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An Evaluation of Bicalutamide in the Treatment of Prostate Cancer
Comprehensive Review
An Evaluation of Bicalutamide in the Treatment of Prostate Cancer Paul F. Schellhammer John W. Davis Department of Urology Eastern Virginia Medical School and Virginia Prostate Center, Norfolk
Clinical Prostate Cancer, Vol. 2, No. 4, 213-219, 2004 Key words: Antiandrogens, Gynecomastia, Monotherapy, Quality of life
Submitted: Sep 8, 2003; Revised: Dec 17, 2003; Accepted: Dec 19, 2003 Address for correspondence: Paul F. Schellhammer, MD Department of Urology Eastern Virginia Medical School 633 Center Drive, #16 Norfolk, VA 25502 Fax: 757-962-8020 e-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1540-0352, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Abstract Although prostate cancer is traditionally considered a disease of old age, improved diagnostic techniques have resulted in early diagnosis, and many men are now treated while still physically and sexually active. Current therapies for prostate cancer often include medical or surgical castration, which cause adverse effects on physical and sexual function; therefore, greater attention has been focused on quality of life. The nonsteroidal antiandrogen bicalutamide is an effective agent with a favorable tolerability profile and, in some settings, represents an alternative to castration. Mature survival data reveal that bicalutamide monotherapy provides survival benefits for untreated locally advanced disease that do not differ significantly from those of castration and maintains better physical capacity and sexual interest. Recent data from a prospective randomized trial demonstrate that bicalutamide given as immediate therapy, either alone or as adjuvant to therapy of curative intent, significantly reduces the risk of objective disease progression in patients with localized or locally advanced prostate cancer. Antiandrogens are also used in combination with castration, a treatment known as combined androgen blockade (CAB), for advanced disease. A randomized trial demonstrated that CAB with bicalutamide is associated with similar survival outcome to CAB with flutamide and is better tolerated. Current evidence demonstrates that bicalutamide currently has a favorable risk–benefit ratio in several stages of prostate cancer and that the role of bicalutamide will be further defined by ongoing studies.
Introduction Prostate cancer is a considerable health problem among older men that causes significant morbidity and mortality. In the United States, the prostate cancer incidence for 2004 is projected at 230,110, with cancer mortality at an estimated 29,900 deaths.1 Early prostate cancer is generally asymptomatic. The prevalence of prostate-specific antigen (PSA) screening and early detection has resulted in earlier diagnosis.2 The most recent data from the National Cancer Database reveal that nearly 80% of men diagnosed with prostate cancer in the United States have stage T1/2 tumors. However, the reproducibility of current staging methods is often unreliable and does not consider important variables such as PSA levels and Gleason grade, and the clinical disease stage is often not indicative of pathologic stage or the activity of the disease.3 Indeed, as many as 50% of men with clinically localized disease are actually found to have more advanced disease when they undergo pathological staging after radical surgery.4 The mainstay of treatment for failures of local therapy and advanced disease is immediate or delayed androgen deprivation. This has been achieved by surgical or medical castration, alone or in combination with an antiandrogen, the latter of which is known as combined androgen
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Bicalutamide for Prostate Cancer blockade (CAB).5 Other than antiandrogen withdrawal when CAB is initially used, there is no standard treatment for patients who have disease progression after first-line hormonal therapy. Further hormonal manipulation or chemotherapy are the therapeutic options.6 The rationale for CAB is based on the finding that, although medical and surgical castration reduce serum testosterone levels by approximately 95%, the intraprostatic level of dihydrotestosterone (DHT), the principal mediator of androgenic activity, is less affected. This is because of the conversion of androgens of adrenal origin to DHT in prostatic cells. The addition of the antiandrogen blocks the actions of these adrenal androgens at the receptor level. An overview of CAB trials recently conducted by the Prostate Cancer Clinical Trialists’ Collaborative Group, involved 27 trials and 8275 patients treated for ≥ 1 year.7 The difference in absolute survival at 5 years was 1.8%, favoring CAB. This difference increased to 2.9% when only trials using nonsteroidal antiandrogens were analyzed. It was concluded that survival cannot be substantially worse for CAB with nonsteroidal antiandrogens than for castration alone, but the gain in survival cannot be better than 5% and is more likely to be between 2% and 3%. Although this advantage negated the excessive optimism initially associated with CAB, the trialists warned against excessive pessimism. They raised the question that if CAB does improve survival by 2%-3%, greater improvements might be achieved with more effective hormonal regimens, particularly if methods of identifying those prostate cancers most likely to respond to prolonged hormonal manipulation become available. Characterization of genomes and proteomes of individual cancers may provide signature profiles that define relative susceptibility to specific interventions.
Pharmacology of Antiandrogens or Androgen Receptor Blockers Antiandrogens block the effects of androgens irrespective of their origin and offer an alternative therapeutic strategy to castration. Chemically, the antiandrogens are classified as steroidal or nonsteroidal compounds. Three nonsteroidal antiandrogens are currently available: flutamide, nilutamide, and bicalutamide. This article focuses on bicalutamide, the most extensively studied antiandrogen. Bicalutamide is an orally active nonsteroidal antiandrogen that is devoid of other endocrine effects. It is an androgen receptor blocker and therefore competitively antagonizes the actions of androgens and other ligands at the receptor level, thereby inhibiting the growth of prostate tumors. Bicalutamide does not act as an agonist or antagonist at other hormone receptors.8 In vitro studies have revealed that, in contrast to flutamide and nilutamide, bicalutamide remains an effective antiandrogen in most mutant prostate cancer cell lines. A recent study, however, has demonstrated that bicalutamide has agonist properties in LNCaP cells that have been subjected to long-term androgen ablation.9 Bicalutamide antagonizes the peripheral and central androgen receptors, thereby blocking the negative feedback mechanism regulating testosterone production.10 Consequently, plasma luteinizing hormone (LH) and testosterone concentrations
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increase during bicalutamide therapy.11,12 Plasma testosterone concentrations are, however, maintained within the normal range because of the peripheral aromatization of excess androgens to estrogens and the negative feedback these estrogens provide. Bicalutamide is well absorbed after oral administration and may be given with or without food.13 The mean elimination half-life of bicalutamide is approximately 7 days and is therefore compatible with once-daily dosing.12,14 The clearance of bicalutamide occurs predominantly by hepatic metabolism. The pharmacokinetics of bicalutamide is not affected by age, renal function, or mild to moderate hepatic impairment.12,14,15 Bicalutamide is highly bound to plasma proteins. Of clinical interest are in vitro studies that have demonstrated that bicalutamide may displace warfarin from its protein-binding sites.16 Patients undergoing anticoagulation with warfarin should therefore have their prothrombin times closely monitored after initiation of bicalutamide therapy. Bicalutamide has the potential to be an effective treatment option for many stages of hormone-sensitive prostate cancer. The initial dose-finding studies of bicalutamide conducted in the pre-PSA era used a 50% decrease in prostatic acid phosphatase (PAP) level as a surrogate endpoint for clinical activity. In these studies, the proportions of patients receiving bicalutamide 10, 30, and 50 mg who had decreases in PAP of ≥ 50% were 33%, 53%, and 83%, respectively.16 Accordingly, a dose of 50 mg was selected for further studies, both as a component of CAB and as monotherapy. Subsequently, during phase II studies, the more sensitive and specific tumor marker of PSA became available, and the response to bicalutamide in terms of PSA reduction was found to be related to dose in the range of 10-200 mg.12 The 150-mg dose was subsequently chosen for development as monotherapy based on the observation that the PSA response, a > 92% reduction, after 3 months of treatment at this dose level was comparable to that seen in patients who had undergone surgical castration.17
Bicalutamide as a Component of Combined Androgen Blockade Combined androgen blockade with bicalutamide has not been compared with castration alone. However, the comparative efficacy of bicalutamide (50 mg per day) and flutamide (250 mg 3 times a day), both in combination with an LHreleasing hormone (LHRH) agonist, has been evaluated in a large, randomized phase III study involving 813 men with metastatic (stage M1) disease.18,19 Mature data (55% deaths) from this study were presented after a median follow-up of 160 weeks. Although no statistically significant differences in disease outcomes were noted, some trends are notable. Men randomized to receive bicalutamide had a 13% lower risk of dying compared with those randomized to flutamide (hazard risk [HR], 0.87; 95% CI, 0.72-1.05; P = 0.15)19 and median survival was extended by 32 weeks in the bicalutamide group (180 weeks vs. 148 weeks). There were no consistent differences between the 2 antiandrogens in their effect on quality of life (QOL) measures. The incidence of diarrhea and the number of withdrawals from treatment because of diarrhea was significantly greater in the flutamide group.
Paul F. Schellhammer, John W. Davis
Bicalutamide Monotherapy in Previously Untreated Advanced Disease Three studies initially evaluated the efficacy of bicalutamide monotherapy at the 50-mg dose for patients with metastatic disease. Although clinical benefits were seen, the benefits of daily bicalutamide doses of 50 mg were inferior to those of castration.23 Subsequently, based on dose-ranging studies of 50-200 mg, as already described, daily bicalutamide 150 mg was evaluated against castration (bilateral orchiectomy or goserelin acetate 3.6 mg every 28 days) in 2 large randomized phase III studies of similar design in men with locally advanced (M0) or stage M1 disease. Survival data of patients with M1 disease (n = 805) were considered mature at a median follow-up of 1.9 years.24 There was a statistically significant difference in overall survival in favor of castration (HR, 1.30; 95% CI, 1.04-1.64; P = 0.02) in these patients, although the difference in estimated median survival was only 42 days (737 days vs. 779 days). A post hoc analysis revealed that bicalutamide 150 mg and castration provided similar survival outcomes in patients with pretreatment PSA levels of ≤ 400 ng/mL. The disadvantage for bicalutamide, therefore, was apparent only in men with the highest tumor burdens at study entry.25 In the M0 subgroup (n = 480), survival data were mature at a median follow-up of 6.3 years (56% deaths). Overall survival did not differ significantly between the bicalutamide 150-mg monotherapy and castration groups (HR, 1.05; 95% CI, 0.811.36; P = 0.70; Figure 1).26 At median follow-up, when 77% of the patients had experienced disease progression, there was no statistically significant difference in time to progression between the 2 groups (HR, 1.20; 95% CI, 0.96-1.51; P = 0.11). The relative impact of bicalutamide monotherapy and castration on QOL was evaluated in these pivotal bicalutamide 150-mg monotherapy trials. Ten domains of QOL were assessed using a validated questionnaire: physical capacity, emotional well being, sexual interest, sexual function, vitality, social function, pain, activity limitation, bed disability, and overall health. Separate
Figure 1 Overall Survival in Patients with Prostate Cancer: Castration Versus Bicalutamide26
100 90 80
Survival Rate (%)
Data indicate that the efficacy of CAB or any form of androgen deprivation may depend on extent of disease. Patients with minimal metastatic disease derive the greatest survival benefit.20 An exploratory analysis of this phase III trial of 813 patients confirmed these findings and also revealed a trend toward longer survival with bicalutamide compared with flutamide in patients with minimal metastatic disease (HR, 0.79; 95% CI, 0.591.07).21 Other exploratory analyses conducted for this trial population revealed outcomes of interest. Prolonged (> 120 days) CAB conferred significant survival benefits compared with shortterm CAB (HR, 0.275; P = 0.0001).22 As early deaths could result in bias (because the patients could not receive prolonged therapy), a further analysis was conducted in patients who lived ≥ 2 years after study entry. In these patients, prolonged CAB increased median survival. These findings suggest that, for some patients, improved survival with CAB is not, as has been suggested, caused solely by blockade of the flare phenomenon that can occur in the early stages of LHRH agonist therapy.
70 60 50 40 30 20 10 0
Castration Bicalutamide 150 mg
P = 0.70
200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2600 2800
Time to Death (Days) Reproduced with permission from Iversen P et al. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol 2000; 164:1579-1582.
analyses of the QOL data were performed at 12 months after randomization for patients with M0 and M1 disease. In patients with M0 disease, bicalutamide showed a significant advantage compared with castration in the domains of physical capacity (P = 0.046) and sexual interest (P = 0.029).27 A post hoc analysis of data on sexual interest was undertaken excluding patients with no sexual interest at study entry. In this exploratory analysis, 64% of those randomized to bicalutamide retained some interest in sex during the first 12 months of the study compared with only 30% of the castration group (P < 0.01).28 The maintenance of sexual interest is explained as follows. Animal experiments suggest that male sex drive is modulated, either directly or indirectly, by the metabolites of testosterone (such as estrogens) rather than by circulating androgens.28 Indeed, it is unlikely that the benefits of bicalutamide on sexual interest could be a direct result of the maintenance of normal testosterone levels, as the administration of a nonsteroidal antiandrogen would negate the effects of circulating androgens by blockade of the hypothalamic androgen receptors. However, the levels of androgen metabolites and their actions would not be affected by the blockade of androgen receptors by bicalutamide. Bicalutamide 150-mg monotherapy has also been compared with different CAB regimens in 2 smaller trials conducted in France and Italy.29,30 In the French study, 235 patients, 93% of whom had M1 disease, were randomized to bicalutamide 100 mg or 150 mg or CAB (goserelin acetate or surgical castration, both in combination with nilutamide 300 mg).29 In the Italian study, 49.5% of the 220 patients had M0 disease at study entry, and CAB consisted of goserelin acetate 3.6 mg plus flutamide 750 mg.30 With relatively short median follow-up times in these 2 trials of 32 and 38 months, respectively, survival between CAB and bicalutamide 150 mg monotherapy was not significantly different. Monotherapy with bicalutamide of 150 mg provides a comparable survival outcome to castration in patients with M0 disease but has less impact on sexual interest. This finding is of consid-
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Bicalutamide for Prostate Cancer
Figure 2 Disease-Free Progression in Patients with Prostate Cancer: Bicalutamide Versus
Placebo36
Disease-Free Progression (%)
100 90 80 70 60 50 40 30 20 Bicalutamide 150 mg Placebo
10 0
200
400
600
800
P < 0.0001
1000
1200
1400
1600
1800
Time (Days) Reproduced with permission from See WA et al. Bicalutamide (‘Casodex’) 150 mg 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 [Published errata appear in: J Urol 2002; 2168:2558; J Urol 2002; 2168(Pt 1):1510]. J Urol 2002; 168:429-435.
erable clinical interest. Sexual activity is unlikely in the absence of sexual interest, and although sexual dysfunction can be treated, there are currently no effective therapies for low libido. Maintenance of physical capacity, which reflects the ability of the patient to take part in the normal activities of daily living such as walking, dressing, bathing, shopping, and bending, is also a vital dimension of QOL. Patients who have disease progression during bicalutamide monotherapy have been found to respond to subsequent medical or surgical castration. Scher and colleagues reported that 33% of those who had progression with bicalutamide 200 mg (n = 15) had a > 80% decrease in PSA level for a median of 6 months after the addition of an LHRH agonist.31 Likewise, of the 23 patients with M1 disease studied by Fabozzi et al, 14 patients (61%) demonstrated a ≥ 50% decrease in PSA level when castration was used after failure of bicalutamide 50 mg.32 Upon progression after monotherapy, some tumors may still be responsive to further hormonal manipulation.
Bicalutamide as Immediate Therapy in Early-Stage Prostate Cancer Adjuvant hormonal therapy with the antiestrogen tamoxifen improves survival in women with early-stage breast cancer,33 and it has been postulated that adjuvant antiandrogen therapy may confer similar benefits in early-stage prostate cancer.34 Based on this rationale, the use of bicalutamide 150 mg after interventions of curative intent, such as radical prostatectomy, radiation therapy, and watchful waiting for patients with early (localized or locally advanced) prostate cancer and those deemed suitable for surveillance (watchful waiting), is being explored in the bicalutamide Early Prostate Cancer (EPC) program.35 This program is the largest treatment study to date in patients with prostate cancer and comprises 3 ongoing, randomized, double-blind, placebo-controlled clinical trials involving 8113 men. The 3 trials are being conducted in various geo-
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graphic regions: North America (n = 3292); Europe, South Africa, Israel, Australia, and Mexico (n = 3603); and Scandinavia (n = 1218). Patients were randomized to receive adjuvant bicalutamide 150 mg or placebo once daily after surgery or irradiation or the initiation of a surveillance strategy or watchful waiting. There were some differences in entry criteria for the 3 studies. In the North American trial, patients must have undergone either radical prostatectomy or radiation therapy, whereas in the other 2 trials, men considered appropriate for watchful waiting were also eligible. Men with lymph node involvement were excluded from the North American trial but could be included in the other 2 trials. Treatment duration also differs by study. In the North American trial, the duration of randomized treatment is 2 years, whereas in the other trials it is ≥ 5 years with the option of indefinite treatment. The primary endpoints of the trial are time to objective progression and overall survival. The results of the first combined analysis of these trials have recently been analyzed with a minimum of 2 years of follow-up (median, 3 years).36 Treatment with bicalutamide 150 mg provided a 42% reduction in the risk of objective progression compared with standard care alone (9.0% vs. 13.8%; HR, 0.58; 95% CI, 0.510.66; P < 0.0001; Figure 2). Reductions in the risk of disease progression were seen across the patient population, irrespective of primary treatment or disease stage. Patients in the EPC program were scheduled to have bone scans at 2 years, or earlier if clinically indicated. Overall, the risk of developing bone metastases (defined as a positive bone scan or death) within 2 years of randomization was reduced by 33% in the bicalutamide group compared with the standard care–alone group (P < 0.0001). The survival endpoint is immature, as at the time of this analysis only 6% of the study population had died. Patients on trial and their physicians remained blinded to their treatment arm and they continue follow-up for progression and the critical survival endpoint. The EPC program is unique in that it is the first large prospective study of adjuvant hormonal therapy in men undergoing radical prostatectomy. More than 4000 patients in the EPC program, representing approximately 55% of the study population, underwent radical prostatectomy. Other randomized data on adjuvant therapy in this setting are limited, with only Messing and colleagues reporting survival outcome.37 This was a small study (n = 98) involving men with clinically localized disease who were found to have lymph node metastases at surgery. Survival data reported at a median follow-up of 7.1 years showed a significant advantage with respect to overall and disease-specific survival for immediate hormonal therapy (medical or surgical castration) compared with therapy deferred until clinical progression. Because the men in the North American trial had node-negative disease, many with clinical T1c-T2a and pathologic T2 disease, long-term follow-up will be necessary before survival outcomes and any differences between arms will be available. These endpoints will occur earlier in the other trials, in which patients with node-positive and more advanced N0 disease were enrolled.
Paul F. Schellhammer, John W. Davis
Bicalutamide Monotherapy as Second-Line Hormonal Therapy The in vitro studies in mutant prostate cancer cells discussed previously suggest that, when a patient experienced progression on flutamide or nilutamide, the tumor may still be responsive to bicalutamide. In a study of patients with different hormone sensitivities, bicalutamide 200 mg resulted in regression or stabilization of bone metastases in 9 of 26 men in whom flutamide therapy had previously failed.31 Patients in whom flutamide therapy had failed often exhibit a PSA response on flutamide withdrawal, known as the flutamide-withdrawal phenomenon. Of the 14 patients studied by Scher et al who did not have a PSA response on flutamide withdrawal, 8 patients (57%) had a stable or decreased PSA level while receiving bicalutamide. Nine of 12 patients (75%) with a PSA response to flutamide withdrawal also had a stable or decreased PSA level that subsequently responded to bicalutamide. The clinical benefits of bicalutamide in terms of bone disease were mainly confined to those exhibiting a PSA response to flutamide withdrawal. In a further study, PSA responses occurred in 22.5% of patients who received bicalutamide 150 mg as second-line therapy.38 These PSA responses were seen almost exclusively in patients who had been treated with a CAB regimen including flutamide. Clinical benefits have also been reported in men in whom conventional hormonal therapy has failed.39 In this phase II study (Southwest Oncology Group 9235), 9 of the 44 patients with adequate PSA data (20%) had a ≥ 50% decrease in PSA levels after the initiation of bicalutamide 150 mg. Responses to flutamide and nilutamide after bicalutamide withdrawal have also been noted.40 The antiandrogens are, in reality, androgen receptor blockers. As such, they are effective in counteracting the effect of the androgen ligand but also have the potential for ligand-independent action, ie, the blockage of cytokines and growth receptors.41,42 These androgen receptor blockers have different chemical structures, as evidenced by their varied side effect profiles and also by the demonstrated therapeutic effect of one blocker in a situation in which another blocker has failed.
Safety and Tolerability of Bicalutamide The tolerability profile of bicalutamide reflects its pharmacology. The most common side effects are gynecomastia and male breast pain.24,26,36,43 The development of gynecomastia during bicalutamide therapy is caused by the blockade of androgenic activity in the male breast and the increase in the peripheral aromatization of androgens to estrogens. In the 2 large pivotal studies of bicalutamide monotherapy, the incidences of gynecomastia and breast pain in patients with M0 disease were 49.4% and 40.1%, respectively,26 whereas in the castration group, the corresponding proportions of patients with these events were 4.4% and 1.9%, respectively. However, only 1.3% of patients with M0 disease in these studies withdrew because of gynecomastia.26 In the EPC studies, 66% of patients reported gynecomastia and 73% reported breast pain.36 Overall, 15.6% of patients in the bicalutamide group withdrew because of these events. This is not unexpected in the adjuvant setting in
which side effects are not as well accepted because of the greater uncertainty of benefits. In patients who withdrew from therapy with these ongoing events, gynecomastia and breast pain improved or resolved in 70% and 90% of cases, respectively. The resolution rate for gynecomastia was dependent on the duration of therapy. For patients who had taken bicalutamide for < 6 months, the resolution rate at 1 year was 64%, but for those treated for > 18 months, the resolution rate was 29%. A blinded placebo-controlled study of the efficacy and tolerability of a single dose of 10 Gy electron beam radiation in reducing the incidence and severity of bicalutamide-induced gynecomastia and breast pain has been conducted.44 The incidence and severity of gynecomastia was significantly reduced. However, a significant reduction in only the severity of breast pain was seen. The irradiation was generally well tolerated, with only transient skin irritation and erythema.44 The efficacy and tolerability of irradiation to treat existing gynecomastia and breast pain has also been investigated. In this open trial, 41 patients received 12 Gy electron beam irradiation in 2 equal fractions on consecutive days. Improvement in gynecomastia or breast pain was seen in approximately 35% of patients, with stabilization in approximately a further 25%.45 The effects of antiestrogens in preventing gynecomastia have been investigated in 2 trials. A blinded randomized US trial showed that use of tamoxifen concurrently with bicalutamide 150 mg significantly reduced the incidence of breast pain or gynecomastia: only 12% of patients experienced gynecomastia or breast pain after 3 months of tamoxifen therapy with bicalutamide, compared with 70% in the bicalutamidealone arm.46 A concern with coadministation of tamoxifen and bicalutamide is an increase in testosterone, which may decrease the efficacy of bicalutamide. Although there was no evidence of impaired tumor control in the 2 studies, as judged by a decrease in PSA levels, long-term clinical outcome data would be needed before tamoxifen could be recommended for long-term administration. In the pivotal monotherapy trials, 13.1% of patients with M0 disease and 10.9% of patients with M1 disease reported hot flashes as an adverse event.26 In the comparative study of bicalutamide and flutamide in the CAB setting, diarrhea was less frequent with bicalutamide, and resulted in few withdrawals, compared with flutamide.19 The incidence of diarrhea was 26% in the flutamide group compared with 12% in the bicalutamide group (P < 0.001) and led to withdrawal in 6% and 0.5% of patients, respectively. In the EPC studies, diarrhea occurred in 6.3% of patients in the bicalutamide group and 6.4% in the placebo group. The problems of alcohol intolerance and loss of light–dark adaptation associated with nilutamide19 are not evident with bicalutamide. Interstitial pneumonitis, also reported with nilutamide,19 has rarely been reported with bicalutamide and no causal relationship has been established.47 Hepatotoxicity, sometimes fatal, has been reported with flutamide.48 In contrast, with bicalutamide, abnormalities in liver function have only occasionally been reported and these either resolved spontaneously or on treatment withdrawal.27,36 To our knowledge, only one case of fatal hepatic failure occurring during bicalutamide therapy has been published, and it seems
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Bicalutamide for Prostate Cancer unlikely that bicalutamide was the causative agent as the patient had only received 2 days therapy with bicalutamide after receiving flutamide treatment for the previous 3 months.49 Osteoporosis is increasingly recognized as a long-term complication of castration.50 Preliminary clinical evidence suggests that bicalutamide does not cause bone loss. Bone density measurements in a small subgroup of men with M0 disease who received continuous treatment for a median of 287 weeks showed no evidence of bone metastases at follow-up and revealed that femoral neck and total hip bone mineral density was close to that expected for their age.26
Regulatory Issues Bicalutamide 50 mg is licensed as a component of CAB worldwide. Bicalutamide 150 mg monotherapy is licensed in more than 57 countries worldwide as an alternative to castration for patients with locally advanced disease for whom immediate hormonal therapy is indicated. As of May 2002, bicalutamide 150 mg has also received regulatory approval in 11 European countries as immediate therapy for patients with localized or locally advanced prostate cancer, who would otherwise be considered candidates for watchful waiting or adjuvant therapy with primary curative intent. Because the US adjuvant trial of bicalutamide in patients at low risk did not show statistically significant benefits, bicalutamide did not receive approval from the Food and Drug Administration when it was sought in 2002. The benefits demonstrated in the non-US trials, which enrolled patients at higher risk, were not deemed transferable to the US population of patients with prostate cancer. Ongoing follow-up of the US trial continues to capture the necessary number of events to permit a meaningful analysis.
Conclusions Because of increased awareness of prostate cancer and improved detection methods, patients are presenting with earlier-stage disease and at a younger age than before. Drug therapy for prostate cancer therefore needs to consider patients’ QOL as well as survival endpoints. The nonsteroidal antiandrogens present novel agents for prostate cancer, interfering with androgen receptor activation by specific competitive blocking at the receptor site. They were developed to negate the effects of testosterone and dihydrotestosterone through a more direct mechanism than agents previously used which altered the hypothalamic-pituitary-gonadal axis by interfering with LH release. Their development illustrates the drive toward better understanding of molecular physiology and the continued development of site- and function-specific molecules to accomplish therapeutic intervention with ever-lessening side-effect profiles. Bicalutamide has been the most extensively studied antiandrogen in clinical trials. It has demonstrated a favorable safety profile, is the least likely to be associated with the paradoxic stimulation of the mutated androgen receptor, has a convenient once-daily dosing schedule, and has therapeutic effects that are challenging the traditional approaches to androgen deprivation in the treatment of all stages of the prostate cancer continuum. Bicalutamide is the only
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antiandrogen with phase III data supporting its use as an alternative to castration in men requiring immediate hormonal monotherapy for locally advanced disease. When CAB is selected for advanced disease, bicalutamide provides the advantage of once-daily dosing and fewer side effects. Bicalutamide can also be used as a salvage regimen in those whose has progressed with other forms of androgen-deprivation therapy.
References 1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004; 54:8-29. 2. Stewart AK, Bland KI, McGinnis LS Jr, et al. Clinical highlights from the National Cancer Data Base, 2000. CA Cancer J Clin 2000; 50:171-183. 3. Campbell T, Blasko J, Crawford ED, et al. Clinical staging of prostate cancer: reproducibility and clarification of issues. Int J Cancer 2001; 96:198-209. 4. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281:1591-1597. 5. Kirby RS. Recent advances in the medical management of prostate cancer. Br J Clin Pract 1996; 50:88-93. 6. Small EJ, Reese DM, Vogelzang NJ. Hormone-refractory prostate cancer: an evolving standard of care. Semin Oncol 1999; 26:61-67. 7. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet 2000; 355:1491-1498. 8. Furr BJ, Tucker H. The preclinical development of bicalutamide: pharmacodynamics and mechanism of action. Urology 1996; 47:13-25. 9. Culig Z, Hoffmann J, Erdel M, et al. Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer 1999; 81:242-251. 10. McLeod DG, Iversen P. Gynecomastia in patients with prostate cancer: a review of treatment options. Urology 2000; 56:713-720. 11. Verhelst J, Denis L, Van Vliet P, et al. Endocrine profiles during administration of the new non-steroidal anti-androgen Casodex in prostate cancer. Clin Endocrinol (Oxf ) 1994; 41:525-530. 12. Tyrrell CJ, Denis L, Newling D, et al. 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; 33:39-53. 13. Cockshott ID, Oliver SD, Young JJ, et al. The effect of food on the pharmacokinetics of the bicalutamide (‘Casodex’) enantiomers. Biopharm Drug Dispos 1997; 18:499-507. 14. Cockshott ID, Cooper KJ, Sweetmore DS, et al. The pharmacokinetics of Casodex in prostate cancer patients after single and during multiple dosing. Eur Urol 1990; 18(suppl 3):10-17. 15. Cockshott ID, Sotaniemi EA, Cooper KJ, et al. The pharmacokinetics of Casodex enantiomers in subjects with impaired liver function. Br J Clin Pharmacol 1993; 36:339-343. 16. Denis L, Mahler C. Pharmacodynamics and pharmacokinetics of bicalutamide: defining an active dosing regimen. Urology 1996; 47:26-28. 17. Kaisary AV. Current clinical studies with a new nonsteroidal antiandrogen, Casodex. Prostate Suppl 1994; 5:27-33. 18. Schellhammer P, Sharifi R, Block N, et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Casodex Combination Study Group. Urology 1995; 45:745-752. 19. Schellhammer PF, Sharifi R, Block NL, et al. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Casodex Combination Study Group. Urology 1997; 50:330-336. 20. Soloway MS. Combined androgen blockade: An optimal therapy for minimally advanced prostate cancer? Br J Urol 1998; 81:87-95. 21. Soloway MS, Schellhammer PF, Sharifi R, et al. Bicalutamide and flutamide, each in combination with luteinizing hormone-releasing hormone analogs in advanced prostate cancer: exploratory analysis of impact of extent of disease by bone scan on outcome. Prostate J 2000;
Paul F. Schellhammer, John W. Davis 2:137-145. 22. Sarosdy MF, Schellhammer PF, Johnson R, et al. Does prolonged combined androgen blockade have survival benefits over short-term combined androgen blockade therapy? Urology 2000; 55:391-395. 23. Bales GT, Chodak GW. A controlled trial of bicalutamide versus castration in patients with advanced prostate cancer. Urology 1996; 47:38-43. 24. 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; 33:447-456. 25. Kaisary AV, Iversen P, Tyrrell CJ, et al. Is there a role for antiandrogen monotherapy in patients with metastatic prostate cancer? Prostate Cancer Prostatic Dis 2001; 4:196-203. 26. 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; 164:1579-1582. 27. Iversen P, Tyrrell CJ, Kaisary AV, et al. Casodex (bicalutamide) 150mg 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; 51:389-396. 28. 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; 87:47-56. 29. Fourcade RO, Chatelain C, Poterre M, et al. An open multicentre randomised study to compare the effect adn safety of 'Casodex' (bicalutamide) 150 mg monotherapy with castration plus nilutamide in metastatic prostate cancer. Eur Urol 1998; 33(suppl 1):88 (Abstract #349). 30. 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 study. J Clin Oncol 1999; 17:2027-2038. 31. Scher HI, Liebertz C, Kelly WK, et al. Bicalutamide for advanced prostate cancer: the natural versus treated history of disease. J Clin Oncol 1997; 15:2928-2938. 32. Fabozzi SJ, Kolm P, Schellhammer PF. PSA response to secondary androgen deprivation following failed treatment of metastatic prostate cancer wtih the antiandrogen casodex. Urol Oncol 1995; 1:64-66. 33. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1998; 351:1451-1467. 34. Chodak GW, Kolvenbag GJ. Will the experience with tamoxifen in breast cancer help define the role of antiandrogens in prostate cancer? Prostate Cancer Prostatic Dis 2001; 4:72-80. 35. See WA, McLeod D, Iversen P, et al. The bicalutamide Early Prostate Cancer Program. Demography. Urol Oncol 2001; 6:43-47. 36. See WA, Wirth MP, McLeod D, et al. Bicalutamide (‘Casodex’) 150
37.
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40. 41. 42.
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45. 46. 47. 48. 49. 50.
mg 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 [Published errata appear in: J Urol 2002; 2168:2558. J Urol 2002; 2168 (Pt 1):1510]. J Urol 2002; 168:429-435. Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999; 341:1781-1788. Joyce R, Fenton MA, Rode P, et al. High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy. J Urol 1998; 159:149-153. Kucuk O, Fisher E, Moinpour CM, et al. Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: a Southwest Oncology Group study (SWOG 9235). Urology 2001; 58:53-58. Kassouf W, Tanguay S, Aprikian AG. Nilutamide as second line hormone therapy for prostate cancer after androgen ablation fails. J Urol 2003; 169:1742-1744. Bruchovsky N, Klotz LH, Sadar M, et al. Intermittent androgen suppression for prostate cancer: Canadian Prospective Trial and related observations. Mol Urol 2000; 4:191-199. Sadar MD. Androgen-independent induction of prostate-specific antigen gene expression via cross-talk between the androgen receptor and protein kinase A signal transduction pathways. J Biol Chem 1999; 274:7777-7783. McLeod DG. Tolerability of nonsteroidal antiandrogens in the treatment of advanced prostate cancer. Oncologist 1997; 2:18-27. Payne H, Tyrrell C, Bakke A, et al. Prophylactic breast irradiation significantly reduces the incidence of bicalutamide (‘Casodex’)-induced gynecomastia. Int J Radiat Oncol Biol Phys 2002; 54(suppl):135-156 (Abstract #230). Van Poppel H, Tyrrell C, Van Cangh P, et al. Efficacy and tolerability of radiotherapy as treatment for bicalutamide-induced breast pain and gynaecomastia in prostate cancer. Eur J Cancer Suppl 2003; 1:S265. Saltzstein D, Cantwell A, Sieber P, et al. Prophylactic tamoxifen significantly reduces the incidence of bicalutamide-induced gynaecomastia and breast pain. BJU Int 2002; 90(suppl 2):120-121. McCaffrey JA, Scher HI. Interstitial pneumonitis following bicalutamide treatment for prostate cancer. J Urol 1998; 160:131. Wysowski DK, Fourcroy JL. Flutamide hepatotoxicity. J Urol 1996; 155:209-212. Dawson LA, Chow E, Morton G. Fulminant hepatic failure associated with bicalutamide. Urology 1997; 49:283-284. Daniell HW, Dunn SR, Ferguson DW, et al. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000; 163:181-186.
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An Evaluation of Bicalutamide in the Treatment of Prostate Cancer Paul F. Schellhammer John W. Davis Department of Urology Eastern Virginia Medical School and Virginia Prostate Center, Norfolk
Clinical Prostate Cancer, Vol. 2, No. 4, 213-219, 2004 Key words: Antiandrogens, Gynecomastia, Monotherapy, Quality of life
Submitted: Sep 8, 2003; Revised: Dec 17, 2003; Accepted: Dec 19, 2003 Address for correspondence: Paul F. Schellhammer, MD Department of Urology Eastern Virginia Medical School 633 Center Drive, #16 Norfolk, VA 25502 Fax: 757-962-8020 e-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1540-0352, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Abstract Although prostate cancer is traditionally considered a disease of old age, improved diagnostic techniques have resulted in early diagnosis, and many men are now treated while still physically and sexually active. Current therapies for prostate cancer often include medical or surgical castration, which cause adverse effects on physical and sexual function; therefore, greater attention has been focused on quality of life. The nonsteroidal antiandrogen bicalutamide is an effective agent with a favorable tolerability profile and, in some settings, represents an alternative to castration. Mature survival data reveal that bicalutamide monotherapy provides survival benefits for untreated locally advanced disease that do not differ significantly from those of castration and maintains better physical capacity and sexual interest. Recent data from a prospective randomized trial demonstrate that bicalutamide given as immediate therapy, either alone or as adjuvant to therapy of curative intent, significantly reduces the risk of objective disease progression in patients with localized or locally advanced prostate cancer. Antiandrogens are also used in combination with castration, a treatment known as combined androgen blockade (CAB), for advanced disease. A randomized trial demonstrated that CAB with bicalutamide is associated with similar survival outcome to CAB with flutamide and is better tolerated. Current evidence demonstrates that bicalutamide currently has a favorable risk–benefit ratio in several stages of prostate cancer and that the role of bicalutamide will be further defined by ongoing studies.
Introduction Prostate cancer is a considerable health problem among older men that causes significant morbidity and mortality. In the United States, the prostate cancer incidence for 2004 is projected at 230,110, with cancer mortality at an estimated 29,900 deaths.1 Early prostate cancer is generally asymptomatic. The prevalence of prostate-specific antigen (PSA) screening and early detection has resulted in earlier diagnosis.2 The most recent data from the National Cancer Database reveal that nearly 80% of men diagnosed with prostate cancer in the United States have stage T1/2 tumors. However, the reproducibility of current staging methods is often unreliable and does not consider important variables such as PSA levels and Gleason grade, and the clinical disease stage is often not indicative of pathologic stage or the activity of the disease.3 Indeed, as many as 50% of men with clinically localized disease are actually found to have more advanced disease when they undergo pathological staging after radical surgery.4 The mainstay of treatment for failures of local therapy and advanced disease is immediate or delayed androgen deprivation. This has been achieved by surgical or medical castration, alone or in combination with an antiandrogen, the latter of which is known as combined androgen
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Bicalutamide for Prostate Cancer blockade (CAB).5 Other than antiandrogen withdrawal when CAB is initially used, there is no standard treatment for patients who have disease progression after first-line hormonal therapy. Further hormonal manipulation or chemotherapy are the therapeutic options.6 The rationale for CAB is based on the finding that, although medical and surgical castration reduce serum testosterone levels by approximately 95%, the intraprostatic level of dihydrotestosterone (DHT), the principal mediator of androgenic activity, is less affected. This is because of the conversion of androgens of adrenal origin to DHT in prostatic cells. The addition of the antiandrogen blocks the actions of these adrenal androgens at the receptor level. An overview of CAB trials recently conducted by the Prostate Cancer Clinical Trialists’ Collaborative Group, involved 27 trials and 8275 patients treated for ≥ 1 year.7 The difference in absolute survival at 5 years was 1.8%, favoring CAB. This difference increased to 2.9% when only trials using nonsteroidal antiandrogens were analyzed. It was concluded that survival cannot be substantially worse for CAB with nonsteroidal antiandrogens than for castration alone, but the gain in survival cannot be better than 5% and is more likely to be between 2% and 3%. Although this advantage negated the excessive optimism initially associated with CAB, the trialists warned against excessive pessimism. They raised the question that if CAB does improve survival by 2%-3%, greater improvements might be achieved with more effective hormonal regimens, particularly if methods of identifying those prostate cancers most likely to respond to prolonged hormonal manipulation become available. Characterization of genomes and proteomes of individual cancers may provide signature profiles that define relative susceptibility to specific interventions.
Pharmacology of Antiandrogens or Androgen Receptor Blockers Antiandrogens block the effects of androgens irrespective of their origin and offer an alternative therapeutic strategy to castration. Chemically, the antiandrogens are classified as steroidal or nonsteroidal compounds. Three nonsteroidal antiandrogens are currently available: flutamide, nilutamide, and bicalutamide. This article focuses on bicalutamide, the most extensively studied antiandrogen. Bicalutamide is an orally active nonsteroidal antiandrogen that is devoid of other endocrine effects. It is an androgen receptor blocker and therefore competitively antagonizes the actions of androgens and other ligands at the receptor level, thereby inhibiting the growth of prostate tumors. Bicalutamide does not act as an agonist or antagonist at other hormone receptors.8 In vitro studies have revealed that, in contrast to flutamide and nilutamide, bicalutamide remains an effective antiandrogen in most mutant prostate cancer cell lines. A recent study, however, has demonstrated that bicalutamide has agonist properties in LNCaP cells that have been subjected to long-term androgen ablation.9 Bicalutamide antagonizes the peripheral and central androgen receptors, thereby blocking the negative feedback mechanism regulating testosterone production.10 Consequently, plasma luteinizing hormone (LH) and testosterone concentrations
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increase during bicalutamide therapy.11,12 Plasma testosterone concentrations are, however, maintained within the normal range because of the peripheral aromatization of excess androgens to estrogens and the negative feedback these estrogens provide. Bicalutamide is well absorbed after oral administration and may be given with or without food.13 The mean elimination half-life of bicalutamide is approximately 7 days and is therefore compatible with once-daily dosing.12,14 The clearance of bicalutamide occurs predominantly by hepatic metabolism. The pharmacokinetics of bicalutamide is not affected by age, renal function, or mild to moderate hepatic impairment.12,14,15 Bicalutamide is highly bound to plasma proteins. Of clinical interest are in vitro studies that have demonstrated that bicalutamide may displace warfarin from its protein-binding sites.16 Patients undergoing anticoagulation with warfarin should therefore have their prothrombin times closely monitored after initiation of bicalutamide therapy. Bicalutamide has the potential to be an effective treatment option for many stages of hormone-sensitive prostate cancer. The initial dose-finding studies of bicalutamide conducted in the pre-PSA era used a 50% decrease in prostatic acid phosphatase (PAP) level as a surrogate endpoint for clinical activity. In these studies, the proportions of patients receiving bicalutamide 10, 30, and 50 mg who had decreases in PAP of ≥ 50% were 33%, 53%, and 83%, respectively.16 Accordingly, a dose of 50 mg was selected for further studies, both as a component of CAB and as monotherapy. Subsequently, during phase II studies, the more sensitive and specific tumor marker of PSA became available, and the response to bicalutamide in terms of PSA reduction was found to be related to dose in the range of 10-200 mg.12 The 150-mg dose was subsequently chosen for development as monotherapy based on the observation that the PSA response, a > 92% reduction, after 3 months of treatment at this dose level was comparable to that seen in patients who had undergone surgical castration.17
Bicalutamide as a Component of Combined Androgen Blockade Combined androgen blockade with bicalutamide has not been compared with castration alone. However, the comparative efficacy of bicalutamide (50 mg per day) and flutamide (250 mg 3 times a day), both in combination with an LHreleasing hormone (LHRH) agonist, has been evaluated in a large, randomized phase III study involving 813 men with metastatic (stage M1) disease.18,19 Mature data (55% deaths) from this study were presented after a median follow-up of 160 weeks. Although no statistically significant differences in disease outcomes were noted, some trends are notable. Men randomized to receive bicalutamide had a 13% lower risk of dying compared with those randomized to flutamide (hazard risk [HR], 0.87; 95% CI, 0.72-1.05; P = 0.15)19 and median survival was extended by 32 weeks in the bicalutamide group (180 weeks vs. 148 weeks). There were no consistent differences between the 2 antiandrogens in their effect on quality of life (QOL) measures. The incidence of diarrhea and the number of withdrawals from treatment because of diarrhea was significantly greater in the flutamide group.
Paul F. Schellhammer, John W. Davis
Bicalutamide Monotherapy in Previously Untreated Advanced Disease Three studies initially evaluated the efficacy of bicalutamide monotherapy at the 50-mg dose for patients with metastatic disease. Although clinical benefits were seen, the benefits of daily bicalutamide doses of 50 mg were inferior to those of castration.23 Subsequently, based on dose-ranging studies of 50-200 mg, as already described, daily bicalutamide 150 mg was evaluated against castration (bilateral orchiectomy or goserelin acetate 3.6 mg every 28 days) in 2 large randomized phase III studies of similar design in men with locally advanced (M0) or stage M1 disease. Survival data of patients with M1 disease (n = 805) were considered mature at a median follow-up of 1.9 years.24 There was a statistically significant difference in overall survival in favor of castration (HR, 1.30; 95% CI, 1.04-1.64; P = 0.02) in these patients, although the difference in estimated median survival was only 42 days (737 days vs. 779 days). A post hoc analysis revealed that bicalutamide 150 mg and castration provided similar survival outcomes in patients with pretreatment PSA levels of ≤ 400 ng/mL. The disadvantage for bicalutamide, therefore, was apparent only in men with the highest tumor burdens at study entry.25 In the M0 subgroup (n = 480), survival data were mature at a median follow-up of 6.3 years (56% deaths). Overall survival did not differ significantly between the bicalutamide 150-mg monotherapy and castration groups (HR, 1.05; 95% CI, 0.811.36; P = 0.70; Figure 1).26 At median follow-up, when 77% of the patients had experienced disease progression, there was no statistically significant difference in time to progression between the 2 groups (HR, 1.20; 95% CI, 0.96-1.51; P = 0.11). The relative impact of bicalutamide monotherapy and castration on QOL was evaluated in these pivotal bicalutamide 150-mg monotherapy trials. Ten domains of QOL were assessed using a validated questionnaire: physical capacity, emotional well being, sexual interest, sexual function, vitality, social function, pain, activity limitation, bed disability, and overall health. Separate
Figure 1 Overall Survival in Patients with Prostate Cancer: Castration Versus Bicalutamide26
100 90 80
Survival Rate (%)
Data indicate that the efficacy of CAB or any form of androgen deprivation may depend on extent of disease. Patients with minimal metastatic disease derive the greatest survival benefit.20 An exploratory analysis of this phase III trial of 813 patients confirmed these findings and also revealed a trend toward longer survival with bicalutamide compared with flutamide in patients with minimal metastatic disease (HR, 0.79; 95% CI, 0.591.07).21 Other exploratory analyses conducted for this trial population revealed outcomes of interest. Prolonged (> 120 days) CAB conferred significant survival benefits compared with shortterm CAB (HR, 0.275; P = 0.0001).22 As early deaths could result in bias (because the patients could not receive prolonged therapy), a further analysis was conducted in patients who lived ≥ 2 years after study entry. In these patients, prolonged CAB increased median survival. These findings suggest that, for some patients, improved survival with CAB is not, as has been suggested, caused solely by blockade of the flare phenomenon that can occur in the early stages of LHRH agonist therapy.
70 60 50 40 30 20 10 0
Castration Bicalutamide 150 mg
P = 0.70
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Time to Death (Days) Reproduced with permission from Iversen P et al. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol 2000; 164:1579-1582.
analyses of the QOL data were performed at 12 months after randomization for patients with M0 and M1 disease. In patients with M0 disease, bicalutamide showed a significant advantage compared with castration in the domains of physical capacity (P = 0.046) and sexual interest (P = 0.029).27 A post hoc analysis of data on sexual interest was undertaken excluding patients with no sexual interest at study entry. In this exploratory analysis, 64% of those randomized to bicalutamide retained some interest in sex during the first 12 months of the study compared with only 30% of the castration group (P < 0.01).28 The maintenance of sexual interest is explained as follows. Animal experiments suggest that male sex drive is modulated, either directly or indirectly, by the metabolites of testosterone (such as estrogens) rather than by circulating androgens.28 Indeed, it is unlikely that the benefits of bicalutamide on sexual interest could be a direct result of the maintenance of normal testosterone levels, as the administration of a nonsteroidal antiandrogen would negate the effects of circulating androgens by blockade of the hypothalamic androgen receptors. However, the levels of androgen metabolites and their actions would not be affected by the blockade of androgen receptors by bicalutamide. Bicalutamide 150-mg monotherapy has also been compared with different CAB regimens in 2 smaller trials conducted in France and Italy.29,30 In the French study, 235 patients, 93% of whom had M1 disease, were randomized to bicalutamide 100 mg or 150 mg or CAB (goserelin acetate or surgical castration, both in combination with nilutamide 300 mg).29 In the Italian study, 49.5% of the 220 patients had M0 disease at study entry, and CAB consisted of goserelin acetate 3.6 mg plus flutamide 750 mg.30 With relatively short median follow-up times in these 2 trials of 32 and 38 months, respectively, survival between CAB and bicalutamide 150 mg monotherapy was not significantly different. Monotherapy with bicalutamide of 150 mg provides a comparable survival outcome to castration in patients with M0 disease but has less impact on sexual interest. This finding is of consid-
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Bicalutamide for Prostate Cancer
Figure 2 Disease-Free Progression in Patients with Prostate Cancer: Bicalutamide Versus
Placebo36
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200
400
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P < 0.0001
1000
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1400
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Time (Days) Reproduced with permission from See WA et al. Bicalutamide (‘Casodex’) 150 mg 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 [Published errata appear in: J Urol 2002; 2168:2558; J Urol 2002; 2168(Pt 1):1510]. J Urol 2002; 168:429-435.
erable clinical interest. Sexual activity is unlikely in the absence of sexual interest, and although sexual dysfunction can be treated, there are currently no effective therapies for low libido. Maintenance of physical capacity, which reflects the ability of the patient to take part in the normal activities of daily living such as walking, dressing, bathing, shopping, and bending, is also a vital dimension of QOL. Patients who have disease progression during bicalutamide monotherapy have been found to respond to subsequent medical or surgical castration. Scher and colleagues reported that 33% of those who had progression with bicalutamide 200 mg (n = 15) had a > 80% decrease in PSA level for a median of 6 months after the addition of an LHRH agonist.31 Likewise, of the 23 patients with M1 disease studied by Fabozzi et al, 14 patients (61%) demonstrated a ≥ 50% decrease in PSA level when castration was used after failure of bicalutamide 50 mg.32 Upon progression after monotherapy, some tumors may still be responsive to further hormonal manipulation.
Bicalutamide as Immediate Therapy in Early-Stage Prostate Cancer Adjuvant hormonal therapy with the antiestrogen tamoxifen improves survival in women with early-stage breast cancer,33 and it has been postulated that adjuvant antiandrogen therapy may confer similar benefits in early-stage prostate cancer.34 Based on this rationale, the use of bicalutamide 150 mg after interventions of curative intent, such as radical prostatectomy, radiation therapy, and watchful waiting for patients with early (localized or locally advanced) prostate cancer and those deemed suitable for surveillance (watchful waiting), is being explored in the bicalutamide Early Prostate Cancer (EPC) program.35 This program is the largest treatment study to date in patients with prostate cancer and comprises 3 ongoing, randomized, double-blind, placebo-controlled clinical trials involving 8113 men. The 3 trials are being conducted in various geo-
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graphic regions: North America (n = 3292); Europe, South Africa, Israel, Australia, and Mexico (n = 3603); and Scandinavia (n = 1218). Patients were randomized to receive adjuvant bicalutamide 150 mg or placebo once daily after surgery or irradiation or the initiation of a surveillance strategy or watchful waiting. There were some differences in entry criteria for the 3 studies. In the North American trial, patients must have undergone either radical prostatectomy or radiation therapy, whereas in the other 2 trials, men considered appropriate for watchful waiting were also eligible. Men with lymph node involvement were excluded from the North American trial but could be included in the other 2 trials. Treatment duration also differs by study. In the North American trial, the duration of randomized treatment is 2 years, whereas in the other trials it is ≥ 5 years with the option of indefinite treatment. The primary endpoints of the trial are time to objective progression and overall survival. The results of the first combined analysis of these trials have recently been analyzed with a minimum of 2 years of follow-up (median, 3 years).36 Treatment with bicalutamide 150 mg provided a 42% reduction in the risk of objective progression compared with standard care alone (9.0% vs. 13.8%; HR, 0.58; 95% CI, 0.510.66; P < 0.0001; Figure 2). Reductions in the risk of disease progression were seen across the patient population, irrespective of primary treatment or disease stage. Patients in the EPC program were scheduled to have bone scans at 2 years, or earlier if clinically indicated. Overall, the risk of developing bone metastases (defined as a positive bone scan or death) within 2 years of randomization was reduced by 33% in the bicalutamide group compared with the standard care–alone group (P < 0.0001). The survival endpoint is immature, as at the time of this analysis only 6% of the study population had died. Patients on trial and their physicians remained blinded to their treatment arm and they continue follow-up for progression and the critical survival endpoint. The EPC program is unique in that it is the first large prospective study of adjuvant hormonal therapy in men undergoing radical prostatectomy. More than 4000 patients in the EPC program, representing approximately 55% of the study population, underwent radical prostatectomy. Other randomized data on adjuvant therapy in this setting are limited, with only Messing and colleagues reporting survival outcome.37 This was a small study (n = 98) involving men with clinically localized disease who were found to have lymph node metastases at surgery. Survival data reported at a median follow-up of 7.1 years showed a significant advantage with respect to overall and disease-specific survival for immediate hormonal therapy (medical or surgical castration) compared with therapy deferred until clinical progression. Because the men in the North American trial had node-negative disease, many with clinical T1c-T2a and pathologic T2 disease, long-term follow-up will be necessary before survival outcomes and any differences between arms will be available. These endpoints will occur earlier in the other trials, in which patients with node-positive and more advanced N0 disease were enrolled.
Paul F. Schellhammer, John W. Davis
Bicalutamide Monotherapy as Second-Line Hormonal Therapy The in vitro studies in mutant prostate cancer cells discussed previously suggest that, when a patient experienced progression on flutamide or nilutamide, the tumor may still be responsive to bicalutamide. In a study of patients with different hormone sensitivities, bicalutamide 200 mg resulted in regression or stabilization of bone metastases in 9 of 26 men in whom flutamide therapy had previously failed.31 Patients in whom flutamide therapy had failed often exhibit a PSA response on flutamide withdrawal, known as the flutamide-withdrawal phenomenon. Of the 14 patients studied by Scher et al who did not have a PSA response on flutamide withdrawal, 8 patients (57%) had a stable or decreased PSA level while receiving bicalutamide. Nine of 12 patients (75%) with a PSA response to flutamide withdrawal also had a stable or decreased PSA level that subsequently responded to bicalutamide. The clinical benefits of bicalutamide in terms of bone disease were mainly confined to those exhibiting a PSA response to flutamide withdrawal. In a further study, PSA responses occurred in 22.5% of patients who received bicalutamide 150 mg as second-line therapy.38 These PSA responses were seen almost exclusively in patients who had been treated with a CAB regimen including flutamide. Clinical benefits have also been reported in men in whom conventional hormonal therapy has failed.39 In this phase II study (Southwest Oncology Group 9235), 9 of the 44 patients with adequate PSA data (20%) had a ≥ 50% decrease in PSA levels after the initiation of bicalutamide 150 mg. Responses to flutamide and nilutamide after bicalutamide withdrawal have also been noted.40 The antiandrogens are, in reality, androgen receptor blockers. As such, they are effective in counteracting the effect of the androgen ligand but also have the potential for ligand-independent action, ie, the blockage of cytokines and growth receptors.41,42 These androgen receptor blockers have different chemical structures, as evidenced by their varied side effect profiles and also by the demonstrated therapeutic effect of one blocker in a situation in which another blocker has failed.
Safety and Tolerability of Bicalutamide The tolerability profile of bicalutamide reflects its pharmacology. The most common side effects are gynecomastia and male breast pain.24,26,36,43 The development of gynecomastia during bicalutamide therapy is caused by the blockade of androgenic activity in the male breast and the increase in the peripheral aromatization of androgens to estrogens. In the 2 large pivotal studies of bicalutamide monotherapy, the incidences of gynecomastia and breast pain in patients with M0 disease were 49.4% and 40.1%, respectively,26 whereas in the castration group, the corresponding proportions of patients with these events were 4.4% and 1.9%, respectively. However, only 1.3% of patients with M0 disease in these studies withdrew because of gynecomastia.26 In the EPC studies, 66% of patients reported gynecomastia and 73% reported breast pain.36 Overall, 15.6% of patients in the bicalutamide group withdrew because of these events. This is not unexpected in the adjuvant setting in
which side effects are not as well accepted because of the greater uncertainty of benefits. In patients who withdrew from therapy with these ongoing events, gynecomastia and breast pain improved or resolved in 70% and 90% of cases, respectively. The resolution rate for gynecomastia was dependent on the duration of therapy. For patients who had taken bicalutamide for < 6 months, the resolution rate at 1 year was 64%, but for those treated for > 18 months, the resolution rate was 29%. A blinded placebo-controlled study of the efficacy and tolerability of a single dose of 10 Gy electron beam radiation in reducing the incidence and severity of bicalutamide-induced gynecomastia and breast pain has been conducted.44 The incidence and severity of gynecomastia was significantly reduced. However, a significant reduction in only the severity of breast pain was seen. The irradiation was generally well tolerated, with only transient skin irritation and erythema.44 The efficacy and tolerability of irradiation to treat existing gynecomastia and breast pain has also been investigated. In this open trial, 41 patients received 12 Gy electron beam irradiation in 2 equal fractions on consecutive days. Improvement in gynecomastia or breast pain was seen in approximately 35% of patients, with stabilization in approximately a further 25%.45 The effects of antiestrogens in preventing gynecomastia have been investigated in 2 trials. A blinded randomized US trial showed that use of tamoxifen concurrently with bicalutamide 150 mg significantly reduced the incidence of breast pain or gynecomastia: only 12% of patients experienced gynecomastia or breast pain after 3 months of tamoxifen therapy with bicalutamide, compared with 70% in the bicalutamidealone arm.46 A concern with coadministation of tamoxifen and bicalutamide is an increase in testosterone, which may decrease the efficacy of bicalutamide. Although there was no evidence of impaired tumor control in the 2 studies, as judged by a decrease in PSA levels, long-term clinical outcome data would be needed before tamoxifen could be recommended for long-term administration. In the pivotal monotherapy trials, 13.1% of patients with M0 disease and 10.9% of patients with M1 disease reported hot flashes as an adverse event.26 In the comparative study of bicalutamide and flutamide in the CAB setting, diarrhea was less frequent with bicalutamide, and resulted in few withdrawals, compared with flutamide.19 The incidence of diarrhea was 26% in the flutamide group compared with 12% in the bicalutamide group (P < 0.001) and led to withdrawal in 6% and 0.5% of patients, respectively. In the EPC studies, diarrhea occurred in 6.3% of patients in the bicalutamide group and 6.4% in the placebo group. The problems of alcohol intolerance and loss of light–dark adaptation associated with nilutamide19 are not evident with bicalutamide. Interstitial pneumonitis, also reported with nilutamide,19 has rarely been reported with bicalutamide and no causal relationship has been established.47 Hepatotoxicity, sometimes fatal, has been reported with flutamide.48 In contrast, with bicalutamide, abnormalities in liver function have only occasionally been reported and these either resolved spontaneously or on treatment withdrawal.27,36 To our knowledge, only one case of fatal hepatic failure occurring during bicalutamide therapy has been published, and it seems
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Bicalutamide for Prostate Cancer unlikely that bicalutamide was the causative agent as the patient had only received 2 days therapy with bicalutamide after receiving flutamide treatment for the previous 3 months.49 Osteoporosis is increasingly recognized as a long-term complication of castration.50 Preliminary clinical evidence suggests that bicalutamide does not cause bone loss. Bone density measurements in a small subgroup of men with M0 disease who received continuous treatment for a median of 287 weeks showed no evidence of bone metastases at follow-up and revealed that femoral neck and total hip bone mineral density was close to that expected for their age.26
Regulatory Issues Bicalutamide 50 mg is licensed as a component of CAB worldwide. Bicalutamide 150 mg monotherapy is licensed in more than 57 countries worldwide as an alternative to castration for patients with locally advanced disease for whom immediate hormonal therapy is indicated. As of May 2002, bicalutamide 150 mg has also received regulatory approval in 11 European countries as immediate therapy for patients with localized or locally advanced prostate cancer, who would otherwise be considered candidates for watchful waiting or adjuvant therapy with primary curative intent. Because the US adjuvant trial of bicalutamide in patients at low risk did not show statistically significant benefits, bicalutamide did not receive approval from the Food and Drug Administration when it was sought in 2002. The benefits demonstrated in the non-US trials, which enrolled patients at higher risk, were not deemed transferable to the US population of patients with prostate cancer. Ongoing follow-up of the US trial continues to capture the necessary number of events to permit a meaningful analysis.
Conclusions Because of increased awareness of prostate cancer and improved detection methods, patients are presenting with earlier-stage disease and at a younger age than before. Drug therapy for prostate cancer therefore needs to consider patients’ QOL as well as survival endpoints. The nonsteroidal antiandrogens present novel agents for prostate cancer, interfering with androgen receptor activation by specific competitive blocking at the receptor site. They were developed to negate the effects of testosterone and dihydrotestosterone through a more direct mechanism than agents previously used which altered the hypothalamic-pituitary-gonadal axis by interfering with LH release. Their development illustrates the drive toward better understanding of molecular physiology and the continued development of site- and function-specific molecules to accomplish therapeutic intervention with ever-lessening side-effect profiles. Bicalutamide has been the most extensively studied antiandrogen in clinical trials. It has demonstrated a favorable safety profile, is the least likely to be associated with the paradoxic stimulation of the mutated androgen receptor, has a convenient once-daily dosing schedule, and has therapeutic effects that are challenging the traditional approaches to androgen deprivation in the treatment of all stages of the prostate cancer continuum. Bicalutamide is the only
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antiandrogen with phase III data supporting its use as an alternative to castration in men requiring immediate hormonal monotherapy for locally advanced disease. When CAB is selected for advanced disease, bicalutamide provides the advantage of once-daily dosing and fewer side effects. Bicalutamide can also be used as a salvage regimen in those whose has progressed with other forms of androgen-deprivation therapy.
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