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Keywords:

  • bicalutamide;
  • antiandrogen monotherapy;
  • prostate cancer;
  • localized;
  • locally advanced

SUMMARY

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES

The mainstay of hormonal therapy in prostate cancer has been medical or surgical castration, both of which are associated with loss of libido and impotence, and may not always be acceptable to the patient. Antiandrogen monotherapy is an alternative treatment option to castration. There are two types of antiandrogen, i.e. steroidal (cyproterone acetate, CPA), and nonsteroidal (bicalutamide, flutamide and nilutamide). Data comparing survival outcome with CPA and castration are limited and conflicting. Furthermore, CPA is associated with loss of libido and erectile dysfunction. Large phase III trials have established that monotherapy with bicalutamide 150 mg once daily provides a survival outcome that is not significantly different to that after castration in men with locally advanced, non-metastatic disease, while conferring significant advantages for sexual interest and physical capacity. Current data are inadequate to draw conclusions on the comparative efficacy of flutamide and castration, while nilutamide is not licensed for monotherapy. Recent data reveal that bicalutamide 150 mg given once daily in addition to standard care (radical prostatectomy, radiotherapy or ‘watchful waiting’) significantly delays the progression of early (localized or locally advanced) prostate cancer. Bicalutamide has a more favourable side-effect profile than the other antiandrogens and is more likely to promote compliance.


INTRODUCTION

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES

Prostate cancer is a slow-growing hormone-dependent disease in which there is a natural progression from localized to hormone-refractory disease (Fig. 1). The early stages of prostate cancer are frequently asymptomatic and until recently most men were diagnosed with metastatic disease [1]. However, because of the increased awareness in at-risk populations, the increased availability of PSA testing, and increased screening in some countries, the proportion of patients diagnosed while the disease is still clinically localized or locally advanced has increased [1]. Earlier detection may result in patients receiving therapy for prolonged periods and when younger than was previously the case. Therefore, therapies for prostate cancer need to be not only effective, but also well tolerated with a minimal effect on quality of life.

image

Figure 1. The prostate cancer continuum.

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Androgen deprivation therapy is a well established treatment for prostate cancer. There are several types of androgen deprivation therapy: surgical castration (bilateral orchidectomy); medical castration using LHRH analogues such as goserelin (Zoladex™, AstraZenaca); antiandrogen monotherapy; and maximum androgen blockade (MAB, a combination of castration and an antiandrogen).

Treatment options involving castration are invariably associated with loss of libido, impotence [2] and fatigue [3], and may not always be suitable or acceptable, particularly for younger patients. Until recently antiandrogens were only used as a component of MAB, but increasing evidence suggests that monotherapy with certain antiandrogens is an attractive alternative to castration-based therapy. The first antiandrogen in widespread use was the steroidal compound cyproterone acetate (CPA, Androcur™, Schering-Plough, NJ, USA). Nonsteroidal antiandrogens, bicalutamide (Casodex™, AstraZeneca), flutamide (Eulexin™, Schering-Plough) and nilutamide (Anandron™, Aventis Pharma), have since been developed.

This article reviews the evidence on the efficacy of the antiandrogens as monotherapy for prostate cancer and compares them for their pharmacological properties, tolerability and factors affecting compliance. Recent developments in the use of bicalutamide 150 mg in early (localized or locally advanced) prostate cancer are also highlighted.

PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES

Prostate cells are normally dependent on the androgens testosterone and dihydrotestosterone to stimulate function, growth and division. The antiandrogens compete with these androgens for binding sites on the androgen receptors in the prostate cell nucleus, thereby promoting apoptosis (regulated cell death) and inhibiting prostate cancer growth.

There are two structurally distinct types of antiandrogen, i.e. steroidal and nonsteroidal (Fig. 2) [4]. CPA is a synthetic derivative of hydroxyprogesterone and in addition to blocking androgen receptors, has progestational and antigonadotrophic properties [4]. CPA therefore inhibits the release of LH, decreasing serum testosterone levels, and causing a severe suppression of libido and loss of erectile potency [4]. Indeed, the incidence of these side-effects is similar to that in men treated by castration [2].

image

Figure 2. The structures of available antiandrogens.

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  • The nonsteroidal antiandrogens, bicalutamide, flutamide and nilutamide are pure antiandrogens and do not suppress testosterone secretion [2,4]. Indeed, serum testosterone levels generally increase during monotherapy with these drugs [2], although because there is an increase in the peripheral conversion of androgens to oestrogens by aromatase, testosterone levels usually remain within the normal range. It has been suggested that sexual drive in humans is influenced by the metabolites of testosterone (e.g. oestrogens) acting either directly or by modifying neural androgen metabolism [2]. As these pathways are not blocked by nonsteroidal antiandrogens, these drugs therefore offer the possibility of maintaining sexual interest and potency [2].

STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES

There are limited data on the use of steroidal antiandrogen monotherapy and only one comparative study of CPA and castration has reported survival data. This was an open randomized study of goserelin, diethylstilboestrol (DES) and CPA comprising two arms [5]; patients with no contraindications to DES (arm A, n= 137) were randomized at 2 : 1 : 1 to goserelin, CPA or DES, while those with contraindications to DES or for whom the investigator did not wish to use DES (arm B, n= 223) were randomized at 2 : 1 to either goserelin or CPA. CPA was associated with significantly poorer median survival (64 weeks) than goserelin (> 194 weeks) in arm A, but no difference was seen in arm B (130 vs 132 weeks, respectively) (Table 1) [5–12]. Adjusting for baseline characteristics did not account for the differences in median survival in arm A. A further study comparing CPA monotherapy (300 mg/day), goserelin and MAB (goserelin plus CPA) found that CPA was less effective than goserelin, but not the MAB regimen, in terms of delaying progression, but no survival data are available (Table 1) [6]. It is difficult to draw any definite conclusion about the relative efficacy of CPA and castration from these data. Furthermore, no dose-finding studies of CPA monotherapy have been conducted, so the most effective dose is unknown. Based on current data, the only advantage of CPA over castration appears to be the lower incidence of hot flushes associated with its use [5,13].

Table 1.  Comparative studies of antiandrogen monotherapy with standard therapy for locally advanced, non-metastatic (M0) or metastatic (M1) prostate cancer
Antiandrogen anddose, mg ×/dayComparatorNo. and typeof patientsMedianfollow-upProgressionSurvival outcome (median)Reference
  • *

    Up to 33 of these patients were enrolled in a third group, given DES (exact number not stated); NSD, no significant difference.

CPA 100 × 3Goserelin223 (M0/M1)Not statedNo data130 vs 132 weeks [ 5 ]
CPA 100 × 3Goserelin<137* (M0/M1)Not statedNo data64 vs > 194 weeks [ 5 ]
CPA 300 × 1Goserelin or MAB175/175/175 (M1)Not statedCPA inferior to goserelin (P = 0.016) NSD vs MABNo data [ 6 ]
Flutamide 250 × 3Orchidectomy54/50 (M1)>3 yearsMedian time to progression 370 vs 396 days (P = 0.9)NSD [ 7 ]
Flutamide 250 × 3MAB149/170 (M0/M1)2 yearsNSDNSD [ 8 ]
Bicalutamide 150 × 1Goserelin542/263 (M1)1.9 yearsHR for time to progression 1.44 (P < 0.001)737 vs 779 days (HR 1.30, P = 0.02) [ 9 ]
Bicalutamide 150 × 1Goserelin or orchidectomy320/160 (M0)6.3 yearsHR for time to progression 1.20 (P = 0.11)63.5 vs 69.9 months (HR 1.05, P = 0.70) [ 10 ]
Bicalutamide 150 × 1MAB120/115 (93% M1)32 monthsNSD19.3 vs 16.5 months [ 11 ]
Bicalutamide 150 × 1MAB108/112 (M0/M1)38 monthsNSD44 vs 45 months [ 12 ]

STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES

NILUTAMIDE AND FLUTAMIDE

Trial experience with nilutamide monotherapy is limited to one small non-comparative study involving 26 patients with metastatic disease given nilutamide 100 mg three times daily (the dose used when nilutamide is administered as a component of MAB) [14]. The median progression-free survival in these patients was 9 months, with a median overall survival of 23 months. There have been no comparative trials of nilutamide with other antiandrogens or with castration [15]. The limited available data on nilutamide monotherapy means that no meaningful conclusions about the role of nilutamide in this setting can be determined. Nilutamide is not licensed as monotherapy.

Flutamide has been used as monotherapy for more than two decades, but no dose-finding studies against a currently accepted endpoint (e.g. PSA response) have been published. Although several phase III studies have been conducted, these have several drawbacks, including the use of non-standard comparators (e.g. DES), short treatment duration, limited follow-up and inadequate statistical power to detect differences in survival outcome [7,8,16–20]. Of these, only two studies comparing flutamide with standard therapy for advanced disease (castration or MAB) have reported survival data [7,8]. In both studies, flutamide monotherapy was associated with a similar survival outcome to castration-based therapy (Table 1).

BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES

Early studies with bicalutamide monotherapy used the 50 mg dosage licensed for use in MAB. An overall analysis of these studies showed that although bicalutamide 50 mg/day monotherapy had clinical benefits, it was inferior to castration in terms of survival (median difference 97 days) [21]. Subsequent dose-ranging studies established that monotherapy with bicalutamide 150 mg given once daily achieved a PSA response similar to that seen with castration and was well tolerated [22]. Accordingly, the 150 mg dosage of bicalutamide was chosen for further evaluation as monotherapy.

The efficacy, tolerability and quality of life benefits of bicalutamide 150 mg/day monotherapy vs castration were assessed in two large phase III studies of patients with locally advanced, non-metastatic (M0) or metastatic (M1) prostate cancer [9,23].

Survival data in 805 patients with M1 disease were analysed at 1.9 years of follow-up (43% deaths) [9]. Bicalutamide 150 mg monotherapy was less effective than castration in these patients, although the difference in median survival was only 6 weeks (Table 1). However, a post hoc analysis of data showed that in bicalutamide-treated patients, the survival outcome was related to the PSA level at study entry, and that in patients with M1 and a PSA level of < 400 ng/mL, bicalutamide 150 mg monotherapy and castration provided similar survival outcomes [24]. Furthermore, in 288 symptomatic patients the subjective response rate was significantly greater with bicalutamide than castration (70% vs 58%) [24].

Mature survival data in 480 patients with M0 were obtained after a median 6.3 years of follow-up (56% mortality) [10]. On this analysis, survival outcome was not significantly different between bicalutamide 150 mg monotherapy and castration (hazard ratio, HR, 1.05, 95% CI 0.81–1.36, P = 0.70; (Fig. 3; Table 1). There was also no statistically significant difference between the groups in time to progression (HR 1.20, 95% CI 0.96–1.51, P= 0.11).

image

Figure 3. Kaplan-Meier probability for time to death after treatment with bicalutamide 150 mg (red solid line) vs castration (green dotted line) in patients with M0 disease [ 10 ].

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Two much smaller ongoing studies are comparing bicalutamide 150 mg monotherapy and MAB (Table 1) [11,12]. One of these studies enrolled mainly patients with M1 [11], whereas in the other study half the patients had M0 disease [12]. At the latest follow-up the survival outcome with bicalutamide 150 mg monotherapy did not differ significantly from that with MAB in either study (Table 1).

When choosing among treatment options providing similar survival outcome, quality-of-life issues are an important consideration. Many patients are sexually and physically active before the diagnosis of prostate cancer, and treatments that have less effect on these aspects of quality of life may be more attractive to such patients. Quality of life was evaluated in the bicalutamide monotherapy studies using a validated questionnaire covering 10 domains of quality of life (emotional well-being, sexual interest, sexual function, vitality, physical capacity, social function, activity limitation, pain, bed disability, and overall health). The results at 1 year after randomization favoured bicalutamide 150 mg monotherapy in both M0 and M1 patients. In patients with M0, bicalutamide provided significant benefits in the domains of sexual interest (P = 0.029) and physical capacity (P = 0.046; Fig. 4) [10]. Differences favouring bicalutamide over castration were also seen in six other domains, although these were not statistically significant (Fig. 4) [10]. The overall health domain, which was based on the answer to one question, favoured castration, but the difference was not statistically significant. The results for the sexual function domain were not analysed statistically because there were too few respondents to this question (70) [2]. The quality of life findings were similar in patients with M1, with significant advantages for bicalutamide monotherapy over castration for sexual interest (P = 0.041) and physical capacity (P = 0.032) [9].

image

Figure 4. Quality-of-life analysis at 12 months in patients with M0 disease receiving bicalutamide 150 mg or castration [ 10 ].

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As about half the men reported no sexual interest before study entry, additional analyses excluding these patients were undertaken [2]. In patients with M0 disease, compared with patients in the castration group, significantly (P < 0.01) more patients receiving bicalutamide 150 mg monotherapy maintained their interest in sex and felt they were still sexually attractive (Table 2) [2]. There was also a trend favouring bicalutamide for the proportion of men who felt that others found them sexually attractive (Table 2). Results were similar in the analysis of patients with M1, although only the result for the proportion of men maintaining some interest in sex (67% vs 40%) was statistically significant [2].

Table 2.  The number (%) of patients with locally advanced prostate cancer retaining sexual interest, feeling sexually attractive and feeling that others find them sexually attractive (last value carried forward) at 12 months [ 2 ]
DomainBicalutamide 150 mgCastration
Continued interest in sex125 (64)73 (30)
Feeling sexually attractive  99 (71)48 (42)
Feeling others find them sexually attractive  91 (71)50 (52)

Testosterone is involved in bone homeostasis, and osteoporosis is a recognized long-term complication of castration [25]. A small study investigated bone mineral density (BMD) in 29 patients with M0 enrolled in the two large bicalutamide monotherapy trials who received randomized treatment for a median of ≈ 5 years and had no evidence of bone metastases at follow-up [26]. BMD at the lumbar spine, femoral neck and total hip in bicalutamide-treated patients was similar to that in an age-matched population, whereas in eight castrated patients there was a clinically significant reduction in BMD at all three sites [26]. Thus, patients receiving bicalutamide monotherapy may have a lower risk of osteoporotic fractures than castrated patients.

In conclusion, there are considerably more data supporting the use of bicalutamide monotherapy as an alternative to castration for patients with locally advanced, non-metastatic prostate cancer for whom immediate hormone therapy is indicated than for any of the other antiandrogens (Table 1). Indeed, bicalutamide 150 mg monotherapy is now licensed for this indication in> 30 countries worldwide. There is also evidence that many patients with M1 disease have a clinical benefit from bicalutamide 150 mg monotherapy.

BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES

Studies show that in breast cancer, a hormone-dependent malignancy analogous to prostate cancer, adjuvant anti-oestrogen therapy (tamoxifen) significantly improves both 10-year progression-free and overall survival in early disease [27]. These findings provide a rationale for evaluating adjuvant antiandrogen therapy in patients with early prostate cancer.

The ‘Casodex’ Early Prostate Cancer (EPC) programme, the largest clinical trial programme of prostate cancer treatment to date, was designed to evaluate the efficacy and tolerability of bicalutamide 150 mg given in addition to standard care (radical prostatectomy, radiotherapy or ‘watchful waiting’) in patients with localized or locally advanced disease. The programme comprises three trials of similar design which are being conducted in North America, in Europe, South Africa, Israel, Australia and Mexico, and in Scandinavia. In all, 8113 patients were randomized to receive either bicalutamide 150 mg/day (4052) or placebo (4061) [28].

The first combined analysis of the EPC programme showed that, after a median follow-up of 3 years (minimum 2 years), bicalutamide significantly reduced objective disease progression by 42% compared with standard care alone (HR 0.58, 95% CI 0.51–0.66; P << 0.001) [28]. This reduction in risk occurred across the entire study population irrespective of primary treatment. Only 6% of the study population had died at the time of this analysis (< 2% from prostate cancer). The follow-up continues to establish if bicalutamide will confer a survival gain in this setting.

The results from the EPC programme are an important advance in prostate cancer as this is the first large prospective study to show that adjuvant hormonal therapy can reduce the risk of disease progression in men undergoing radical prostatectomy.

TOLERABILITY OF ANTIANDROGENS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES

STEROIDAL ANTIANDROGENS

CPA has an unfavourable side-effect profile, principally because of its progestogenic and steroidal properties, and cannot be recommended for routine use. Most patients treated with CPA have loss of libido, and impotence [4,20,29]. In addition, CPA is associated with cardiovascular side-effects (incidence 4–40%) and adverse changes in serum lipoproteins and carbohydrate metabolism [4,29,30], toxicity that will adversely affect cardiovascular risk in patients with pre-existing cardiovascular problems or diabetes. CPA has also been associated with a high incidence of hepatotoxicity [29].

NON-STEROIDAL ANTIANDROGENS

The most common side-effects of nonsteroidal antiandrogen monotherapy are gynaecomastia and male breast pain, and these events occur more frequently than with castration alone [29,31]. Gynaecomastia is an expected pharmacological effect of nonsteroidal antiandrogen monotherapy and is caused by an imbalance in the normal ratio of androgenic and oestrogenic activity [32]. This is a result of an increase in oestrogen levels (after peripheral aromatization of elevated serum testosterone levels) and direct antagonism of androgen action in breast tissue. In the two large phase III studies comparing bicalutamide monotherapy with castration, gynaecomastia and breast pain were reported by 49.4% and 40.1% of bicalutamide-treated patients with M0, respectively, after 6.3 years of follow-up [10]. However, gynaecomastia and breast pain were well tolerated, as only 1.3% of patients withdrew because of these events [10]. In the EPC programme, the incidence of gynaecomastia and breast pain in the bicalutamide 150 mg group was 66.2% and 72.8%, respectively [28]. However, both events were mild to moderate in> 90% of cases and most gynaecomastia (70%) and breast pain (90%) events improved or resolved when patients withdrew from therapy [28]. The incidence of gynaecomastia and breast pain reported during monotherapy with flutamide is similar to that for bicalutamide [29,33].

Hot flushes, commonly seen with castration, are much less frequent with nonsteroidal antiandrogen monotherapy. The incidence of hot flushes in patients with M0 in the two pivotal bicalutamide monotherapy trials was 13.1%, compared with half of patients undergoing castration [10]. In the EPC programme, hot flushes occurred in 9.0% and 5.2% of patients receiving bicalutamide and placebo, respectively [28].

As noted earlier, monotherapy with nonsteroidal antiandrogens should theoretically preserve libido and potency. In the pivotal studies of bicalutamide 150 mg monotherapy in advanced disease, about two-thirds of men maintained sexual interest, while sexual function was slightly reduced by 18%[2]. Fewer than 10% of patients in these studies reported loss of libido or erectile potency as an adverse event [10]. Likewise, in the EPC programme, low incidences of decreased libido and impotence (3.6% and 9.0%, respectively) were reported by patients receiving bicalutamide 150 mg in addition to standard care [28]. In general, in studies with flutamide monotherapy in advanced disease, about two-thirds of previously sexually potent men retained potency and sexual interest [2], although in one study [20] only ≈ 20% of patients treated with flutamide maintained sexual function and interest (similar to findings in the CPA comparator group).

There are differences between the nonsteroidal antiandrogens in other than pharmacological side-effects. With flutamide monotherapy, diarrhoea occurs in up to 20% of patients and may lead to treatment withdrawal [31]. In contrast, in the EPC studies, the incidence of diarrhoea with bicalutamide was comparable with placebo (6.3% vs 6.4%, respectively) [28]. Hepatotoxicity, occasionally fatal, has also been noted with flutamide therapy [31], whereas in the EPC studies abnormal liver function occurred infrequently (3.4% for bicalutamide vs 1.9% for placebo) and changes were rarely severe [28]. Likewise, no cases of significant hepatotoxicity were noted during the studies comparing bicalutamide monotherapy and castration [10]. When given as a component of MAB, nilutamide is associated with a high incidence of visual disturbances (delayed adaptation to darkness) and alcohol intolerance [15], effects not associated with either flutamide or bicalutamide [31]. Interstitial pneumonitis and hepatic dysfunction have also been reported [15,31]. In the single small (26 men) study of nilutamide monotherapy, the most common adverse non-pharmacological events were slow adaptation to darkness (31%), nausea (27%) and alcohol intolerance (19%) [14].

In conclusion, while there are no comparative studies of the antiandrogens as monotherapy in prostate cancer patients, current data reveal that bicalutamide has a more favourable side-effect profile than CPA and the other nonsteroidal antiandrogens. The principal side-effects of bicalutamide monotherapy are gynaecomastia and breast pain. Several options are available for the management of gynaecomastia and/or breast pain associated with antiandrogen monotherapy, including prophylactic or therapeutic irradiation or surgery [32]. Studies of prophylactic options are underway in bicalutamide-treated patients. Recently presented data show that a single dose of prophylactic irradiation (10 Gy) to the breast before initiating bicalutamide 150 mg therapy significantly reduces the incidence and severity of gynaecomastia, and the severity, although not the incidence, of breast pain [34].

DOSING AND COMPLIANCE

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES

Patient compliance with a drug regimen is important if the treatment is to be fully effective. In addition to factors such as efficacy and tolerability, the complexity and convenience of the dosing schedule influence patient compliance, and patients are likely to be more compliant with a once-daily than a thrice daily drug regimen [36]. Restrictions on the timing of drug administration in relation to mealtimes may also affect compliance.

There are notable differences between the antiandrogens in the dosing regimen. CPA is poorly absorbed from the gastrointestinal tract and must be taken after food, whereas the nonsteroidal antiandrogens are well absorbed and are not affected by food intake [35]. Bicalutamide has a long elimination half-life of ≈ 7 days, allowing for a once-daily dosing regimen [36]. Flutamide is a prodrug; the elimination half-life of the active metabolite 2-hydroxyflutamide is 5–6 h [13] and therefore, to maintain therapeutic serum levels, flutamide must be administered three times daily. Although CPA has a relatively long half-life (30–40 h) [13], it is usually administered in two or three divided doses [35]. Thus, of the antiandrogens approved for monotherapy, the dosing regimen of bicalutamide is the most favourable for patient compliance.

CONCLUSIONS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES

In view of changing patient demographics and the earlier diagnosis and treatment of prostate cancer, many patients are likely to receive prolonged hormonal therapy. In this context there is a need for well-tolerated alternative therapies to castration. This review shows that there are extensive data to support the use of bicalutamide 150 mg monotherapy as an alternative to castration in men with advanced disease, for whom immediate hormonal therapy is indicated; bicalutamide is associated with advantages in maintenance of libido and physical capacity, while the survival outcome is similar. Comparative survival data on the other antiandrogens compared with castration are limited. Furthermore, CPA, flutamide and nilutamide are less well tolerated than bicalutamide. Recent data also support the use of bicalutamide 150 mg once daily in early prostate cancer (localized and locally advanced disease), either as immediate therapy alone or as adjuvant to primary treatment of curative intent.

REFERENCES

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES
  • 1
    Mettlin C, Murphy GP, Rosenthal DS, Menck HR. The National Cancer Data Base report on prostate carcinoma after the peak in incidence rates in the US. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998; 83: 167984
  • 2
    Iversen P, Melezinek I, Schmidt A. Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function. BJU Int 2001; 87: 4756
  • 3
    Stone P, Hardy J, Huddart R, A'Hern R, Richards M. Fatigue in patients receiving hormone therapy. Eur J Cancer 2000; 36: 113441
  • 4
    Furr BJA, Kaisary AV. Treatment: hormonal manipulation: Antiandrogens. In KaisaryAV Murphy GP, DenisL, GriffithsK eds Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment. London: Martin Dunitz, 1999: 277 – 90
  • 5
    Moffat LE. Comparison of Zoladex, diethylstilboestrol and cyproterone acetate treatment in advanced prostate cancer. Eur Urol 1990; 18 (Suppl. 3): 267
  • 6
    Thorpe SC, Azmatullah S, Fellows GJ, Gingell JC, O'Boyle PJ. A prospective, randomised study to compare goserelin acetate (Zoladex®) versus cyproterone acetate (Cyprostat®) versus a combination of the two in the treatment of metastatic prostatic carcinoma. Eur Urol 1996; 29: 4754
  • 7
    Boccon-Gibod L, Fournier G, Bottet P et al. Flutamide versus orchidectomy in the treatment of metastatic prostate carcinoma. Eur Urol 1997; 32: 3915
  • 8
    Pavone-Macaluso M. Flutamide monotherapy versus combined androgen blockade in advanced prostate cancer. Interim report of an Italian multicentre, randomised study. SIU 23rd Congress 1994: A354
  • 9
    Tyrrell CJ, Kaisary AV, Iversen P et al. A randomised comparison of ‘Casodex’ (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 1998; 33: 44756
  • 10
    Iversen P, Tyrrell CJ, Kaisary AV et al. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol 2000; 164: 157982
  • 11
    Fourcade RO, Chatelain C, Poterre M. An open multicentre randomised study to compare the effect and safety of ‘Casodex’ (bicalutamide) 150 mg monotherapy with castration plus nilutamide in metastatic prostate cancer. Eur Urol 1998; 33 (Suppl. 1): 88 (A349)
  • 12
    Boccardo F, Rubagotti A, Barichello M et al. Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients. Results of an Italian prostate cancer project (PONCAP) study. J Clin Oncol 1999; 17: 202738
  • 13
    Mahler C, Verhelst J, Denis L. Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer. Clin Pharmacokinet 1998; 34: 40517
  • 14
    Decensi AU, Boccardo F, Guarneri D et al. Monotherapy with nilutamide, a pure nonsteroidal antiandrogen, in untreated patients with metastatic carcinoma of the prostate. J Urol 1991; 146: 37781
  • 15
    Dole EJ, Holdsworth MT. Nilutamide: an antiandrogen for the treatment of prostate cancer. Ann Pharmacother 1997; 31: 6575
  • 16
    Dudov A, Todorov D. Goserelin versus flutamide in previously untreated advanced prostate cancer. Can J Infect Dis 1995; 6: 396 (A3034)
  • 17
    Jacobo E, Schmidt JD, Weinstein SH, Flocks RH. Comparison of flutamide (SCH-13521) and diethylstilbestrol in untreated advanced prostatic cancer. Urology 1976; 8: 2313
  • 18
    Lund F, Rasmussen F. Flutamide versus stilboestrol in the management of advanced prostatic cancer. A controlled prospective study. Br J Urol 1988; 61: 1402
  • 19
    Chang A, Yeap B, Davis T et al. Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol. J Clin Oncol 1996; 14: 22507
  • 20
    Schröder FH, Collette L, De Reijke TM, Whelan P. Prostate cancer treated by anti-androgens: is sexual function preserved? EORTC Genitourinary Group. European Organization for Research and Treatment of Cancer. Br J Cancer 2000; 82: 28390
  • 21
    Kolvenbag GJ, Nash A. Bicalutamide dosages used in the treatment of prostate cancer. Prostate 1999; 39: 4753
  • 22
    Tyrrell CJ, Denis L, Newling D, Soloway M, Channer K, Cockshott ID. Casodex 10–200 mg daily, used as monotherapy for the treatment of patients with advanced prostate cancer. An overview of the efficacy, tolerability and pharmacokinetics from three phase II dose-ranging studies. Casodex Study Group. Eur Urol 1998; 33: 3953
  • 23
    Iversen P, Tyrrell CJ, Kaisary AV et al. Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer: results from two multicenter randomized trials at a median follow-up of 4 years. Urology 1998; 51: 38996
  • 24
    Kaisary AV, Iversen P, Tyrrell CJ, Carroll K, Morris T. Is there a role for antiandrogen monotherapy in patients with metastatic prostate cancer? Prost Cancer Prost Dis 2001; 4: 196203
  • 25
    Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000; 63: 1816
  • 26
    Tyrrell CJ, Blake GM, Iversen P et al. ‘Casodex’ may preserve bone mineral density of patients with advanced prostate cancer. BJU Int 2000; 86 (Suppl. 3): MP6.1.09
  • 27
    Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer. an overview of the randomised trials. Lancet 1998; 351: 145167
  • 28
    See WA, Wirth MP, McLeod DG et al. Bicalutamide as immediate therapy either alone or as adjuvant to standard care in patients with localized or locally advanced prostate cancer: first analysis of the Early Prostate Cancer Program. J Urol 2002; 168: 42935
  • 29
    Migliari R, Muscas G, Murru M, Verdacchi T, De Benedetto G, De Angelis M. Antiandrogens: a summary review of pharmacodynamic properties and tolerability in prostate cancer therapy. Arch Ital Urol Androl 1999; 71: 293302
  • 30
    Paisey RB, Kadow C, Bolton C, Hartog M, Gingell JC. Effects of cyproterone acetate and a long-acting LHRH analogue on serum lipoproteins in patients with carcinoma of the prostate. J R Soc Med 1986; 79: 2101
  • 31
    McLeod DG. Tolerability of nonsteroidal antiandrogens in the treatment of advanced prostate cancer. Oncologist 1997; 2: 1827
  • 32
    McLeod DG, Iversen P. Gynecomastia in patients with prostate cancer. a review of treatment options. Urology 2000; 56: 71320
  • 33
    Oosterlinck W, Casselman J, Mattelaer J, Van Velthoven R, Kurjatkin O, Schulman C. Tolerability and safety of flutamide in monotherapy, with orchiectomy or with LHRH-a in advanced prostate cancer patients. A Belgian multicenter study of 905 patients. Eur Urol 1996; 30: 45863
  • 34
    Tyrrell C, Morris T, Carroll K. Prophylactic breast irradiation significantly reduces the incidence of bicalutamide-induced gynaecomastia. Eur Urol 2002; 41 (Suppl. 1): 136 (A536)
  • 35
    Kaisary AV. Compliance with hormonal treatment for prostate cancer. Br J Hosp Med 1996; 55: 35966
  • 36
    Cockshott ID, Cooper KJ, Sweetmore DS, Blacklock NJ, Denis L. The pharmacokinetics of Casodex in prostate cancer patients after single and during multiple dosing. Eur Urol 1990; 18 (Suppl. 3): 107
Abbreviations
MAB

maximum androgen blockade

CPA

cyproterone acetate

DES

diethylstilboestrol

HR

hazard ratio

BMD

bone mineral density

EPC

Early Prostate Cancer (programme).

TAKE-HOME MESSAGES

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. PHARMACOLOGICAL PROPERTIES OF ANTIANDROGENS
  5. STUDIES OF STEROIDAL ANTIANDROGEN MONOTHERAPY
  6. STUDIES OF NONSTEROIDAL ANTIANDROGEN MONOTHERAPY
  7. BICALUTAMIDE AS MONOTHERAPY FOR METASTATIC AND LOCALLY ADVANCED PROSTATE CANCER
  8. BICALUTAMIDE MONOTHERAPY FOR EARLY PROSTATE CANCER
  9. TOLERABILITY OF ANTIANDROGENS
  10. DOSING AND COMPLIANCE
  11. CONCLUSIONS
  12. REFERENCES
  13. TAKE-HOME MESSAGES
  • •  
    Treatment options for prostate cancer involving castration may not be suitable or acceptable for patients, particularly for younger men;
  • •  
    Survival outcome with bicalutamide 150 mg monotherapy in previously untreated patients with M0 prostate cancer is not significantly different to that achieved with castration;
  • •  
    At 12 months, bicalutamide 150 mg monotherapy confers significant advantages over castration with respect to physical capacity and sexual interest;
  • •  
    More data exist to support the use of bicalutamide monotherapy as an alternative to castration in patients for whom immediate hormonal therapy is indicated, particularly M0 patients, than for any of the other antiandrogens;
  • •  
    Bicalutamide 150 mg given as immediate or adjuvant therapy in addition to standard care significantly reduces the risk of disease progression in men with early (localized or locally advanced) prostate cancer;
  • •  
    Of the available antiandrogens, bicalutamide has the more favourable side-effect profile.