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and Prostatic (2001) 4, 72±80 ß 2001 Publishing Group All rights reserved 1365±7852/01 $15.00 www.nature.com/pcan Will the experience with in cancer help de®ne the role of in ?

GW Chodak1* & GJCM Kolvenbag2 1The Midwest Prostate and Urology Health Center, Chicago, IL, USA; and 2AstraZeneca, Wilmington, DE, USA

Breast and prostate are the two predominant hormone-responsive tumours. The use of the antioestrogen tamoxifen in the treatment of has evolved over the past 30 y from treatment for advanced breast cancer to prevention. Tamoxifen is currently the endocrine treatment of choice for advanced breast cancer and for adjuvant therapy in a broad spectrum of women whose primary tumours have functional oestrogen receptors. It has also been shown to reduce the incidence of breast cancer in high-risk women. Non- steroidal therapy is used in the treatment of prostate cancer, but its role is still being de®ned. The clinical development of tamoxifen and that of the antiandrogens are reviewed and parallels are uncovered which provide insight into contemporary and future management of hormone-responsive prostate cancer. Prostate Cancer and Prostatic Diseases (2001) 4, 72±80.

Keywords: hormone-responsive tumours; tamoxifen; prostate cancer; non-steroidal antiandrogens;

Introduction than 100 years ago.1 Ablative endocrine surgery became a mainstay in the palliative treatment of metastatic breast In the battle against advanced breast and prostate can- cancer, providing tumour control in approximately 30% cers, the use of endocrine manipulation has been accepted of unselected women. It was not until the mid-1940s that as ®rst-line treatment. Non- ther- a medical treatment, diethylstilbestrol (DES), was devel- apy is used in the treatment of prostate cancer, but its role oped for postmenopausal women.2 is still being de®ned. This paper draws parallels between Development of non-steroidal antioestrogens, particu- the clinical development of tamoxifen and that of the larly tamoxifen, provided the next advance in hormonal antiandrogens to provide insights into the potential role therapy for breast cancer. Tamoxifen was developed of the antiandrogens in the therapy of prostate cancer. initially in 1969 as a possible oral contraceptive, but preliminary trials in humans showed that the compound failed to work as an antifertility drug.3 At about the same Tamoxifen in the treatment of breast time, tamoxifen was shown to inhibit the growth of experimental hormone-dependent tumours.4 The parallel cancer discovery that the presence of oestrogen receptors in History and development tumour tissue might predict the hormone responsiveness of advanced breast cancer5 led to an evaluation of tamox- Regression of breast cancer as the result of endocrine ifen's ability to control tumour growth. Early trials with therapy (ie ) was ®rst described more tamoxifen demonstrated that it was effective in the treat- ment of advanced breast cancer and had lower compared with other endocrine treatments.6,7 *Correspondence: G Chodak, The Midwest Prostate and Urology Oestrogen receptors reside in the nucleus of the cell. Health Center, 4646 N. Marine Drive, Suite A2400, Chicago, IL 60640, USA. When bound by oestrogen the receptor molecules dimer- Received 12 October 2000; revised 31 January 2001; ise to form functional transcription factors, which are accepted 26 February 2001 able to bind and activate promotor regions of The role of antiandrogens in prostate cancer GW Chodak & GJCM Kolvenbag oestrogen-activated genes. Tamoxifen is a type I antioes- of age, menopausal status, or adjuvant tamoxifen treat- 73 trogen that binds to the oestrogen receptor, blocking the ment. Although there was some bene®t in patients with binding of oestrogen and causing a change in the shape of truly oestrogen-receptor negative tumours, the certainty the receptor complex, which prevents it functioning as a of bene®t for these patients was less clear and remains a transcription factor. The oestrogen-activated genes that matter for research. mediate breast cancer cell replication are thus inactivated. The optimal duration of adjuvant tamoxifen therapy In addition to oestrogen, adrenal are remains controversial and continues to be the subject of thought to play a role in the development of breast evaluation in ongoing clinical studies. In the mid-1990s, cancer. Postmenopausal women with breast cancer have analyses of several trials indicated that 5 y of adjuvant been found to have elevated plasma levels of adrenal tamoxifen produced greater reductions in the risk of androgens,8 and these elevated levels have also been seen recurrence and death than did 1 or 2 y of treatment.40,42,43 in women who later developed breast cancer.9 Results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-14; which evaluated 5yvs 10 y of adjuvant tamoxifen treatment for early-stage breast cancer, indicated no advantage for continuation of Study results tamoxifen beyond 5 y in women with node-negative, oestrogen-receptor positive breast cancers.44 However, Tamoxifen, like other endocrine treatments, produced the results of a randomized trial conducted by the Eastern an objective response in approximately one-third of un- Cooperative Oncology Group (ECOG)45 indicated that selected women with advanced breast cancer. The obser- women with node-positive, oestrogen-receptor positive vation of the predictive value of the oestrogen receptor tumours experienced a longer time to relapse with tamox- for responsiveness to endocrine therapy in a subset of ifen therapy continued beyond 5 y (P ˆ 0.014), but the patients with breast cancers5,10 prompted oestrogen survival difference for this subgroup was not statistically receptor measurements in several clinical studies11 ± 14 signi®cant (P ˆ 0.81). and provided the basis for a predictive test to select patients who would be more likely to respond to tamox- ifen therapy. Results showed approximately 50 ± 60% of patients with oestrogen-receptor positive tumours Breast responded to tamoxifen therapy. It was also demon- strated that, by measuring levels, The ®nding of a decrease in contralateral breast cancer response to endocrine treatment could be further incidence after adjuvant tamoxifen therapy con®rmed a improved.15 Women with oestrogen and progesterone large amount of preclinical evidence that tamoxifen could receptor-positive tumours have a 70% probability of block both the initiation and the progression of breast response to tamoxifen, whereas only 10% of women cancer in animal models.4,46 These data led to the theory lacking these markers will respond.16 that the drug might play a role in breast cancer preven- Various studies compared tamoxifen treatment for tion, and studies were undertaken to test this hypothesis. advanced breast cancer with other types of endocrine Proving the value of tamoxifen in the prevention of therapy including oestrogens,17 androgens,18 proges- breast cancer required very large (13 000 ± 20 000 subjects), tins,19,20 ,21,22 oophorectomy,23,24 and randomized, placebo-controlled, double-blind clinical adrenalectomy.25 Generally, tamoxifen achieved response trials; three trials were started in Europe and North rates similar to those seen with other endocrine therapies America.47 The initial results of one trial, the Breast but was associated with considerably less toxicity. The Cancer Prevention Trial, conducted by the NSABP, high objective response rate combined with low acute became available in 1998.48 The study showed that toxicity established tamoxifen as the treatment of choice tamoxifen (n ˆ 6681), when compared with placebo for advanced relapsed metastatic breast cancer, parti- (n ˆ 6707), lowered the incidence of breast cancer by cuarly in patients with oestrogen-receptor positive 49% (two-sided P < 0.00001) in high-risk women (eg tumours and those with non-life-threatening visceral those aged  60 y; those aged 35 ± 59 y with a 5-year in which a rapid response is not essential. predicted risk for breast cancer of at least 1.66%; or Many multicentre trials of tamoxifen as adjuvant ther- those with a history of lobular carcinoma in situ). The apy were begun between 1975 and 1982.13,26 ± 37 These risk decreased in women aged  49 y (44%), 50 ± 59 y trials varied considerably in design and in the dosage and (51%), and  60 y (55%). The incidence of breast cancer duration of treatment. Generally, the results of these trials was reduced in women with a history of lobular carci- tended to point in the same direction: a reduction in the noma in situ or atypical hyperplasia. Tamoxifen also risk of relapse and death for patients receiving tamoxifen reduced the incidence of non-invasive breast cancer by compared with those receiving placebo. By the early 50%. Tamoxifen administration did not alter the average 1990s, 10-y data from adjuvant trials had become avail- annual rate of ischaemic heart disease, but hip, radius able.38 ± 41 Analysis of the ®ndings indicated that tamox- (Colles'), and spine fractures were reduced. The rate of ifen 20 mg/day given as adjuvant therapy for 2 ± 5 y after endometrial cancer increased in the tamoxifen group primary treatment reduced the odds of recurrence and predominantly in women aged  50 y. All endometrial death each year for at least 10 y in most patient subsets. cancers in the tamoxifen group were stage I (localized Speci®cally, this bene®t was observed in women with disease); no endometrial cancer deaths have occurred in breast cancer that was oestrogen-receptor positive and this group. No cases of cancer or increases in the also in women with breast cancer for whom no oestrogen incidences of colon, rectal, ovarian, or other tumours were receptor measurement was available; it was independent observed in the tamoxifen group. The rates of stroke,

Prostate Cancer and Prostatic Diseases The role of antiandrogens in prostate cancer GW Chodak & GJCM Kolvenbag

74 pulmonary embolism, and deep vein were oestrogen receptors. Tamoxifen has also been shown to elevated in the tamoxifen group; these occurred more reduce the incidence of breast cancer in women at frequently in women aged  50 y. increased risk for the disease. Although predominantly acting as an antioestrogen, tamoxifen acts as an oestrogen on the endometrium, bone, and cardiovascular system. Such oestrogenic action provides a protective effect against osteoporo- sis49,50 and ,51,53 but may stimulate Prostate cancer 54 endometrial cancer proliferation. History and development Adjuvant tamoxifen therapy has been associated with certain toxic effects. Although it is rare, the most Hunter, Scottish anatomist and surgeon to St George's important toxic effect is the development of endometrial Hospital, ®rst suspected a relationship between testicular cancer which, in large clinical trials, has been reported factors and prostate growth in the late 1700s. In the 1940s, to occur at a rate that is 2 ± 3 times greater than that it was the seminal work of Huggins and Hodges65 that observed in untreated women.55 ± 58 In this regard, it is established the value of and oestrogens in important to put the risk : bene®t ratio of tamoxifen the management of advanced prostate cancer. They therapy into perspective. Tamoxifen therapy for showed that surgical castration or medical castration women with breast cancer results in a survival advan- with oestrogen therapy produced a dramatic reduction tage that far outweighs the risk of endometrial in cancer mass and clinical remissions in 80% of patients cancer.59,60 Healthy women who are using tamoxifen with advanced metastatic disease. Huggins received the as a preventative measure for breast cancer may experi- Nobel Prize in Medicine in 1966 for this work. ence an increased incidence of endometrial cancer, and In the late 1960s, a large multicentre Veterans Admin- they must be carefully monitored, with periodic pelvic istration study established that oestrogen (DES), although examinations, to decrease the probability of developing effective in advanced prostate cancer, had signi®cant advanced uterine . Any abnormal uterine cardiovascular and thromboembolic morbidity and mor- bleeding should be investigated. tality rates at a dose of 5 mg/day.66 ± 69 Eventually other Other toxic effects noted with tamoxifen include effective and less toxic ways of inhibiting - thromboembolic phenomena. In the Breast Cancer Pre- mediated action in metastatic prostate cancer were vention Trial,48 three times as many cases of pulmonary developed. embolism (17 vs six cases) and 1.5 times as many cases -releasing hormone (LHRH) ago- of deep (30 vs 19 cases) were seen in nists were discovered by Schally and co-workers.70 After tamoxifen-treated women than in those receiving pla- causing a brief surge of LHRH and synthesis, cebo. These events were more frequent in women aged the continued administration of an LHRH  50 y. resulted in a shutdown of the synthesis of luteinizing Recent preliminary studies have suggested a protective hormone in the which led to a cessation in action in breast cancer for a selective oestrogen modula- the production of testosterone in the testes.71 Develop- tor, , initially developed for the prevention of ment of LHRH provided a medical alternative to osteoporosis. An initial analysis of the Multiple Outcomes DES without the unacceptable cardiovascular side effects. of Raloxifene Evaluation (MORE) study, conducted in Clinical data established that LHRH agonist therapy was 7704 postmenopausal women with osteoporosis, suggests as effective as surgical castration72 ± 74 or DES therapy.75,76 a >70% reduction in the incidence of breast cancer after Two LHRH agonists are commonly used in the United treatment with raloxifene for 30 months (mean), com- States for the treatment of prostate cancer: leuprolide and pared with placebo.61 Additionally, a meta-analysis of . LHRH agonists cause impotence, hot ¯ashes, nine placebo-controlled trials (including MORE) invol- and loss of libido, as do orchiectomy and oestrogens. ving around 12 000 patients showed a 58% reduction in Tumour ¯are reactions may occur transiently but can be relative breast cancer risk with raloxifene.62 It should be prevented by antiandrogens or by low-dose oestrogen noted that breast cancer development was not a primary treatment administered for several weeks.77 Long-term outcome measure of MORE and the meta-analysis ®nd- androgen suppression with LHRH agonists or orchiect- ings were based on only 49 cases of breast cancer. omy may result in loss of bone mineral density and put Furthermore, in the only with raloxifene in men at risk of osteoporotic fractures.78,79 advanced breast cancer, women were treated with high- Antiandrogen monotherapy was another approach dose raloxifene (300 mg/day). The authors concluded that evaluated in the hope of avoiding the side effects and further study of high-dose raloxifene as monotherapy for psychological morbidity of orchiectomy and the cardio- advanced breast cancer was probably unwarranted.63 The vascular side effects of oestrogen. These agents prevent ongoing Study of Tamoxifen and Raloxifene (STAR, also the interaction of (DHT) and testos- known as NSABP P-2) has been speci®cally designed to terone with their receptors on the prostate cancer cell. compare tamoxifen and raloxifene (given for 5 y) for Two steroidal antiandrogens evaluated in the 1980s, breast cancer risk reduction in approximately 22 000 megestrol acetate80 and ,81 are syn- high-risk postmenopausal women.64 thetic analogues of progesterone which bind to the pro- In summary, based on evidence from clinical trials gesterone receptor. These synthetic progestins block involving more than 35 000 women, tamoxifen has androgen action and also suppress androgen production; become the endocrine treatment of choice for advanced however, they also show variable levels of androgenic breast cancer and for adjuvant therapy in a broad spec- activity,82 and are associated with elevated levels of trum of women whose primary tumours have functional prostate-speci®c antigen (PSA) in some patients.83

Prostate Cancer and Prostatic Diseases The role of antiandrogens in prostate cancer GW Chodak & GJCM Kolvenbag

Ketoconazole, an imidazole derivative useful as an anti- Phase II and III trials.104,105 In a combined analysis of 75 fungal agent, was also evaluated because of its ability to three comparative studies involving 1196 patients with inhibit the synthesis of both testicular and adrenal andro- advanced disease, bicalutamide monotherapy at 50 mg/ gens.84 These drugs did not generate enthusiasm in the day was associated with statistically signi®cantly shorter United States because of unacceptable side effects,85,86 survival when compared with surgical or medical castra- and research interest shifted to non-steroidal antiandro- tion (25 vs 28 months, respectively).106 However, when gens, which lack the progestational side effects of their combined with an LHRH agonist, bicalutamide 50 mg/ steroidal counterparts. In 1989, ¯utamide was the ®rst day demonstrated at least equivalent survival and was non- better tolerated than a corresponding ¯utamide (250 mg steroidal antiandrogen to receive and Drug three times daily) combination regimen.107,108 Administration approval for use in combination with A meta-analysis of CAB trials has recently been pub- the LHRH agonist leuprolide.87 lished,109 including all CAB vs castration trials. However, Orchiectomy, DES, and LHRH agonists all act by this made no clear distinction between non-steroidal inhibiting production of testosterone in the testes. How- antiandrogens and steroidal antiandrogens in its conclu- ever, the adrenal glands are believed to produce as much sions. Steroidal antiandrogens (cyproterone acetate) in as 30% of the body's supply of androgens.88 These addition to castration actually had a detrimental effect androgens, which are closely related to testosterone, can on overall survival, while non-steroidal antiandrogens also be converted to DHT and can promote prostate showed a small survival bene®t.109,110 None of the over- cancer growth.89 ± 93 The concept of total androgen block- view analyses have looked at duration of therapy. ade using a combination of either bilateral orchiectomy or Recently Sarosdy et al111 suggested that prolonged anti- a LHRH agonist with an antiandrogen was postulated to androgen use as part of CAB did result in a signi®cant provide greater ef®cacy by decreasing the overall effects prolongation of overall survival. This supports the prin- of androgens (both from the testes and the adrenal ciple that a patient will not bene®t from antiandrogen glands) on prostate cancer growth. therapy if he is no longer able to take the right dose, eg due to tolerability or compliance. Because no limits on tolerability were reached with Antiandrogens in combination therapy and bicalutamide 50 mg/day and the PSA response to bicalu- monotherapy tamide is dose-related, subsequent trials investigated a 150 mg daily dosage. Bicalutamide 150 mg/day was com- The ®rst discussion of total androgen blockade is credited pared with surgical or medical castration in two large, to Bracci et al.94 Early non-randomized studies by Labrie randomized, Phase III trials involving previously et al95 ± 101 led to the ®rst large, randomized, placebo- untreated patients with locally advanced or metastatic controlled trial of total androgen blockade by the disease.112 In the subset of patients (n ˆ 480) with locally National Cancer Institute (Intergroup 0036 study).87 This advanced, non-metastatic disease (T3-4 Nx M0), the ana- study clearly demonstrated a survival advantage in lysis of the pooled data from several trials demonstrated patients with metastatic disease receiving total androgen that survival for those treated with bicalutamide 150 mg/ blockade using daily injections of an LHRH agonist day was no different from survival in the group treated (leuprolide) plus ¯utamide compared with an LHRH with castration (HR ˆ 0.93; 95% CI 0.66, 1.31).113 In the agonist alone, however, it also raised questions regarding subgroup (n ˆ 808) with metastatic disease, survival with the bene®t and role of this therapy. First, the overall bicalutamide 150 mg monotherapy was slightly but sig- survival bene®t of approximately 6 months is relatively ni®cantly shorter (6 weeks) than that seen with castration. modest and must be balanced against the added costs and Patients treated with bicalutamide monotherapy had the adverse reactions (gynaecomastia and diarrhoea) signi®cantly better palliation (subjective response) and observed in patients taking leuprolide and ¯utamide. maintained sexual interest and physical capacity to a Second, the therapeutic effect of non-steroidal antiandro- signi®cantly greater extent than did those patients treated gens may consist of the short-term blockade of the ¯are by castration.114 reaction that accompanies LHRH agonist treatment, and In these trials of bicalutamide 150 mg monotherapy the use of these agents may not be necessary over the long versus castration, a subgroup was assessed for effects of term. A Southwest Oncology Group Intergroup trial long-term (>5 y) treatment on their bone mineral density. (SWOG-INT 0105)102 was undertaken to con®rm the Bone mineral density (BMD) was assessed in 29 patients bene®ts of combined androgen blockade (CAB) reported (21 patients received bicalutamide, eight patients castra- in the Intergroup 0036 study. The principal difference tion) with no bone metastases. After a median follow-up from the earlier trial was that bilateral orchiectomy of 5.5 y with treatment uninterrupted, BMD for bicaluta- replaced therapy with leuprolide. There was a small, mide-treated patients was as good as BMD in age- statistically insigni®cant difference between the two matched controls, while BMD in castrated patients was groups (CAB vs orchiectomy) in overall survival. lower. One of the seven castrated patients had BMD at a Bicalutamide was the second non-steroidal antiandro- level with a considerable risk of fracture.113 gen marketed in the United States and has become the There is evidence that second-line treatment with bica- most widely prescribed antiandrogen. The compound has lutamide may provide a bene®t after failure of primary a long plasma elimination half-life, compatible with once- treatment with ¯utamide. For example, Scher et al115 daily dosing, and has a higher binding af®nity to the observed that 10 of 26 patients who progressed on than ¯utamide.103 Clinical trials with ¯utamide treatment had a >50% decline in serum PSA bicalutamide began in 1987. A 50 mg daily dose of levels after initiation of bicalutamide 200 mg/day as bicalutamide was initially evaluated as monotherapy in second-line therapy. Similarly, Joyce et al116 found that

Prostate Cancer and Prostatic Diseases The role of antiandrogens in prostate cancer GW Chodak & GJCM Kolvenbag

76 six of 14 patients who progressed on ¯utamide treatment mized to treatment with bicalutamide or placebo as adju- demonstrated bene®t with bicalutamide 150 mg/day. vant to standard care (either prostatectomy, radiation or Unlike oestrogen receptors in breast cancer, androgen watchful waiting). Enrolment of 8113 patients was com- receptors frequently undergo mutation during endocrine pleted in 1998.129 At a median follow-up of 3 years, treatment.117,118 It is not known whether progression after bicalutamide signi®cantly reduced the risk of disease successful antiandrogen treatment is related to mutation, progression in these patients.130 Longer follow-up is but the observed responsiveness to bicalutamide in needed to determine whether adjuvant antiandrogen ther- patients who progress on ¯utamide treatment supports apy in early prostate cancer will have a bene®t in terms of evidence that different antiandrogens interact survival. differently with wild-type and/or mutant androgen receptors.119 In some patients, withdrawal of antiandro- gen treatment actually enhances tumour responsiveness, Prostate cancer prevention suggesting agonist activity at androgen receptors; this phenomenon has most commonly been observed for Given the impact of antioestrogen therapy with tamoxifen ¯utamide but has also been reported for bicalutamide on breast cancer prevention, it seems logical to investigate and steroidal antiandrogens, as well as for tamoxifen in the potential role of antiandrogen therapy in prostate breast cancer.120 ± 122 Data on the responsiveness of cancer prevention. The enzyme 5a-reductase is responsi- patients who progress on bicalutamide to alternative ble for conversion of testosterone to DHT, which has a antiandrogen treatments are scant; for example, no greater af®nity than testosterone for the androgen recep- 130 study has examined the responsiveness to ¯utamide.115 tor and is thought to modulate prostatic growth. Controlled, adequately powered clinical trials in de®ned , a 5a-reductase inhibitor, is approved for 131 populations are required to determine the impact of treatment of benign prostatic hypertrophy. Finasteride second-line antiandrogen treatment on survival. Further- may hold promise as a chemopreventive agent and is more, the mechanisms responsible for the sensitivity to being evaluated in the Prostate Cancer Prevention Trial, bicalutamide after progression on ¯utamide treatment which has already enrolled more than 18 000 men to deserve further study. receive either active treatment or placebo daily for 132 A third non-steroidal antiandrogen, , 7y. It is anticipated that results of this trial will be recently became commercially available in the United available in 2004. Of concern, however, are the disap- States. Both ¯utamide and bicalutamide are indicated pointing preliminary ®ndings with ®nasteride as a che- 133 for use in combination with an LHRH agonist; nilutamide mopreventative agent. In 27 patients with an elevated is indicated in combination with bilateral orchiectomy. A PSA level but not prostate cancer, treatment with ®nas- discussion of nilutamide is beyond the scope of this teride for 12 months decreased the PSA level by 48% but paper. had no signi®cant effect on the extent of hyperplastic epithelium in the peripheral zone. Similar to identifying healthy women at risk of breast Antiandrogens as adjuvant therapy cancer, it will be important to be able to identify healthy men at increased risk of prostate cancer. Risk factors With the widespread use of prostate speci®c antigen that will have to be taken into account include age, (PSA) testing, the number of patients with prostate race, having a ®rst-degree family member with a history cancer diagnosed at an early stage is increasing. However, of prostate cancer, having had a biopsy of the prostate despite earlier detection, many men still have cancer that gland (regardless of outcome), elevated PSA level, and/or is not con®ned to the prostate, and, therefore, cure is not high-grade prostatic intraepithelial neoplasia (PIN). The possible with surgery alone.123 This observation under- spectrum of histopathological changes referred to as scores the need for an effective, systemic adjuvant treat- high-grade PIN is the most likely precursor lesion of inva- ment for men with early-stage disease. The proven bene®t sive prostate cancer.134 Clinicopathological studies sug- of adjuvant antioestrogen therapy in women with early gest that PIN predates prostate cancer by 10 y or breast cancer raises the possibility that adjuvant anti- more.135,136 High-grade PIN is currently the best marker androgen therapy might have a similar bene®t for men available to identify men with an increased risk of pros- with early prostate cancer. tate cancer diagnosis. It is probably not a good surrogate Early controlled trials evaluating adjuvant therapy in endpoint with which to replace prostate cancer diagnosis prostate cancer demonstrated promising progression-free for a prevention trial. Androgen deprivation therapy survival bene®ts for regimens including estramustine124 decreases the prevalence and extent of high-grade PIN, goserelin plus cyproterone acetate,125 goserelin alone,126 implying that the dysplastic prostatic epithelium is andro- and an LHRH agonist plus ¯utamide.127 The trial of gen-dependent.137 Interestingly, the preliminary study of goserelin plus cyproterone acetate also showed an overall ®nasteride as a chemopreventative agent demonstrates survival bene®t.125 that blockade of 5a-reductase appears to have less effect Two controlled trials have considered non-steroidal on high-grade PIN than other forms of androgen suppres- antiandrogen monotherapy as adjuvant therapy. Wirth sion.133 Of the antiandrogens available, bicalutamide is an et al128 reported that, in 365 men, time to recurrence of attractive candidate as a chemopreventive agent, as its disease could be delayed by ¯utamide adjuvant to radical side effects are more tolerable than those of other forms of prostatectomy. In 1995, a large clinical trial was initiated androgen deprivation therapy. to compare bicalutamide 150 mg/day with placebo in For breast cancer, determinations of the cellular con- patients with localized or locally advanced prostate centrations of oestrogen and progesterone-receptors in the cancer (stage T1b-T4, N0-Nx, M0). Patients were rando- tumour are clinically useful in predicting prognosis and

Prostate Cancer and Prostatic Diseases The role of antiandrogens in prostate cancer GW Chodak & GJCM Kolvenbag Table 1 Bene®ts of tamoxifen in breast cancer and of antiandrogens in prostate cancer 77

Treatment setting Tamoxifen Antiandrogen

Advanced disease Monotherapy Objective response in approximately 33% Monotherapy with bicalutamide for patients with T3-T4, of unselected women; 50 ± 60% of Nx, M0 prostate cancer results in similar survival to patients with oestrogen-receptor positive castration, but a greater proportion of bicalutamide tumours respond and women with patients maintained sexual interest and physical capacity oestrogen- and progesterone-receptor- compared with patients treated by castration112 positive tumours have a 70% probability of response. Very well tolerated13,16,17 Combined hormonal blockade Ongoing trials of complete oestrogen In combination with an LHRH agonist, non-steroidal blockade in premenopausal women antiandrogens demonstrated improved survival using combination LHRH agonist and compared with an LHRH agonist alone87,108 tamoxifen therapy suggest improved results compared with medical castration alone142 Adjuvant therapy in addition to Reduced the odds of recurrence and death Ongoing trials are investigating role as neoadjuvant and standard care each year for at least 10 y in most patient adjuvant therapy. Evidence is accumulating that use of subsets with localized disease38 ± 41 hormonal therapy in addition to standard care for localized and locally advanced disease will prolong survival125,143 Prevention Lowered the risk of breast cancer by 49% Androgen deprivation therapy decreases the prevalence in high-risk women48 and extent of high-grade PIN137 Positive side effects Bone mineral density preservation49,50 Bone mineral density preservation113 Cardioprotective51 ± 53 Ongoing trials are evaluating potential bene®cial effects on blood lipids outcome to therapeutic endocrine manipulations. Andro- parallel development strategies for antiandrogen treatment gens mediate the growth of prostate cancer cells. Intra- for metastatic prostate cancer initially, with adjuvant ther- cellular action of androgens is mediated by the androgen apy under investigation, and perhaps to be followed by receptor, which is a key element of the androgen signal prevention. The most notable distinction between antioes- transduction cascade and a target of endocrine therapy trogen therapy for breast cancer and antiandrogen therapy for prostate cancer. Therefore, the qualitative (point muta- for prostate cancer is the lack of a clinical correlation tions) and quantitative (receptor ampli®cation) alterations between the ef®cacy of antiandrogen treatment and andro- of androgen receptor expression in prostate cancer and gen receptor status. A further limitation to the comparison their possible implications for tumour progression and of these two diseases is the high mutation rate of androgen treatment are of great interest. There have been vari- receptors during endocrine treatment which is not seen in able results regarding the clinical signi®cance of cells oestrogen receptors. expressing androgen receptors in prostate cancer. Conse- The particular characteristics of the individual endo- quently, the predictive value of androgen receptor content crine agents have also been a factor in shaping the roles of of prostate cancers in patient outcome is controver- endocrine manipulation in these two cancers, and in this sial.138 ± 140 Indeed, the molecular mechanisms that con- regard, tamoxifen and the antiandrogens share several tribute to hormone refractoriness and progression of common features (Table 1). The success of tamoxifen in prostate cancers are poorly understood.141 Therefore, the treatment of breast cancer is reason to be cautiously much additional experimental work will be necessary to optimistic that similar success may be achieved with de®ne the genetic and molecular steps associated with antiandrogen therapy in prostate cancer. progression of prostate cancer, as well as to translate these biological ®ndings into clinical applications. Acknowledgement D Lawrence Wickerham, MD is acknowledged for critical Summary review of the manuscript. The use of endocrine manipulation in the treatment of both breast and prostate cancers has been shaped by the increased understanding of the pathophysiological roles References of oestrogen and androgen, respectively, in promoting 1 Beatson G. On the treatment of inoperable carcinoma of the tumour growth. In particular, combined hormonal block- mamma: suggestion of a new method of treatment with illus- ade, which both reduces androgen and oestrogen produc- trative cases. Lancet 1896; ii: 102 ± 107, 162 ± 167. tion and prevents the cellular activity of these hormones, 2 Haddow A et al. In¯uence of synthetic oestrogens upon has produced improved survival rates over monotherapy advanced malignant disease. Br Med J 1944; ii: 393 ± 398. or medical castration in both diseases. Antioestrogen ther- 3 Klopper A, Hall M. 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Prostate Cancer and Prostatic Diseases The role of antiandrogens in prostate cancer GW Chodak & GJCM Kolvenbag

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