The limited advantage of combined
treatment over monotherapy must, however, be
balanced against higher side effects and costs. The
additional costs for one quality-adjusted life-year
gained by using combined androgen blockade over
orchiectomy alone has been estimated to be US$1
million [Prostate Cancer Trialists’ Collaborative
Group 2000]. Combined androgen blockade is an
option for patients with advanced or metastatic
prostate cancer. It is, however, not the standard
form of androgen ablative therapy for primary
application [33].
5. Adjuvant treatment after radiotherapy or
radical prostatectomy
A great body of data from prospective randomised
trials supports the use of adjuvant hormonal
treatment after external beam radiotherapy.
High-risk patients with locally advanced disease
or positive lymph nodes seem to benefit from
immediate androgen deprivation after external
beam radiotherapy whereas in earlier stages the
differences tend to diminish [27]. The beneficial
effect of adjuvant hormonal therapy in the
external beam radiotherapy setting has been
attributed to an elimination of occult metastases
and to a potential additive effect by induction of
apoptosis [34]. It is, however, still unknown to
which degree the observed survival advantages
may be attributed to hormonal therapy alone. Data
from the Bicalutamide Early Prostate Cancer
Program suggest that bicalutamide monotherapy
may possibly be similarly effective as castration in
the adjuvant setting after radiotherapy [18], ran-
domised comparisons are, however, not available
up to date.
Conclusive evidence from randomised studies on
the efficacy of adjuvant endocrine treatment and
particularly of adjuvant antiandrogen treatment
after radical prostatectomy is still lacking. In
patients with positive lymph nodes, a small random-
ized study demonstrated a survival advantage for
immediate hormonal therapy (castration) versus
treatment at metastatic or symptomatic progression
 european urology 51 (2007) 306–314
[35]. In a multicentric randomised trial of 352
patients with locally advanced, lymph node-nega-
tive prostate cancer after radical prostatectomy,
adjuvant flutamide was compared to no adjuvant
treatment. Tumor progression was significantly
delayed in the flutamide arm ( p = 0.0041) but there
was no difference in overall survival after a median
follow-up of 6.1 years ( p = 0.92) [36]. Similarly, the
EPC studies on bicalutamide have so far only shown
a delay in PSA-defined progression without any
effect on overall survival in patients after radical
prostatectomy (see above).
6. Neoadjuvant treatment prior to
radiotherapy or radical prostatectomy
Prior to radical prostatectomy, neoadjuvant hormo-
nal treatment is not recommended for routine clinical
use [23]. In patients with locally advanced prostate
cancer selected for external beam radiotherapy,
however, in one radomised trial, neoadjuvant com-
bined androgen blockade (flutamide and goserelin)
significantly improved local control, progression rate
and overall survival in the Gleason score 2–6 subgroup
[37]. Comparable evidence is not available for anti-
androgenic monotherapy. Considering the prostate
volume reduction, bicalutamide monotherapy seems
to be less effective than LHRH analogues [38].
7. Step-up hormonal treatment
Because of the uncertainties surrounding the tim-
ing, side effects and costs of hormonal treatment,
alternative treatments especially in patients with a
low tumor burden have been considered. The so-
called step-up treatment (stepwise escalation of
androgen withdrawal, for instance starting with an
antiandrogen and later adding a 5-a-reductase
inhibitor) is frequently used in clinical practice.
However, hardly any studies investigating this
treatment option have been published. Oh and co-
workers treated patients with PSA relapse after
curative treatment or newly diagnosed metastatic
disease initially with flutamide and finasteride. The
authors suggested that such a strategy is feasible
and effective in terms of PSA control. All patients
who failed under the initial oral regimen experi-
enced more than 50% decline in PSA when even-
tually androgen ablation treatment was undertaken
[29]. Randomized studies comparing step-up hor-
monal treatment with early or deferred con-
ventional androgen deprivation might be of
considerable clinical interest.
311
8. Prevention of ‘‘flare-up’’ phenomenon in
patients receiving LHRH agonists
When given for the first time, long-acting LHRH
agonists cause a transient testosterone increase by
stimulating pituitary LHRH receptors. This so called
‘‘flare-up’’ phenomenon may cause fatal complica-
tions in patients with far advanced disease. Simul-
taneous antiandrogen application may decrease the
incidence of initial disease progression. It has been
recommended to start such treatment at the same
day as the first LHRH analogue depot injection and
maintain it for a two week period. In high risk
patients (impending spinal cord compression),
however, surgical castration should be preferred
[23].
9. Antiandrogen withdrawal syndrome and
secondary hormonal manipulations
Failure after initial hormonal treatment does not
necessarily mean treatment refractory disease
progression. Secondary hormonal manipulations
are a safe and effective but short-term option in
patients with failure after primary hormonal
therapy [4]. When an antiandrogen is part of the
treatment regimen, discontinuation may result in
the so-called antiandrogen withdrawal syndrome,
described for the first time by Kelly and Scher [39].
The incidence of this effect has been reported to be
15 to 20% and it lasts for five months on average
[4]. Replacement of an initially given antiandrogen
by an alternative substance may also result in a
PSA response [40]. Mutations in the androgen
receptor gene are supposed to account for this
phenomenon by enabling the antiandrogens to act
as receptor agonists [41]. Similar observations
were reported after replacement of bicalutamide
or flutamide as part of a failing combined andro-
gen blockade by nilutamide [42]. After initial
antiandrogen monotherapy, orchiectomy at the
time of failure of initial treatment may lead to a
PSA response and to symptomatic improvement
[43]. Second-line treatment with bicalutamide has
been shown to improve symptoms and decrease
pain in patients without prior antiandrogen
therapy [4]. A 50% PSA decrease has been
described after second line treatment with non-
steroidal antiandrogens in 14–50% of cases [4].
Responders to second-line hormonal treatment
may be expected to survive significantly longer
than non-responders [40]. Overall, however, it
is still doubtful whether secondary hormonal
manipulations do actually improve survival [4].
312 european urology 51 (2007) 306–314
However, the suppression of testicular androgens
should be continued when the disease is hormone
refractory, since a withdrawal of treatment may
decrease survival [4].
10. Conclusions
Antiandrogens are an established treatment option
in patients with prostate cancer either as mono-
therapy or in combination with LHRH analogues. In
patients with a limited tumor burden, non-ste-
roidal antiandrogen monotherapy seems as effec-
tive as castration. Antiandrogens which preserve
testosterone levels can also preserve libido and
sexual function in previously sexually active
patients. Thus some side effects of castration
may be avoided by antiandrogen monotherapy,
but frequent gynecomastia (bicalutamide) and the
risk of hepatotoxicity (cyproterone, nilutamide,
flutamide) and a hitherto unexplained trend
towards increased mortality when given to patients
with localized prostate cancer prohibit their uncri-
tical use. These risks have to be individually
balanced against improved quality of life compared
to castration treatment. Antiandrogens may be
used as part of combined androgen blockade
regimens. PSA progression under combined andro-
gen blockade may respond to discontinuation or
change of the antiandrogen.
Conflict of interest
Professor M. P. Wirth is principal investigator of the
‘‘Bicalutamide Early Prostate Cancer Program’’
which is supported by AstraZeneca.
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314 european urology 51 (2007) 306–314
Editorial Comment
Steven P. Balk, Glenn J. Bubley,
Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, MA, United States
sbalk@bidmc.harvard.edu
Mary-Ellen Taplin, Dana Farber Cancer Institute,
Harvard Medical School, Boston, MA, United States
This article is a timely review of androgen recep-
tor antagonist (antiandrogen) clinical trials and the
current role of these drugs in prostate cancer treat-
ment. The nonsteroidal antiandrogens were widely
used in the late 1970s and 1980s in combination
with orchiectomy or luteinising hormone-releasing
hormone (LHRH) agonist therapies (combined
androgen blockade) to prevent androgen receptor
activation by residual adrenal androgens, but ran-
domised trials showed only a small survival advan-
tage with increased toxicity. These results led to a
marked decline in the initial use of antiandrogen
combination therapies and the conclusion that
complete androgen receptor blockade is not more
effective than monotherapy. However, it now
appears clear that the androgen receptor is reacti-
vated and largely refractory to antiandrogens in
prostate cancers that relapse subsequent to andro-
gen-deprivation therapy, indicating that complete
androgen receptor blockade is not achieved with
currently available antiandrogens and that more
potent antagonists (possibly functioning through
alternative mechanisms such as androgen receptor
degradation) may be more effective [1].
Antiandrogens (primarily bicalutamide) have also
been examined as initial monotherapy and appear
comparable to castration in some stages of disease,
although high doses may be required. In contrast,
bicalutamide monotherapy may be inferior to pla-
cebo in patients in watchful waiting therapy and
inferior to castration in patients with greater disease
burden (and may therefore be less effective in
patients with short prostate-specific antigen dou-
bling times). Nonetheless, as emphasised in the
review, bicalutamide may be preferable in some
patients due to a better side effect profile than cas-
tration (likely reflecting, in part, normal or increased
levels of testosterone, which can be converted to
estrogen by aromatase) [2]. However, it should be
emphasised that these hormonal differences could
also affect efficacy, including the apparent synergy
between radiation and androgen deprivation [3].
Based on these observations, it is prudent to limit
hormonal therapy (antiandrogen or castration) to
patients who have been shown to benefit [4], to
consider intermittent androgen-deprivation ther-
apyasanalternative, andto use antiandrogen mono-
therapy cautiously in cases where its efficacy has not
been directly compared to castration.
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