Journal of Cancer Research and Clinical Oncology

, Volume 132, Supplement 1, pp 17–26

Antiandrogen treatments in locally advanced prostate cancer: are they all the same?

Authors

    • Urology DepartmentSouthmead Hospital
Original Paper

DOI: 10.1007/s00432-006-0133-5

Cite this article as:
Gillatt, D. J Cancer Res Clin Oncol (2006) 132: 17. doi:10.1007/s00432-006-0133-5

Abstract

Purpose

The objectives are to review the published literature and to evaluate the weight of evidence for clinical effectiveness, safety, and tolerability of the currently available antiandrogens in the treatment of locally advanced prostate cancer. This article covers efficacy as monotherapy relative to castration and as adjuvant to radiotherapy and radical prostatectomy as well as adverse-effect and quality-of-life data.

Methods

The current literature from online databases between 1986 and the present, relating to antiandrogen treatments in men with locally advanced disease given either as monotherapy or as adjuvant to radical radiotherapy or prostatectomy, was reviewed. Antiandrogens researched included the non-steroidal antiandrogens, bicalutamide (‘Casodex’), flutamide, and nilutamide, and the steroidal antiandrogen cyproterone acetate (CPA).

Results

The most comprehensively investigated and reported antiandrogen is bicalutamide, which has shown survival outcomes similar to those observed with castration in patients with locally advanced prostate cancer. In contrast, only limited clinical data are available for the other non-steroidal antiandrogens (flutamide and nilutamide) and the steroidal antiandrogen CPA in patients with locally advanced disease. In terms of safety and tolerability, CPA is associated with loss of libido and erectile dysfunction. CPA is also associated with cardiovascular risk and there have been occasional reports of fatal fulminant hepatitis and hepatocellular carcinoma. Gynecomastia is quite rare with CPA, which is in contrast to the non-steroidal antiandrogens. There are no direct comparisons between the three non-steroidal antiandrogens in terms of quality of life, but available evidence suggests that bicalutamide has a more favorable safety and tolerability profile than nilutamide and flutamide. Unlike CPA, non-steroidal antiandrogens appear to be better tolerated than castration, allowing patients to maintain sexual activity, physical ability, and bone mineral density, but these agents have a higher incidence of gynecomastia and breast pain (mild to moderate in > 90% of cases). Gynecomastia and breast pain, however, can be effectively managed.

Conclusions

The available evidence indicates that the different antiandrogens should not be regarded as equivalents in clinical practice and so the choice of treatment for patients with prostate cancer should be made on an individual basis. It is, therefore, important for clinicians to discuss the efficacy and tolerability profiles of all available treatment options with their patients to enable them to choose a treatment program that best fits with their lifestyle.

Introduction

Prostate cancer is the most commonly diagnosed male cancer in the USA and will account for approximately 33% of new cancer cases and 9% of cancer deaths in 2006, which is third behind cancers of the lung/bronchus and the colon/rectum (Jemal et al. 2006). In Europe, prostate cancer is the second most commonly diagnosed male cancer (15.5% of new cases) behind lung cancer, and only cancers of the lung and colon/rectum account for more male cancer deaths (Boyle and Ferlay 2005). As a result of increased awareness and earlier detection by prostate-specific antigen (PSA) screening, the overall incidence of prostate cancer is continuing to rise, although at a slower rate than in previous years (Jemal et al. 2006). In addition, a greater proportion of younger men with locally advanced disease are now being identified.

Androgen deprivation by hormonal therapy has historically been the mainstay of treatment for managing advanced prostate cancer. However, the shift towards an earlier diagnosis has shown an evolution towards increasing its use in men with non-metastatic disease or with recurrent disease after therapy of curative intent (i.e., radiotherapy or radical prostatectomy) (Aus et al. 2005). Castration-based therapy is the predominant form of androgen deprivation therapy, and the luteinizing hormone-releasing hormone (LHRH) agonist goserelin (‘Zoladex’) is the most widely studied. In patients with locally advanced disease, goserelin has been shown to significantly improve overall survival when given as adjuvant to radiotherapy (Bolla et al. 2002; Pilepich et al. 2005). When given as adjuvant to radical prostatectomy, castration-based therapy (goserelin or orchiectomy) has also been shown to significantly improve overall survival in node-positive patients with locally advanced disease (Messing et al. 1999, 2003).

Castration, however, is associated with impotence and loss of libido (Iversen et al. 2000), which can be a major cause of distress for men with prostate cancer. Other adverse effects associated with this therapy include decreased muscle mass and loss of bone mass, which can lead to progressive osteoporosis (Kirby 1998; Daniell et al. 2000; Berruti et al. 2002). While these effects are generally manageable, long-term castration is increasingly being used in men where quality-of-life issues, such as maintenance of sexual activity and physical ability, are of considerable importance to them (Aus et al. 2005). Alternative hormonal therapies that are both effective and better tolerated are, therefore, clearly needed.

Antiandrogens are a class of drug with a different mechanism of action to castration therapies. Unlike LHRH agonists, which downregulate LHRH receptors by interfering with the hypothalamic-pituitary-gonadal axis, antiandrogens compete with circulating androgens for binding sites on their receptors within the prostate cell, thus promoting apoptosis and inhibiting prostate cancer growth.

Antiandrogens are classified into two structurally distinct types: steroidal antiandrogens (cyproterone acetate [CPA]) and non-steroidal antiandrogens (bicalutamide [‘Casodex’], flutamide, nilutamide) (Fig. 1). Both classes of agents act as competitors of androgens at the receptor level. While this is the sole action of non-steroidal antiandrogens, steroidal antiandrogens also have progestational activity that decreases serum testosterone levels, leading to loss of libido and sexual function (Isurugi et al. 1980; Anderson 2003). In contrast, the non-steroidal antiandrogens (sometimes known as ‘pure’ antiandrogens) do not suppress testosterone and estrogen levels, allowing sexual potency to be retained (Verhelst et al. 1994; Migliari et al. 1999; Iversen et al. 2001).
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Fig. 1

Structures of the available steroidal (cyproterone acetate) and non-steroidal (bicalutamide, flutamide, nilutamide) antiandrogens

Historically, antiandrogens were used only in combination with castration. However, there is increasing evidence to suggest that antiandrogens can be as effective and better tolerated than castration therapy in locally advanced prostate cancer. This makes antiandrogen therapy a very attractive alternative to castration, particularly in patients who wish to maintain sexual and physical activity (Iversen et al. 2000; Anderson 2003; McLeod et al. 2006).

This article considers whether all the available antiandrogens can be regarded as equivalents in treating locally advanced prostate cancer. This has been achieved first by reviewing the efficacy of these agents as monotherapy and as adjuvant therapy to radiotherapy or radical prostatectomy and, secondly, by reviewing the agents in terms of their tolerability profiles both versus castration and within their own class.

Is antiandrogen monotherapy as effective as castration in locally advanced prostate cancer?

In locally advanced prostate cancer, clinical data suggest that antiandrogen monotherapy can be as effective as castration-based therapies in locally advanced disease (Aus et al. 2005). The data that support this statement are presented below.

CPA

No comparative survival data of CPA versus castration in the locally advanced setting (M0 disease alone) are available in the public domain.

Non-steroidal antiandrogens

Comparative studies of non-steroidal antiandrogen monotherapy versus castration alone in patients with locally advanced disease have been carried out with bicalutamide only. No studies of either flutamide or nilutamide monotherapy are available; nilutamide is not licensed for monotherapy in this setting.

A study pooling two open-label, multicenter studies of identical design has evaluated whether bicalutamide monotherapy may be an alternative to castration in patients with locally advanced prostate cancer. In this study, a combined total of 480 patients with T3–4, M0 disease were randomized to receive either bicalutamide 150 mg or castration (orchiectomy or goserelin 3.6 mg every 28 days) (Iversen et al. 2000). After a median follow-up of 6.3 years, mortality was 56%, with no significant difference between the two groups in terms of overall survival (hazard ratio [HR] 1.05; 95% confidence interval [CI] 0.81, 1.36; P = 0.70) (Fig. 2) or time to progression (HR 1.20; 95% CI 0.96, 1.51; P = 0.11) for bicalutamide relative to castration.
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Fig. 2

Kaplan–Meier curve of overall survival following treatment with bicalutamide 150 mg versus castration in M0 patients (Iversen et al. 2000)

Summary

The data suggest that bicalutamide 150 mg provides a survival outcome similar to that observed with castration in patients with locally advanced disease. Comparative survival data on other antiandrogens versus castration in this setting are not available.

Is there a role for antiandrogen therapy as adjuvant to radiotherapy or radical prostatectomy in locally advanced disease?

With a shift to earlier diagnosis of prostate cancer, an increasing proportion of patients are undergoing primary therapy of curative intent (radiotherapy or radical prostatectomy) (Mettlin et al. 1998). Both radiotherapy and radical prostatectomy alone have been shown to provide long-term control of prostate cancer in men with localized disease (Pound et al. 1999; Shipley et al. 1999; Hull et al. 2002; Bill-Axelson et al. 2005). Although the addition of hormonal therapy to these treatments is not recommended in patients with localized disease (McLeod et al. 2006), it does appear to improve outcomes in patients with locally advanced disease, with available data demonstrating significant clinical benefits (Bolla et al. 2002; Pilepich et al. 2005; Aus et al. 2005; McLeod et al. 2006). The efficacy data available for antiandrogens adjuvant to radiotherapy and radical prostatectomy are discussed overleaf.

CPA

To date, no data have been published on the role of CPA as adjuvant to radical prostatectomy or radiotherapy in men with locally advanced prostate cancer.

Non-steroidal antiandrogens

The efficacy of bicalutamide 150 mg as an adjuvant to therapy of curative intent in men with locally advanced disease was assessed as part of the bicalutamide early prostate cancer (EPC) program (Wirth et al. 2004b; McLeod et al. 2006). The EPC program consists of three randomized, double-blind, placebo-controlled studies prospectively designed to allow combined analysis of the results. In total, 8,113 men with localized or locally advanced prostate cancer (T3–4, any N, M0; or any T, N +, M0) were randomized to bicalutamide 150 mg or placebo, in addition to standard care (radiotherapy, radical prostatectomy, or watchful waiting). The median follow-up of this analysis was 7.4 years. In locally advanced patients who received primary therapy of curative intent, bicalutamide 150 mg significantly improved progression-free survival compared with radiotherapy or radical prostatectomy alone (n = 2,024) (HR 0.69; 95% CI 0.58, 0.82; P < 0.001) (McLeod et al. 2006). In terms of overall survival in these men, there was no significant difference between the two treatment groups (HR 0.95; 95% CI 0.77, 1.16; P = 0.59) (McLeod et al. 2006).

The progression-free survival benefit observed with bicalutamide adjuvant to radiotherapy or radical prostatectomy in the EPC program, however, was greatest in the men who had received radiotherapy (n = 305) (HR 0.56; 95% CI 0.40, 0.78; P < 0.001). In addition, bicalutamide 150 mg adjuvant to radiotherapy was associated with a significant improvement in overall survival (HR 0.65; 95% CI 0.44, 0.95; P = 0.03), largely because of a reduced risk of prostate cancer-related death (16.1% in the bicalutamide group vs. 24.3% with standard care alone) (McLeod et al. 2006).

In patients with locally advanced disease who received radical prostatectomy in the EPC program, bicalutamide 150 mg also significantly improved progression-free survival compared with radical prostatectomy alone (n = 1,719) (HR 0.75; 95% CI 0.61, 0.91; P = 0.004) (McLeod et al. 2006). The overall survival rates, however, were similar both with and without bicalutamide (McLeod et al. 2006).

No data are currently available on the effect of flutamide as an adjuvant to radiotherapy, but a prospective, randomized trial has evaluated flutamide 750 mg adjuvant to radical prostatectomy compared with radical prostatectomy alone in patients with lymph node-negative prostate cancer (n = 309) (Wirth et al. 2004a). At 6.1 years’ median follow-up, flutamide 750 mg adjuvant to radical prostatectomy significantly improved progression-free survival (HR 0.51; 95% CI 0.32, 0.81; P = 0.004). Similar to the EPC trial, there was no difference in overall survival between the two treatment groups (HR 1.04; 95% CI 0.53, 2.02; P = 0.92) (Wirth et al. 2004a).

No data on nilutamide as adjuvant to therapies of curative intent appear to be available.

Summary

Data from the EPC program show that bicalutamide 150 mg adjuvant to radiotherapy significantly improves progression-free survival and overall survival (as a result of reduced prostate cancer-related deaths) in patients with locally advanced disease. Data on other antiandrogens in this setting are not available.

In the radical prostatectomy setting, both bicalutamide 150 mg and flutamide 750 mg can significantly improve progression-free survival, with no difference in overall survival in men with locally advanced prostate cancer. Data on CPA and nilutamide in this setting are not available.

What are the quality of life and tolerability advantages of antiandrogens versus castration?

When considering the range of treatments available for locally advanced cancer, a number of factors must be taken into account in addition to the efficacy benefits of each therapy. These include effects on lifestyle changes and potential treatment-related adverse effects. With the growing trend towards diagnosis at an earlier disease stage and in younger men, the duration of therapy required by patients is increasing. Furthermore, patients are starting to receive hormonal therapy at a time when quality-of-life issues, such as maintenance of sexual and physical activity, are of considerable importance to them. Therefore, adverse-effect data are becoming central to promoting long-term patient compliance.

CPA

In clinical trials, CPA in combination with castration appears to give a lower incidence of hot flashes over castration alone (Migliari et al. 1999). In a double-blind, placebo-controlled study, CPA adjuvant to orchiectomy reduced the incidence of troublesome hot flashes compared with placebo (mean of 2.23 vs. 9.44 hot flashes/day, respectively) (Barradell and Faulds 1994). A reduction in the incidence of hot flashes was also shown when CPA is given in combination with goserelin (36.9 vs. 47.6%, respectively) or buserelin (40 vs. 53%, respectively) compared with placebo (Barradell and Faulds 1994). Furthermore, gynecomastia, a common adverse effect of non-steroidal antiandrogen therapy with CPA, is quite rare (Aus et al. 2005).

However, CPA has been associated with a number of adverse effects. The incidence of cardiovascular adverse effects associated with CPA varies among trials, ranging from 4 to 40% (Aus et al. 2005). In a study by the European Organisation for Research on Treatment of Cancer (EORTC), cardiovascular adverse effects were observed in 22.4% of patients receiving CPA for 3 years, although this was a lower incidence than that recorded in patients receiving medroxyprogesterone acetate or diethylstilbestrol (36 and 59%, respectively) (de Voogt et al. 1986). A relatively high incidence of dyspnea, often severe, has also been reported in some studies with CPA (Barradell and Faulds 1994; Debruyne et al. 1998). Adverse changes in lipoprotein metabolism, including significant reductions in high-density lipoprotein cholesterol and increases in very low-density lipoprotein triglycerides, are also associated with CPA treatment and may have adverse long-term cardiovascular consequences (Paisey et al. 1986; Gillatt et al. 1993).

In a number of individual case studies, a few fatal fulminant hepatitis cases and occasional reports of hepatocellular carcinoma have been reported in patients receiving CPA (Fourcade and McLeod 2004). In addition, long-term daily doses of CPA 300 mg have also been associated with hepatotoxicity and as a result, monitoring of liver function is recommended during CPA treatment (Barradell and Faulds 1994; Migliari et al. 1999). The combination of cardiovascular risk and potential hepatotoxicity means that the usage of CPA should be restricted to patients who are intolerant of non-steroidal antiandrogens (Migliari et al. 1999).

An additional adverse effect observed in patients treated with CPA is impotence or loss of libido as a result of reduced testosterone levels. In a study of CPA versus flutamide in men with metastatic prostate cancer, loss of spontaneous erections occurred in 92% of patients in the CPA group and 80% in the flutamide group, while loss of sexual activity occurred in 88 and 78% of men in the CPA and flutamide groups, respectively (Schröder et al. 2004). The incidence of these events is similar to that observed in men after castration therapy (Jacobi et al. 1980; Thorpe et al. 1996; Iversen et al. 2001).

Thus, CPA is associated with a lower incidence of hot flashes compared with castration, and the development of gynecomastia with this agent is quite rare. However, it is associated with increased cardiovascular risk, potential hepatotoxicity, impotence, and loss of libido.

Non-steroidal antiandrogens

Sexual functioning

One of the most important advantages of non-steroidal antiandrogens is that they allow patients to maintain serum testosterone and estrogen levels, thus offering potential benefits on quality of life and tolerability when compared with castration-based therapies. Loss of libido is particularly important as it is distressing for many men (Higano 2003).

Maintenance of sexual function in trials of bicalutamide has been assessed using validated quality-of-life questionnaires. For example, sexual interest was measured in an analysis of two Phase III studies involving 480 patients randomized to bicalutamide monotherapy or castration (orchiectomy or goserelin 3.6 mg every 28 days) (Iversen et al. 2000). The results showed that men receiving bicalutamide experienced a significant benefit with regard to sexual interest after 12 months of treatment compared with those who had received castration therapy (P = 0.029). Moreover, differences in sexual interest became evident within 1 month of starting treatment (Iversen et al. 2000).

The impact of treatment with bicalutamide on sexual function was also assessed as part of the Scandinavian arm of the EPC program, in which 1,218 men with T1–4, any N, M0 prostate cancer were randomized to receive standard care combined with either bicalutamide 150 mg or placebo (Iversen et al. 2002). In contrast to other studies in the EPC program, more than 80% of patients in this Scandinavian study had not received primary therapy of curative intent. Using the Golombok and Rust Inventory of Sexual Satisfaction (GRISS) questionnaire, the study showed relatively small differences between the treatment groups at all time points. At 48 weeks after randomization, sexual function was retained in 74.9 and 85.0% of bicalutamide and placebo patients, respectively (Iversen et al. 2002).

In an Italian study comparing bicalutamide 150 mg monotherapy with combined androgen blockade (CAB; flutamide 750 mg plus goserelin 3.6 mg depot injection), significantly fewer patients in the bicalutamide group reported erectile dysfunction (69.2 vs. 93.3%, respectively; P = 0.002) or loss of libido (59.6 vs. 85.5%, respectively; P ≤ 0.01) compared with CAB (Boccardo et al. 1999).

Data relating to sexual function in studies of nilutamide and flutamide are currently limited. In an open-label study of nilutamide in 29 previously untreated men with metastatic prostate cancer, 7 claimed maintenance of libido and sexual potency after 10 months of treatment (Decensi et al. 1991). Of these seven patients, all four who subsequently received LHRH agonist therapy for disease progression declared loss of libido and erectile dysfunction (Decensi et al. 1991). In studies of flutamide, sexual interest has generally been assessed in small numbers of patients by self-reporting or direct questioning (Iversen et al. 2001). Overall, around two-thirds of sexually active men receiving flutamide monotherapy retained sexual potency, with a similar proportion appearing to maintain sexual interest (Iversen et al. 2001). As mentioned previously, flutamide has been compared with CPA in men with metastatic prostate cancer and favorable prognostic factors (Schröder et al. 2000). With an average observation time of 2 years, loss of spontaneous erections and sexual activity occurred in 80 versus 92 and 78 versus 88% of men under flutamide versus CPA treatment, respectively. None of these differences reached statistical significance (Schröder et al. 2000, 2004).

Physical capacity

Clinical evidence shows that bicalutamide 150 mg can preserve physical capacity in comparison with castration (Fig. 3) (Iversen et al. 2000). In the quality-of-life assessment carried out as part of the pooled analysis of two Phase III studies, men receiving bicalutamide experienced significant benefits in terms of physical capacity (including activities such as walking, dressing, bathing, shopping, climbing stairs, sports, and bending) after 12 months of treatment compared with those who had received castration therapy (P = 0.046). Similar results were reported in the Italian study comparing bicalutamide with CAB (Boccardo et al. 1999).
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Fig. 3

Bar chart indicating the relative effects (maintenance vs. reduction) of bicalutamide 150 mg compared with castration on the following quality-of-life parameters: bone mineral density (Sieber et al. 2004), sexual interest (Iversen et al. 2000), and physical capacity (Iversen et al. 2000)

Bone mineral density

Although the loss of bone mineral density associated with castration can be reduced with bisphosphonates (Aus et al. 2005), bicalutamide has been shown to maintain bone mineral density (Fig. 3) (Sieber et al. 2004). In a 2-year, open-label study in 103 men with localized or locally advanced (M0) prostate cancer randomized to bicalutamide 150 mg or an LHRH analog (Sieber et al. 2004) castration was associated with a progressive decline in bone mineral density, compared with slight increases in men receiving bicalutamide (P < 0.0001 at week 96). There was also a trend towards a decrease in fat-free mass in the castration group over the course of the treatment. Changes in lipid parameters (high-density, low-density, and very low-density lipoprotein cholesterol) during the study were small and did not differ between groups (Sieber et al. 2004). The effects of bicalutamide on bone mineral density and body composition were also assessed in a 12-month open-label study in which 52 men with M0 disease were randomized to receive bicalutamide 150 mg once daily or leuprolide 3-month depot (Smith et al. 2004). Compared with leuprolide, men receiving bicalutamide experienced a significant increase in bone mineral density at numerous locations, including the lumbar spine, hip, and femoral neck (P < 0.001). Increases in fat mass occurred in both groups during the study, but were significantly lower in the bicalutamide group (6.4 vs. 11.1%; P = 0.01). Changes in lean mass and muscle size and strength were similar between the groups (Smith et al. 2004).

To date, no data comparing the physical effects of flutamide or nilutamide versus castration therapy have been published.

Hot flashes

One adverse effect that is commonly observed in patients receiving castration is hot flashes, which are associated with significant morbidity and can affect social functioning, ability to work, and sleep patterns of those who experience them (Adelson et al. 2005). A recent study using the Functional Assessment of Cancer Therapy (FACT) quality-of-life questionnaire on 55 men who had received castration, either alone or in combination with antiandrogen therapy (flutamide or bicalutamide), has shown that hot flashes significantly reduced the quality of life (P = 0.043) (Nishiyama et al. 2004). However, estrogens, progestin megestrol acetate, medroxyprogesterone acetate, venlafaxine, and CPA have been shown to alleviate hot flashes and associated symptoms (Aus et al. 2005).

In contrast to castration, non-steroidal antiandrogens are generally associated with a relatively low incidence of hot flashes (Fourcade and McLeod 2004). In the pooled analysis of two Phase III bicalutamide studies of 480 patients, 50.0% of patients randomized to castration by orchiectomy or goserelin experienced hot flashes compared with 13.1% receiving bicalutamide (Iversen et al. 2000). In the EPC program, the incidence of hot flashes was similarly low in patients receiving bicalutamide in addition to standard care compared with standard care alone (9.2% for bicalutamide plus standard care vs. 5.4% for standard care alone) (McLeod et al. 2006).

The incidence of hot flashes was also low in studies of flutamide monotherapy when compared with castration. In a study of flutamide versus orchiectomy, the incidence of hot flashes was 26% in the orchiectomy group compared with 7% in patients receiving flutamide (Boccon-Gibod et al. 1997), while in studies of flutamide versus diethylstilbestrol, the incidence of hot flashes was low in both treatment groups (≤ 5%) (Lund and Rasmussen 1988; Chang et al. 1996).

Gynecomastia and breast pain

During non-steroidal antiandrogen treatment, the increase in circulating estrogen levels, combined with the blockade of androgen receptors, leads to a predictable increase in the occurrence of mild-to-moderate gynecomastia and breast pain (Fourcade and McLeod 2004). These are the most common adverse effects associated with treatment with non-steroidal antiandrogens and occur at a similar frequency with bicalutamide, flutamide, and nilutamide (Fourcade and McLeod 2004; Aus et al. 2005).

In randomized, double-blind, placebo-controlled studies, treatment with tamoxifen has been shown to significantly reduce the incidence of gynecomastia and breast pain, both when used prophylactically and for treating existing effects (Conti et al. 2004; Saltzstein et al. 2005; Boccardo et al. 2005). There was no apparent difference in PSA fall when tamoxifen was used with bicalutamide compared with bicalutamide alone, but there are no published data on the long-term effects of using tamoxifen in this way. Electron-beam radiotherapy has also been shown to reduce the incidence and severity of gynecomastia (but with little effect on breast pain) when used prophylactically (Tyrrell et al. 2004). Therapeutic radiotherapy has produced some improvement in symptoms, but these improvements were more effective for breast pain than for gynecomastia (Van Poppel et al. 2005). Radiotherapy-related adverse effects have been reported as minimum (Tyrrell et al. 2004; Van Poppel et al. 2005).

Non-pharmacological adverse effects

Antiandrogens are associated with a number of non-pharmacological adverse effects, with some important differences between members of the class (Aus et al. 2005). Diarrhea appears to occur more frequently during flutamide therapy than with bicalutamide or nilutamide (Fourcade and McLeod 2004). Data from the EPC program have shown that the incidence of diarrhea with bicalutamide is similar to that with placebo (McLeod et al. 2006). Abnormal liver function tests have been associated with all antiandrogen therapies. The highest incidence (up to 25%) is associated with flutamide, which can be a potent hepatotoxin in some patients (Fourcade and McLeod 2004). The incidence of abnormal liver function tests was 3.1% in patients treated with bicalutamide in the EPC program (McLeod et al. 2006). Serious hepatotoxicity is rare with bicalutamide and nilutamide (Fourcade and McLeod 2004).

In general, nilutamide is associated with a higher incidence of adverse effects than the other non-steroidal antiandrogens (Dole and Holdsworth 1997). It increases the risk of interstitial pneumonitis, which is rare in patients receiving bicalutamide or flutamide, and can lead to delayed adaptation to darkness and alcohol intolerance, both of which are unique to nilutamide (Fourcade and McLeod 2004).

Summary

CPA is associated with a lower incidence of hot flashes compared with castration, and the development of gynecomastia with this agent is quite rare. The combination of cardiovascular risk and potential hepatotoxicity means that the use of CPA should be restricted to patients who are intolerant of non-steroidal antiandrogens. Additional adverse effects associated with CPA are impotence and loss of libido.

Unlike CPA, non-steroidal antiandrogens offer potential quality of life and tolerability benefits. Although no direct comparisons of non-steroidal antiandrogens have been undertaken in the monotherapy setting, the three available agents do not appear to differ in their severity of pharmacological adverse effects (namely gynecomastia, breast pain, and hot flashes). However, there do appear to be differences in the non-pharmacological adverse effects, with bicalutamide showing a more favorable safety and tolerability profile than nilutamide and flutamide.

The available data show that patients who receive non-steroidal antiandrogens have a better retention of libido, sexual potency, physical capacity, bone mineral density, lean muscle mass, and reduced incidence of hot flashes compared with castration-based regimes. The most common adverse effects associated with non-steroidal antiandrogen monotherapy, however, are gynecomastia and breast pain, which are generally mild to moderate in > 90% of cases.

Conclusions

In conclusion, the available data demonstrate that antiandrogen monotherapy with bicalutamide 150 mg is as effective as castration in patients with locally advanced prostate cancer. In contrast, there is a relative lack of data evaluating CPA, flutamide, and nilutamide in these patients, so it is not possible to draw conclusions about the efficacy of these agents as antiandrogen monotherapy.

Clinical studies have shown that there is a role for bicalutamide 150 mg in patients with locally advanced disease. Bicalutamide 150 mg adjuvant to radiotherapy can significantly improve progression-free survival and overall survival compared with radiotherapy alone. A significant improvement in progression-free survival, but no difference in overall survival, has been shown with both bicalutamide and flutamide adjuvant to radical prostatectomy. As in the monotherapy setting, there is a lack of data evaluating the efficacy of CPA and nilutamide in this area.

The combination of cardiovascular risk and potential hepatotoxicity with CPA means that it should not be recommended for routine use. No direct comparisons for quality of life have been made between the three non-steroidal antiandrogens, but a review of the available evidence suggests that bicalutamide has a more favorable tolerability profile than flutamide or nilutamide, which is in agreement with the European Association of Urology 2005 guidelines for prostate cancer (Aus et al. 2005). Non-steroidal antiandrogens have advantages over castration in terms of a better retention of libido, sexual potency, physical capacity, bone mineral density, and reduced incidence of hot flashes, but these agents do have a much higher incidence of gynecomastia and breast pain (mild to moderate in > 90% of cases). While some of the adverse effects associated with these therapies can be managed (e.g., when using castration therapy, hot flushes can be managed with estrogens and bone mineral density can be increased with bisphosphonates, and when using non-steroidal antiandrogens, gynecomastia and breast pain can be managed by radiotherapy or tamoxifen), the tolerability profile of each therapy should be considered when selecting an appropriate treatment for a patient.

In summary, non-steroidal antiandrogens are an effective treatment option for patients with locally advanced prostate cancer and have tolerability advantages over castration-based regimes, with bicalutamide shown to offer similar efficacy to castration in this disease setting. Based on available data, the tolerability profiles of both non-steroidal and steroidal antiandrogens suggest that antiandrogens should not be regarded as equivalents in clinical practice.

As the amount of available efficacy and tolerability data continues to increase, clear differences between antiandrogen therapies are emerging. It is, therefore, essential that clinicians discuss these data with their patients, to help them make an informed decision as to which treatment program would best fit their lifestyle.

Acknowledgments

The EPC program was funded by AstraZeneca. Dr. Sarah Goodger of Complete Medical Group provided medical writing support on behalf of AstraZeneca.

Copyright information

© Springer-Verlag 2006