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Prostate Cancer and Prostatic Diseases (1998) 1, 307±314
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Review
Receptor af®nity and potency of
non-steroidal antiandrogens:
translation of preclinical ®ndings
into clinical activity
GJCM Kolvenbag1, BJA Furr2 & GRP Blackledge3
1
Medical Affairs, Zeneca Pharmaceuticals, Wilmington, DE, USA; 2Therapeutic Research
Department, and 3Medical Research Department, Zeneca Pharmaceuticals, Alderley Park,
Maccles®eld, Cheshire, UK
The non-steroidal antiandrogens ¯utamide (Eulexin1), nilutamide (Anandron1)
and bicalutamide (Casodex1) are widely used in the treatment of advanced
prostate cancer, particularly in combination with castration. The naturally
occurring ligand 5a-DHT has higher binding af®nity at the androgen receptor
than the non-steroidal antiandrogens. Bicalutamide has an af®nity two to four
times higher than 2-hydroxy¯utamide, the active metabolite of ¯utamide, and
around two times higher than nilutamide for wild-type rat and human prostate
androgen receptors. Animal studies have indicated that bicalutamide also exhibits greater potency in reducing seminal vesicle and ventral prostate weights and
inhibiting prostate tumour growth than ¯utamide. Although preclinical data can
give an indication of the likely clinical activity, clinical studies are required to
determine effective, well-tolerated dosing regimens. As components of combined
androgen blockade (CAB), controlled studies have shown survival bene®ts of
¯utamide plus a luteinising hormone-releasing hormone analogue (LHRH-A)
over LHRH-A alone, and for nilutamide plus orchiectomy over orchiectomy
alone. Other studies have failed to show such survival bene®ts, including those
comparing ¯utamide plus orchiectomy with orchiectomy alone, and nilutamide
plus LHRH-A with LHRH-A alone. In a direct comparative study, bicalutamide
(50 mg, once daily) was compared with ¯utamide (250 mg, three times daily), each
in combination with an LHRH-A. Both therapies were well tolerated, although
more patients could not tolerate ¯utamide therapy: 25 ¯utamide plus LHRH-A
and 2 bicalutamide plus LHRH-A patients withdrew from therapy due to
diarrhoea. There were no statistically signi®cant differences for time to progression or survival between the two antiandrogens. This clinical trial of
bicalutamide con®rms the prediction from preclinical studies that a 50 mg dose of
bicalutamide would be appropriate for use in patients with advanced prostate
cancer, and demonstrates that this bicalutamide dose is clinically effective when
administered as part of CAB.
Keywords: bicalutamide; ¯utamide; nilutamide; antiandrogen; prostate cancer
Introduction
Most prostatic tumours are stimulated to grow by androgens,1 and consequently androgen withdrawal is effective
Correspondence: Dr GJCM Kolvenbag, Zeneca Pharmaceuticals,
1800 Concord Pike, PO Box 15437, Wilmington, Delaware 198505437, USA.
Received 16 December 1997; revised 25 June 1998; accepted
15 July 1998
as treatment.2,3 Castration, through orchiectomy, or
administration of a luteinising hormone-releasing hormone analogue (LHRH-A), is a well accepted management option in advanced prostate cancer.3 ± 5 However,
although castration ablates androgen release from the
testes, androgen biosynthesis in the adrenals (8 ± 10% of
total circulating androgens) is not affected.6,7 Because of
this, a widely used management strategy for advanced
prostate cancer is combined androgen blockade (CAB), in
which surgical or chemical castration is combined with
Af®nity, potency and activity of non-steroidal antiandrogens
GJCM Kolvenbag et al
308
administration of an antiandrogen.8,9 Monotherapy with
pure antiandrogens is not yet a standard management
option for advanced prostate cancer. However, its potential bene®t of conserving sexual potency may justify its
use, and recent clinical trials have shown comparable
ef®cacy between high-dose pure antiandrogen therapy
and castration.10
Ideally, an antiandrogen should possess high speci®city and af®nity for the androgen receptor, while being
devoid of other hormonal or antihormonal activity. The
®rst antiandrogen to be used clinically was the steroidal
agent cyproterone acetate. However, the use of cyproterone acetate is limited by its progestogenic side effects, and
hepatic toxicity.11 ± 13 A number of pure non-steroidal
antiandrogens have since been developed and three are
currently used in the treatment of advanced (stage D2)
prostate cancer: ¯utamide (Eulexin1, Schering-Plough
International),14 ± 18 nilutamide (Anandron1, Roussel),19
and bicalutamide (Casodex1, Zeneca Pharmaceuticals).20 ± 26
Non-steroidal antiandrogens exert their effects through
competitive inhibition of the binding of testosterone, and
its metabolite 5-a dihydrotestosterone (5a-DHT), to the
nuclear androgen receptor. A number of in vitro, cell and
animal models are available for preclinical studies of the
af®nities and potencies of antiandrogens at this receptor.
Such preclinical data give an indication of the likely
effective doses in man. The aim of this article is to
review the literature which directly compares the relative
af®nity and potency of bicalutamide with ¯utamide and
nilutamide, and to assess how these preclinical ®ndings
translate into clinical activity.
Preclinical ®ndings
Af®nity
The relative binding af®nities of antiandrogens have
generally been calculated in relation to the natural androgen receptor ligand 5a-DHT, or to the synthetic androgen
methyltrienolone (R1881). Most comparative studies
report that although bicalutamide has a lower binding
af®nity than the naturally occurring ligand 5a-DHT, it has
an af®nity of between two and four times higher than 2-
hydroxy¯utamide, the active metabolite of ¯utamide, and
around two times higher than nilutamide, for wild-type
rat,20,27,28 and wild-type human29,30 prostate androgen
receptors (Table 1) (reviewed by Furr32). For example,
Furr et al reported that in a radioligand displacement
study, bicalutamide bound to a wild-type rat prostate
androgen receptor preparation with af®nities of around
50 and 100 times less than 5a-DHT and R1881, respectively, but about four times greater than 2-hydroxy¯utamide.20 Similarly, in a study which also included
nilutamide, bicalutamide had 2.3 times higher af®nity
for rat prostate androgen receptors than either nilutamide
or 2-hydroxy¯utamide.27 Using a normal human prostate
cytosol preparation, bicalutamide was found to have a
binding af®nity around 60 times less than 5a-DHT, but 2.5
and 1.6 times higher than 2-hydroxy¯utamide and nilutamide, respectively.29
Contradictory to the evidence supporting the greater
af®nity of bicalutamide over 2-hydroxy¯utamide, Luo et
al 31 have reported comparable af®nities for these agents
at both wild-type rat and human prostate androgen
receptors (Table 1). However, compared with other studies, the IC50 values (calculated as the concentration of
drug required to produce 50% displacement of [3H]R1881)
were generally over three-fold higher in the work of Luo
et al. 31 The reason for these anomalous results is unclear,
but they may be due to inappropriate assay conditions,
such as excess of receptor, failure to reach equilibrium, or
failure to achieve predicted bicalutamide concentrations,
due to non-speci®c binding of this drug to glass or plastic
containers.32 In addition, bicalutamide is a racemic compound of which the `R' enantiomer shows higher androgen receptor binding af®nity than the `S' enantiomer,33
and thus the ratio of enantiomers would affect binding
characteristics. Whereas for most studies, Casodex1 was
supplied by Zeneca,20,27,29,30 Luo et al synthesised bicalutamide in their laboratory and did not report analytical
data to support whether their agent is identical to the
authentic drug.
Potency
Whilst af®nity de®nes the extent to which a drug binds to
its receptor, potency is the term used to describe the dose
required to produce a given level of response.
Table 1 Relative binding af®nity of bicalutamide, compared with 2-hydroxy¯utamide and nilutamide, for wild-type prostate androgen
receptors
Relative binding af®nitya
IC50 (nM)
Species
b
Rat
Ratc
Rat
Ratb
Humanb
Humanc
Humanb
a
Bicalutamide
2-hydroxy
¯utamide
Nilutamide
Bicalutamide/
2-hydroxy ¯utamide
Bicalutamide/
nilutamide
Reference
190
400
not reported
3595
300
100
2490
700
900
not reported
4565
700
300
2345
not tested
900
not tested
18620
500
not tested
5300
4.0
2.3
3.3
1.3
2.5
3.0
1.0
not tested
2.3
not tested
5.2
1.6
not tested
2.1
[20]
[27]
[28]
[31]
[29]
[30]
[31]
For the purposes of this review, the relative binding af®nity of 2-hydroxy¯utamide or nilutamide, as appropriate, has been assigned a value of 1 in each individual
study, and the value for bicalutamide calculated accordingly.
IC50 values calculated as the concentration of drug required to produce 50% displacement of [3H]R1881 from androgen receptors.
c
IC50 values calculated as the concentration of drug required to produce 50% displacement of [3H]5a-DHT from androgen receptors.
b
Af®nity, potency and activity of non-steroidal antiandrogens
GJCM Kolvenbag et al
Intact rats and dogs. In a comparative study of the
activity of bicalutamide and ¯utamide in mature, intact
male rats, Furr et al 20 observed that following a 14-day
dosing period, both antiandrogens reduced the weights of
the seminal vesicles and ventral prostate glands, but
bicalutamide was more potent at all dose levels tested
(1, 5 and 25 mg/kg) (Figure 1a,b). A number of other
studies with intact rats34±37 support these observations. In
studies performed in the Nieschlag laboratory,34 ± 36 bicalutamide exhibited greater potency than ¯utamide at all
dose levels (10 or 20 mg/kg) and time intervals (7, 14 or
21 d) tested. In a recent study by Hamann et al, 37 20 mg
and 40 mg doses of bicalutamide were more potent than
the same doses of ¯utamide in reducing the weights of
seminal vesicles (weight after two weeks compared with
intact rats: 45% vs 78% at 20 mg/kg; 38% vs 55% at
40 mg/kg) and ventral prostate glands (weight after two
weeks compared with intact rats: 40% vs 62% at 20 mg/
kg; 34% vs 56% at 40 mg/kg). By contrast, Luo et al 31
reported that bicalutamide and ¯utamide (both 16 mg/
kg) had similar potencies in reducing intact rat seminal
vesicle (32% vs 25% respectively) and ventral prostate
(both 47%) weight over seven days. In orchiectomised
rats supplemented with 4-androstenodione implants, ¯utamide showed greater potency than bicalutamide in
reducing both seminal vesicle and ventral prostate
weight, seven days following oral administration (0.4,
1.2, 4.0 and 12.0 mg/kg) (Figure 1c,d). These anomalous
results could again be due to the unknown purity of
bicalutamide used in the study by Luo et al. 31 In addition,
since bicalutamide has a low solubility, authentic Casodex1 is micronised to ensure a small and consistent
particle size to optimise bioavailability. There is no information on the bioavailability of the agents used by Luo et
al, 31 and therefore it is dif®cult to interpret whether their
results re¯ect the true relative potencies of the compounds.
Both bicalutamide23,38 and ¯utamide39 induce atrophy
of the prostate gland in adult male dogs. No comparative
study has been performed, but ED50 values (the dose
required to produce a response in 50% of cases) in noncomparative studies suggest that bicalutamide23 (0.1 mg/
kg) is at least potent in inducing atrophy as ¯utamide
(5 mg/kg).40
No published studies have compared the potency of
nilutamide with either bicalutamide or 2-hydroxy¯utamide in either intact rats or dogs. However, in a noncomparative study in rats, nilutamide (5 ± 10 mg/rat)
produced a signi®cant reduction in the weight of accessory organs, including the seminal vesicles and ventral
prostate, over 30 d.41
Antitumour activity. Studies on the antitumour effect of
antiandrogens have been carried out in rats bearing the
Dunning R3327H prostate tumour.42 In an 11-week, placebo-controlled study, the size of Dunning R3327H
tumours was examined weekly in rats treated with bicalutamide or ¯utamide (both 5 or 25 mg/kg, once daily).23
Both agents, when compared with placebo, caused a
signi®cant inhibition of tumour growth. The inhibition
of tumour growth with bicalutamide was signi®cant by
week 4 (P < 0.05, weeks 4 ± 5; P < 0.01, weeks 6 ± 11),
irrespective of dose. Flutamide appeared less effective,
but produced a signi®cant (P < 0.05) reduction in tumour
309
Figure 1 Comparison of the effects of graded oral doses of bicalutamide
and ¯utamide on inhibition of seminal vesicle and ventral prostate organ
growth, as reported by Furr20 and Luo et al.31 Graded oral doses of
bicalutamide or ¯utamide were orally administered (a, b) daily for 14 d to
intact rats, with placebo-treated controls arbitrarily assigned a value of 0%
and surgically castrated controls a value of 100%; or (c, d) twice daily for
7 d in orchiectomised rats supplemented with 4-androstenodione implants,
with orchiectomised rats assigned a value of 0% and rats which received
only 4-androstenodione implants a value of 100%.
size at weeks 6 ± 11 at a dose of 25 mg/kg and at weeks
7 ± 11 at 5 mg/kg. Even at the higher dose, however, the
mean effect was not as great as that seen with bicalutamide at 5 mg/kg.
An important study by Veldscholte et al 43 describes the
effects of antiandrogen binding to an androgen receptor
present in the human LNCaP prostate tumour cell line,
which has a point mutation in the steroid-binding domain
(codon 877, Thr?Ala). Although bicalutamide, 2-hydroxy¯utamide and nilutamide were all found to bind to the
LNCaP androgen receptor, bicalutamide had no effect on
cell proliferation, whereas an agonist stimulation of cell
proliferation was seen with the other two agents. Bicalutamide did, however, display antiandrogenic properties
in inhibiting R1881-induced LNCaP proliferation. In
another study,30 wild-type and LNCaP androgen receptor
cDNA were transiently transfected into COS cells, along
with a reporter vector that re¯ects androgen-regulated
transcriptional activity. With 2-hydroxy¯utamide, a
higher binding af®nity and a concomitant increase in
receptor stabilisation and agonist activity was observed
at the LNCaP androgen receptor, relative to the wild-type
androgen receptor; at high concentrations, 2-hydroxy¯utamide became an agonist even at the wild-type androgen
receptor. Bicalutamide, in contrast, was an antagonist at
Af®nity, potency and activity of non-steroidal antiandrogens
GJCM Kolvenbag et al
310
both the LNCaP and wild-type androgen receptors, and
did not have a higher binding af®nity or greater stabilising activity at the LNCaP androgen receptor. Whether
these observations have any clinical signi®cance is
unclear, but it could be speculated that androgen receptor
mutations may lead to the effectiveness of bicalutamide in
some tumours that fail to respond or relapse following
primary therapy with ¯utamide. In support of this, a
number of other androgen receptor mutations that display in vitro functional properties similar to that of the
LNCaP androgen receptor, some of which are stimulated
by ¯utamide, have been identi®ed in tumours from
patients who have relapsed following ®rst-line antiandrogen therapy.44,45 When tested, bicalutamide still demonstrated antiandrogenic effects on these mutant receptors.45
Peripheral selectivity
Studies in rats have indicated that bicalutamide may offer
the advantage of peripheral selectivity.23,46 In the Dunning
R3327H prostate tumour model, ¯utamide led to doserelated increases in both serum luteinising hormone (LH)
and testosterone concentrations in rats, due to antagonism of negative feedback effects of androgens on the
hypothalamus and pituitary gland; in contrast, bicalutamide had little effect on these hormone levels.23 Nilutamide acts centrally as well as peripherally and therefore,
like ¯utamide, increases serum LH and testosterone
levels.47 The reason for the peripheral selectivity of bicalutamide is likely to be poor penetration of the agent
across the blood-brain barrier.48
The increases in serum testosterone and LH levels
observed in response to ¯utamide in rats is also seen in
dogs, whereas bicalutamide again appears to exhibit
peripheral selectivity.23,40 Studies to date have shown
that bicalutamide does not exhibit peripheral selectivity
to the same extent in humans.49
Tolerability
No animal studies have compared directly the tolerability
of bicalutamide, ¯utamide and nilutamide. In non-comparative studies to date, however, bicalutamide has been
well tolerated, with no evidence of gastrointestinal or
hepatic problems (as associated with ¯utamide), or
visual disturbances, alcohol intolerance or pulmonary
interstitial disease (as reported for nilutamide).23,50
Indeed, apart from the expected effects on accessory sex
organs and sex-related parameters, bicalutamide has
shown no signi®cant effects in safety pharmacology
tests in rats, and no clinically relevant effects in dogs.
Speci®cally, bicalutamide is a pure antiandrogen and has
no other hormonal or antihormonal activity.
The only effects of bicalutamide in dogs were a small
increase in heart rate and a reduction in the PR interval
following long-term administration at doses of more than
25 times the ED50 value for prostate atrophy; there were
no pathological ®ndings related to this change, and no
impairment of cardiac function.23 Clinical studies with
bicalutamide, however, have revealed that none of the
associated cardiac events reported in dogs is relevant in
man.24,50 Serious cardiac lesions have been observed
following administration of high doses of ¯utamide to
beagle dogs, including chronic myxomatous degeneration, intra-arterial ®brosis, myocardial acidophilic degeneration, vasculitis and perivasculitis; these canine lesions
are not observed at levels of ¯utamide used therapeutically in humans (¯utamide prescribing information). With
regard to sexual function, neither bicalutamide nor ¯utamide affects canine libido or sexual potency.23,40
Summary Ð preclinical studies
Direct comparative studies have shown a number of
differences in the af®nity and potency of bicalutamide,
¯utamide and nilutamide. Although preclinical data for
all three agents are generally favourable and differences
are subtle, bicalutamide appears to have the greatest
af®nity and potency at the androgen receptor.
Studies of af®nity, potency, and tolerability of bicalutamide in rats and dogs give an indication of the likely
clinical activity. However, in any preclinical study the
experiment is dependent on the model used, and animal
studies cannot take fully into account factors unique to
man, such as tissue protein binding, pharmacokinetics,
absorption, distribution, metabolism and excretion. Clinical studies are required to determine clinically effective
and well-tolerated dosing regimens.
Clinical relevance
The ultimate answer to the question of relative therapeutic usefulness of agents lies in head-to-head comparative
studies of ef®cacy and safety using doses that are thought
to be adequate. Only one study has directly compared
non-steroidal antiandrogens: a double-blind, randomised,
multi-centre trial to compare bicalutamide and ¯utamide
as components of CAB.51 Nevertheless, with all new
drugs, non-comparative dose-®nding studies should
®rst be undertaken, with end-points of pharmacokinetics
and tolerability.
Dose-®nding
The initial doses of bicalutamide (10 mg, 30 mg and
50 mg) were chosen based on the preclinical studies in
rats and dogs, which were considered appropriate models
to predict the choice of dosing in man. These bicalutamide
doses were ®rst evaluated in single-dose pharmacokinetic
studies, which demonstrated a linear pharmacokinetic
pro®le, a prolonged absorption (peak plasma concentration at up to 8 h with 10 mg and 30 mg doses and up to
48 h with a 50 mg dose), and favourable tolerability, with
no clinically important adverse results in routine laboratory tests.52 During daily administration, bicalutamide
accumulates about 10-fold at all dose levels, and curve
®tting of multiple-dose data estimates the plasma elimination half-life to be 7 ± 10 d. Bicalutamide undergoes
stereospeci®c metabolism, with the S-enantiomer metabolised primarily by glucuronidation and the R-enantiomer by oxidation to an inactive metabolite prior to
glucuronidation.53 Both the parent enantiomers and
their metabolites are eliminated in the urine and faeces,
but the S-enantiomer is more rapidly cleared, and the
Af®nity, potency and activity of non-steroidal antiandrogens
GJCM Kolvenbag et al
R-enantiomer therefore accounts for about 99% of total
steady-state plasma levels.53 Elimination is unaffected by
age, renal function or hepatic status. In all pharmacokinetic studies, bicalutamide was well tolerated, with no
clinically relevant adverse events in routine laboratory
tests. These data indicate that bicalutamide (50 mg) is
suitable for once-daily oral dosing in man.22
There are several differences in pharmacokinetics
between bicalutamide, ¯utamide and nilutamide. Flutamide, unlike bicalutamide, must be converted to its
active metabolite, and the short plasma elimination
half-life (4 ± 7 h) of 2-hydroxy¯utamide necessitates frequent dosing. Dose-®nding studies with ¯utamide
have recently been reported in benign prostatic hyperplasia54 and are still continuing in prostate cancer.55
Results to date agree with the accepted dosage
(750 mg daily, given in three divided doses) which is
based primarily on animal data.17 The majority of the
activity of nilutamide is attributable to the parent
compound and its plasma elimination half-life (56 h)
does indicate once-daily administration; a 300 mg oral
dose is currently recommended.56 In contrast with
bicalutamide and ¯utamide, however, nilutamide is
predominantly metabolised by the microsomal cytochrome P450 system and eliminated via the hepatic
route; although hepatic dysfunction may be expected
to prolong the elimination of nilutamide to some
degree, no data are available and dosage adjustments
are not currently recommended.56
Treatment of advanced prostate cancer
Trials to evaluate the use of antiandrogens as monotherapy are in progress.10,26,57 ± 67
CAB has generated considerable interest recently and
has been compared with castration alone (medical and
surgical) in numerous clinical trials in patients with
advanced prostate cancer. Three large, randomised,
double-blind studies have demonstrated a statistically
signi®cant improvement for CAB over castration, including two with ¯utamide16,68 and one with nilutamide.19
The largest of these studies (n ˆ 603) showed that, compared with those treated with leuprolide alone, patients
treated with leuprolide and ¯utamide had a longer progression-free survival (16.5 vs 13.9 months) and overall
survival (35.6 vs 28.3 months).68 Although several further
studies have failed to demonstrate a bene®t of CAB over
castration alone,69 ± 73 no study has reported that CAB is
less effective. A recent analysis of a study which enrolled
1387 men with metastatic disease, including more than
300 with minimal disease, did not indicate a bene®t for
¯utamide versus orchiectomy over placebo plus orchiectomy, although a nonsigni®cant trend in time to progression in patients with minimal disease (49 vs 36 months)
was apparent.74
The only clinical study which has directly compared
two non-steroidal antiandrogens was a double-blind,
randomised, multi-centre trial to evaluate bicalutamide
(50 mg, once daily) and ¯utamide (250 mg, three times
daily) as components of CAB, each in combination with
an LHRH-A (Zoladex1 3.6 mg or Lupron Depot1
7.5 mg, every 28 d), in 813 patients with untreated
metastatic stage D2 prostate cancer.51,75 The dose of
¯utamide was chosen based on the demonstrated clinical ef®cacy.68
Responses to therapy with both antiandrogens used in
combination with castration, measured as decreases in
prostate-speci®c antigen (PSA) concentrations, were similar, with a median 99% decrease from baseline after three
months of therapy. With a median duration of follow-up
of 160 weeks, the hazard ratio and 95% con®dence interval indicate that there was no statistical difference
between the two treatments, but bicalutamide plus
LHRH-A achieved a longer median time to progression
compared with ¯utamide plus LHRH-A (97 vs 77 weeks,
respectively). Moreover, the median survival was longer
with bicalutamide plus LHRH-A (180 weeks compared
with 148 weeks with ¯utamide plus LHRH-A) (Figure 2).
Both regimens were well tolerated, but diarrhoea was
signi®cantly less prevalent among patients in the bicalutamide plus LHRH-A group than in the ¯utamide plus
LHRH-A group (12% vs 26%, respectively, P < 0.001); this
led to a lower number of patient withdrawals from the
bicalutamide arm (2 vs 25 patients, respectively).
Although the incidence of haematuria was signi®cantly
higher among the bicalutamide plus LHRH-A group
(12% vs 6% with ¯utamide plus LHRH-A, P ˆ 0.007),
haematuria was considered to be related to therapy for
just one bicalutamide plus LHRH-A and two ¯utamide
plus LHRH-A patients, and did not lead to withdrawal in
any patient.
These clinical results con®rm that the selection of a
50 mg, once-daily dose for bicalutamide was appropriate,
and that this dose is clinically effective when used as part
of CAB.
The suboptimal tolerability to ¯utamide experienced
by some patients should not be underestimated:50 the
incidence of diarrhoea is 5 ± 30%76 and serious ¯utamide
hepatotoxicity is reported in 4 ± 6% of cases.18 Clinical
studies have shown that nilutamide is associated with
visual disturbances in the form of delayed adaptation to
Figure 2 Survival after a median follow-up period of 160 weeks for
patients receiving bicalutamide plus luteinising hormone-releasing hormone analogue (LHRH-A) (n ˆ 404) v ¯utamide plus LHRH-A (n ˆ 409)
in patients with untreated metastatic disease.
311
Af®nity, potency and activity of non-steroidal antiandrogens
GJCM Kolvenbag et al
312
Table 2 Change in prostate speci®c antigen (PSA) levels in patients given
bicalutamide 200 mg daily after progression on ¯utamide treatment: comparison
of ¯utamide withdrawal responders and non-responders (adapted from Scher et
al 78)
Flutamide withdrawal
responders (n ˆ 12)
Flutamide withdrawal
non-resopnders (n ˆ 14)
Change in PSA
n
%
n
%
80% decline
> 50% to < 80% decline
Stable
Progression
2
3
4
3
17
25
33
33
3
2
3
6
21
14
21
43
darkness (11 ± 50%), alcohol intolerance (3 ± 19%), respiratory disturbances that may be related to interstitial pneumopathy (1 ± 4.5%), and hepatic dysfunction (2 ± 33%).50
While most of the safety data for the antiandrogens are
from trials not comparing the antiandrogens with each
other, it does appear that each antiandrogen has its own
tolerability pro®le. This should be taken into account
when choosing the antiandrogen.
Hormone responsiveness in `androgen-independent'
tumours
Although androgen ablation, by either antiandrogen
monotherapy or CAB, can be highly effective in the
treatment of advanced prostate cancer, many patients
experience clinical relapse within a few years. This subsequent phase of the disease is often described as `androgen-independent' or `hormone-refractory'.77 However,
two recent reports from ongoing clinical investigations
have indicated that bicalutamide treatment can be bene®cial for patients who have previously progressed on
¯utamide therapy.77,78 Scher et al 78 found that in 10 out
of 26 patients (38%) who had progressed on ¯utamide,
subsequent treatment with bicalutamide 200 mg caused a
more than 50% decline in PSA levels; an equal proportion
of patients who responded or who did not respond to
¯utamide withdrawal had PSA decreases on bicalutamide treatment (Table 2). Similarly, Joyce et al 77 reported
that of 14 patients with progressive disease and rising
PSA levels following ¯utamide treatment as part of CAB,
seven demonstrated bene®t (stable or responsive disease)
to bicalutamide. These data are consistent with the range
of af®nities and mutant androgen receptor activation
pro®les seen with the different antiandrogens in receptor
binding and antitumour activity studies, as reported earlier in this paper. However, it is not known at this point
the extent to which bicalutamide and ¯utamide are not
cross-resistant, because there are few data on the sensitivity of prostate cancers that have progressed on bicalutamide to subsequent treatment with ¯utamide.
Nevertheless, these data do provide support for a concept
that the term `androgen independence' does not necessarily mean that a tumour is resistant to further hormonal
manipulations and should not be used to describe
tumours that have failed to respond to a particular
endocrine therapy. The term `hormone refractory'
should be reserved for tumours that are resistant to any
form of hormonal manipulation and for which non-hormonal approaches are required.
Further evidence for hormone responsiveness of some
so-called `androgen-independent' tumours is provided by
observations of reduced PSA levels, and often favourable
clinical responses, following the speci®c withdrawal of
non-steroidal antiandrogens in patients who develop
`androgen-independent' disease while receiving CAB.79
This antiandrogen withdrawal phenomenon is most
common following ¯utamide discontinuation, but a similar response has been seen, although less frequently, with
other antiandrogens, including bicalutamide.80 The
mechanism underlying the withdrawal effect is unclear,
but it may be related to the development of cancer cell
clones that have mutated to be dependent on the antiandrogen for growth.45,79
Conclusions
Preclinical data have revealed subtle differences between
non-steroidal antiandrogens in terms of af®nity, potency,
pharmacokinetics and tolerability. Animal studies of ef®cacy and tolerability provide a useful guide to appropriate therapeutic dosing in the clinic, but they are not an
absolute determinant, since bioavailability, distribution,
and pharmacokinetics can differ between animals and
man. In man, the plasma elimination half-lives of bicalutamide (4 ± 7 d) and nilutamide (56 h) offer the potential
for once-daily dosing; in contrast ¯utamide has a relatively short half-life (4 ± 7 h) and more frequent dosing is
necessary. The only clinical study which directly compared non-steroidal antiandrogens in advanced prostate
cancer demonstrated that, in combination with an LHRHA, both bicalutamide (50 mg, once daily) and ¯utamide
(250 mg, three times daily) were equally effective in terms
of time to progression and survival, with a median
survival of 180 weeks for bicalutamide plus LHRH-A
and 148 weeks for ¯utamide plus LHRH-A. This clinical
trial con®rms the prediction from preclinical studies that a
50 mg dose of bicalutamide would be appropriate for use
in patients with advanced prostate cancer, and that this
bicalutamide dose is clinically effective when administered as part of CAB. In terms of tolerability, bicalutamide
seems to have some advantage over ¯utamide and
Af®nity, potency and activity of non-steroidal antiandrogens
GJCM Kolvenbag et al
nilutamide.50 Overall, the observed clinical activity of the
three non-steroidal antiandrogens is in concordance with
preclinical ®ndings.
Acknowledgements
We thank Cath Carsberg, PhD for her editorial assistance.
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