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Prostate Cancer and Prostatic Diseases (1998) 1, 307±314 ß 1998 Stockton Press All rights reserved 1365±7852/98 $12.00 http://www.stockton-press.co.uk/pcan 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 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 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 404) v ¯utamide plus LHRH-A (n 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 12) Flutamide withdrawal non-resopnders (n 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. References 1 Huggins C, Hodges CV. Studies on prostatic cancer. 1. The effect of castration of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1: 293 ± 297. 2 Debruyne FMJ, Dijkman GA. Advances and trends in hormonal therapy for advanced prostate cancer. 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