CASODEX generic
Substance: bicalutamide

Bibliography and References. Review.
List of selected scientific articles (abstracts). Experimental and clinical data.

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Hinyokika Kiyo. 2005 Mar;51(3):211-4.
Successful recovery from interstitial pneumonitis, induced by bicalutamide and leuprorelin acetate given as treatment for prostate cancer.
Shioi K, Sakai N, Yoshida M, Nakamura M.
Department of Urology, Yokosuka Hokubu Kyosai Hospital.

We report a case of interstitial pneumonitis induced by bicalutamide and/or leuprorelin acetate given as therapy for prostate cancer, in which the pneumonitis was successfully managed by steroid treatment. Steroids were given promptly on the day following onset of pneumonitis, and the patient (72 years old) recovered almost completely within one and a half months. Interstitial pneumonitis, induced by hormone treatment given for prostate cancer, is a reversible condition and a quick diagnosis followed by prompt, proper treatment is important to ensure a successful recovery. The patient had been free of interstitial pneumonitis for 14 months, but died of pneumothorax.

Clin Prostate Cancer. 2005 Mar;3(4):215-9.
Combined androgen blockade: the case for bicalutamide.
Klotz L, Schellhammer P.
Sunnybrook & Women's College Health Sciences Centre University of Toronto, Canada; e-mail: laurence.klotz@sw.ca.

Combination therapy consists of castration plus an antiandrogen. Following medical or surgical castration, the androgen receptor can be activated by adrenal androgens, low levels of residual testosterone, and ligand-independent activators. The survival benefit of combination therapy compared with castration alone is one of the most studied questions in urology. Results from trials comparing combination therapy to castration alone are variable. A metaanalysis of 26 randomized trials indicated that the type of antiandrogen used is relevant. Combination therapy using nonsteroidal antiandrogens was associated with a statistically significant overall survival benefit. In contrast, combination therapy using steroidal antiandrogens was associated with reduced survival compared with castration alone. Bicalutamide 50 mg has a number of advantages compared with nilutamide and flutamide when used in combination with castration. These include an improved side-effect profile, once-daily dosing, more potent inhibition of androgen-independent activation of the androgen receptor through favorable interactions with nuclear coactivators and corepressors, and evidence for improved survival in one randomized trial. An analysis combining historic trial data suggests that bicalutamide 50 mg in addition to androgen deprivation may reduce the hazard ratio (HR) for prostate cancer mortality by 20% (HR, 0.80; 95% CI, 0.66-0.98).

Int J Cancer. 2005 Feb 7; [Epub ahead of print]
Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro.
Festuccia C, Gravina GL, Angelucci A, Millimaggi D, Muzi P, Vicentini C, Bologna M.
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.

Progression from an androgen-dependent to an androgen-independent state often occurs in patients with prostate cancer (PCa) who undergo hormonal therapy. We have investigated whether inhibition of the epidermal growth factor receptor (EGFR) signaling pathway affects the antitumor effect of a nonsteroidal antiandrogen. Gefitinib (Iressa), an EGFR tyrosine kinase inhibitor, and bicalutamide (Casodex), a nonsteroidal antiandrogen [androgen receptor (AR) antagonist], were administered alone and in combination to AR-positive human PCa cell lines. FACS analysis showed lower EGFR expression levels on AR-positive cells (LNCaP, CWR22, CWR22R 2152 and AR-transfected DU145 cell lines) compared with AR-negative cells (DU145, PC3 and TSU-Pr1). Moreover, in AR-transfected DU145 cells, chronic treatment with bicalutamide increased EGFR expression to levels similar to androgen-independent DU145 cells. All AR-positive PCa cell lines were sensitive to gefitinib (IC(50) = 0.1-0.6 muM), whereas higher concentrations of bicalutamide were needed to reduce AR-positive PCa cell line proliferation (IC(50) = 0.8-2.0 muM). Low doses of gefitinib increased the antitumor effects of bicalutamide by strongly reducing the IC(50) of bicalutamide (approximately 10-fold). Similarly, bicalutamide increased the antiproliferative effects of gefitinib by reducing the IC(50) of gefitinib (approximately 5-fold). Taken together, our data suggest that in androgen-dependent cell lines, addition of gefitinib in combination with bicalutamide results in concurrent dual inhibition of AR and EGFR/HER2 pathways. This causes a significant delay in the onset of EGFR-driven androgen independence. (c) 2005 Wiley-Liss, Inc.

J Clin Oncol. 2005 Feb 1;23(4):808-15.
Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer.
Boccardo F, Rubagotti A, Battaglia M, Di Tonno P, Selvaggi FP, Conti G, Comeri G, Bertaccini A, Martorana G, Galassi P, Zattoni F, Macchiarella A, Siragusa A, Muscas G, Durand F, Potenzoni D, Manganelli A, Ferraris V, Montefiore F.
University and National Cancer Research Institute, University of Genoa, Genoa, Italy. f.boccardo@unige.it

PURPOSE: To determine whether tamoxifen or anastrozole prevents gynecomastia and breast pain caused by bicalutamide (150 mg) without compromising efficacy, safety, or sexual functioning. PATIENTS AND METHODS: A double-blind, placebo-controlled trial was performed in patients with localized, locally advanced, or biochemically recurrent prostate cancer. Patients (N = 114) were randomly assigned to either bicalutamide (150 mg/d) plus placebo or in combination with tamoxifen (20 mg/d) or anastrozole (1 mg/d) for 48 weeks. Gynecomastia, breast pain, prostate-specific antigen (PSA), sexual functioning, and serum levels of hormones were assessed. RESULTS: Gynecomastia developed in 73% of patients in the bicalutamide group, 10% of patients in the bicalutamide-tamoxifen group, and 51% of patients in the bicalutamide-anastrozole group (P < .001); breast pain developed in 39%, 6%, and 27% of patients, respectively (P = .006). Baseline PSA level decreased by > or = 50% in 97%, 97%, and 83% of patients in the bicalutamide, bicalutamide-tamoxifen, and bicalutamide-anastrozole groups, respectively (P = .07); and adverse events were reported in 37%, 35%, and 69% of patients, respectively (P = .004). There were no major differences among treatments in sexual functioning parameters from baseline to month 6. Elevated testosterone levels occurred in each group; however, free testosterone levels remained unchanged in the bicalutamide-tamoxifen group because of increased sex hormone-binding globulin levels. CONCLUSION: Anastrozole did not significantly reduce the incidence of bicalutamide-induced gynecomastia and breast pain. In contrast, tamoxifen was effective, without increasing adverse events, at least in the short-term follow-up. These data support the need for a larger study to determine any effect on mortality.

Prostate Cancer Prostatic Dis. 2005 Feb 01.
Prevention and management of bicalutamide-induced gynecomastia and breast pain: randomized endocrinologic and clinical studies with tamoxifen and anastrozole.
Saltzstein D, Sieber P, Morris T, Gallo J.
1Urology San Antonio Research PA, Pasteur Medical Plaza, San Antonio, Texas, USA.

A randomized, double-blind, placebo-controlled multicenter trial involving 107 men receiving bicalutamide ('Casodex') 150 mg/day therapy following radical therapy for prostate cancer assessed tamoxifen ('Nolvadex') 20 mg/day and anastrozole ('Arimidex') 1 mg/day for the prophylaxis and treatment of gynecomastia/breast pain. Tamoxifen, but not anastrozole, significantly reduced the incidence of gynecomastia/breast pain when used prophylactically and therapeutically. Serum testosterone levels increased with tamoxifen relative to placebo but prostate-specific antigen levels declined in all treatment groups. Further studies are needed to define the optimum tamoxifen dose and to assess any impact on cancer control. The use of tamoxifen in this setting remains to be investigated.Prostate Cancer and Prostatic Diseases advance online publication, 1 February 2005; doi:10.1038/sj.pcan.4500782.

Prostate Cancer Prostatic Dis. 2005 Feb 15.
Bicalutamide vs cyproterone acetate in preventing flare with LHRH analogue therapy for prostate cancer-a pilot study.
Sugiono M, Winkler MH, Okeke AA, Benney M, Gillatt DA.
1Bristol Urological Institute, Southmead Hospital, UK.

Objective: To evaluate the efficacy of bicalutamide vs cyproterone acetate in preventing PSA flare (as a surrogate for tumour flare) for patients requiring luteinizing hormone-releasing hormone (LHRH) analogue therapy for prostate cancer.Patients and Methods: In this pilot study, 40 men were randomized 1 : 1 to bicalutamide 50 mg o.d. or cyproterone acetate 100 mg t.i.d. 5 days prior to goserelin acetate and continued for 21 days thereafter. PSA, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone were obtained before treatment and on days 6, 8, 10, 16, 21 and 28. Primary end point was PSA. Hormone profile and clinical features including urinary symptoms and bone pain were secondary end points.Results: Both groups were equally matched apart from serum creatinine and ALP. The speed and magnitude of the percentage change in median PSA from baseline was increased for the CPA group but there was no statistically significant difference in the two groups. Although those receiving bicalutamide all showed a testosterone peak, this remained within the normal range. No difference in the frequency of drug-specific adverse events was found. None of the patients died or developed cord compression during the study period.Conclusion: Bicalutamide is able to suppress the initial PSA surge as effectively as cyproterone acetate albeit slightly delayed. A statement whether bicalutamide is equally good at preventing clinical flare cannot be made and should be assessed in an appropriately powered study.Prostate Cancer and Prostatic Diseases advance online publication, 15 February 2005; doi:10.1038/sj.pcan.4500784.

Neoplasma. 2004;51(5):358-67.
Synergic effects of the cyclin-dependent kinase (CDK) inhibitor olomoucine and androgen-antagonist bicalutamide on prostatic cancer cell lines.
Knillova J, Bouchal J, Hlobilkova A, Strnad M, Kolar Z.
Institute of Pathology, Laboratory of Molecular Pathology, Faculty of Medicine, Palacky University, CZ-77515 Olomouc, Czech Republic.

Currently, mechanisms leading to both apoptosis induction and the development of hormone-independence of prostate carcinoma cells are intensively studied. Attention is also given to the possibility of restoring cell sensitivity to hormone-antagonists. The present study focuses on the effect of the combined synthetic cyclin-dependent kinase [CDK] inhibitor, olomoucine and the antiandrogen bicalutamide on hormone-insensitive (DU-145) and hormone-sensitive (LNCaP) prostate cancer cell lines. In both cell lines reduction in cell viability was significantly higher when olomoucine and bicalutamide were applied in combination when compared to separate application of both these drugs. The setting of optimal concentrations for both substances was important for the final effect on both cell lines. The proliferation arrest was accompanied by a decrease in cyclin D1 expression and the activation of p21Waf1/Cip1 and p27Kip1 pathways in both cell lines. Contrary to the previously described effect of 200 microM olomoucine, weak AR induction after treatment with effective concentrations of olomoucine was not seen in the hormone- insensitive cell line DU-145. The related reaction of DU-145 and LNCaP cell lines to treatment with combined olomoucine and bicalutamide likely provides evidence that the inhibitory effect of bicalutamide may not only be associated with its antiandrogenic properties. The tested substances probably influence different regulatory pathways and these have co-operative impact on the cell cycle outcome. Understanding antitumor and antihormone actions of both agents is essential for the development of novel therapeutic schemes integrating substances with different action. Our results show that the combination of synthetic CDK inhibitors and hormone- antagonists may be one of a number of possible alternatives.

J Urol. 2004 Nov;172(5 Pt 1):1871-6.
Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6.
Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K; Scandinavian Prostatic Cancer Group.
Department of Urology, University of Copenhagen, Rigshospitalet and Herlev Hospital, Copenhagen, Denmark. piv@rh.dk

PURPOSE: We evaluated the benefits of adding 150 mg bicalutamide to standard care, that is radical prostatectomy, radiotherapy or watchful waiting (WW), in patients with localized or locally advanced prostate cancer. MATERIALS AND METHODS: A total of 1,218 men with T1-4, M0, any N prostate cancer were recruited from 62 Scandinavian centers and randomized 1:1 to 150 mg bicalutamide or placebo plus standard care. Primary end points were progression-free survival (PFS) and overall survival. RESULTS: At a median 5.3-year followup patients with locally advanced disease had improved survival with bicalutamide (HR 0.68, 95% CI 0.50 to 0.92), while those with localized disease had decreased survival with bicalutamide (HR 1.47, 95% CI 1.06 to 2.03). Bicalutamide significantly improved PFS, decreasing the risk of disease progression by 43% compared with placebo (HR 0.57, 95% CI 0.48 to 0.68, p<0.0001). The rate of events was 35.4% for bicalutamide and 46.2% for placebo. Patients with locally advanced disease gained the greatest PFS benefits with bicalutamide (HR 0.40, 95% CI 0.31 to 0.52). Since 81% of the trial population were untreated before entry and would otherwise have undergone WW, the findings essentially reflect the results of immediate hormone therapy vs WW. CONCLUSIONS: Bicalutamide (150 mg) provides significant benefit in patients with locally advanced disease. In previously untreated patients there may be a tumor burden below which endocrine therapy provides no benefit or may even decrease survival.

J Urol. 2004 Nov;172(5 Pt 1):1865-70.
Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years.
Wirth MP, See WA, McLeod DG, Iversen P, Morris T, Carroll K; Casodex Early Prostate Cancer Trialists' Group.
Department of Urology, Technical University of Dresden, Dresden, Germany. Manfred.Wirth@uniklinikum-dresden.de

PURPOSE: We evaluated the efficacy and tolerability of 150 mg bicalutamide daily given in addition to standard care, in patients with localized or locally advanced prostate cancer. MATERIALS AND METHODS: The bicalutamide Early Prostate Cancer program consists of 3 randomized, double blind, placebo controlled trials prospectively designed for combined analysis. A total of 8,113 men with T1b-T4, M0, any N (N0 in 1 trial) prostate cancer were randomized to bicalutamide 150 mg/day (4,052) or placebo (4,061) in addition to standard care (radical prostatectomy, radiotherapy or watchful waiting). Primary end points were objective progression-free survival (PFS) and overall survival. RESULTS: At median 5.4 years of followup (21.6% progression events) bicalutamide significantly improved PFS in the overall population. This result was driven by positive results in trials 24 and 25, with the North American trial (trial 23) showing no difference. Patients with locally advanced disease gained most benefit from bicalutamide in terms of PFS, irrespective of underlying therapy. Overall survival was similar in the bicalutamide and placebo groups, across the program and in each trial. Among watchful waiting patients survival appeared to be improved with bicalutamide in those with locally advanced disease, whereas survival appeared to be reduced with bicalutamide in those with localized disease. The most common adverse events with bicalutamide were gynecomastia and breast pain. Other adverse events occurred with a similarly low incidence in the 2 treatment groups. CONCLUSIONS: This analysis confirms that bicalutamide provides benefit in patients with locally advanced disease. The current data suggest that early or adjuvant hormonal therapy for patients at low risk of disease progression, such as those with localized disease, is not appropriate.

Clin Pharmacokinet. 2004;43(13):855-78.
Bicalutamide: clinical pharmacokinetics and metabolism.
Cockshott ID.
AstraZeneca, Macclesfield, UK.

Bicalutamide is a nonsteroidal pure antiandrogen given at a dosage of 150 mg once daily as monotherapy for the treatment of early (localised or locally advanced) nonmetastatic prostate cancer. It is used at a dosage of 50 mg once daily in combination with a luteinising hormone-releasing hormone analogue or surgical castration for the treatment of advanced prostate cancer. Bicalutamide is a racemate and its antiandrogenic activity resides almost exclusively in the (R)-enantiomer, with little, if any, activity in the (S)-enantiomer. (R)-Bicalutamide is slowly and saturably absorbed, but absorption is unaffected by food. It has a long plasma elimination half-life (1 week) and accumulates about 10-fold in plasma during daily administration. (S)-Bicalutamide is much more rapidly absorbed and cleared from plasma; steady-state concentrations (Css) of (R)-bicalutamide are 100-fold higher than those of (S)-bicalutamide. Css increases linearly with doses up to 50 mg, but nonlinearly at higher doses, reaching a plateau above 300 mg. Css is higher in Japanese than in Caucasians, but no relationship with degree of renal impairment, bodyweight or age exists. Although mild-to-moderate hepatic impairment does not affect pharmacokinetics, there is evidence for slower elimination of (R)-bicalutamide in subjects with severe hepatic impairment. Bicalutamide metabolites are excreted almost equally in urine and faeces with little or no unchanged drug excreted in urine; conversely, unchanged drug predominates in plasma. Bicalutamide in faeces is thought to arise from hydrolysis of bicalutamide glucuronide and from unabsorbed drug. Bicalutamide appears to be cleared almost exclusively by metabolism; this is largely mediated by cytochrome P450 (CYP) for (R)-bicalutamide, but glucuronidation is the predominant metabolic route for (S)-bicalutamide. (S)-Bicalutamide is metabolised in vitro by CYP3A4, and it is probable that this isoenzyme is also responsible for the metabolism of (R)-bicalutamide. In vitro data suggest that (R)-bicalutamide has the potential to inhibit CYP3A4 and, to a lesser extent, CYP2C9, 2C19 and 2D6. However, using midazolam as a specific CYP3A4 marker, no clinically relevant inhibition is observed in vivo with bicalutamide 150mg. Although bicalutamide is a CYP inducer in laboratory animals, dosages < or = 150 mg/day have shown no evidence of enzyme induction in humans. Daily administration of bicalutamide increases circulating levels of gonadotrophins and sex hormones; although testosterone increases by up to 80%, concentrations in most patients remain within the normal range. Bicalutamide produces a dose-related decrease in prostate-specific antigen (PSA) at dosages < or = 150 mg/day. However, little relationship is observed between median PSA reduction and (R)-bicalutamide Css.

Curr Cancer Drug Targets. 2004 Aug;4(5):455-61.
Antiandrogens in prostate cancer endocrine therapy.
Culig Z, Bartsch G, Hobisch A.
Department of Urology, University of Innsbruck, Austria. zoran.culig@uibk.ac.at

Prostate cancer is the most frequently diagnosed tumor in industrialized countries. Endocrine therapy, which is based on interference with androgen signaling is only palliative. Drugs used in prostate cancer therapy are luteinizing hormone releasing hormone (LHRH) agonists and antiandrogens. Application of LHRH agonists leads to suppression of the levels of circulating androgens, and antiandrogens block the function of the androgen receptor (AR). The steroidal antiandrogen cyproterone acetate and nonsteroidal compounds hydroxyflutamide and bicalutamide are used most frequently. They prevent acquisition of a transcriptionally active conformation of the AR. It became clear that tumors progress to therapy resistance in the presence of the AR which might be structurally altered. These mutations generate receptors that respond to other steroids and antiandrogens by increased activation. In addition, AR expression increases during endocrine treatment. AR is also activated by nonsteroidal compounds such as growth factors, interleukin-6, and neuropeptides. Therefore, new experimental approaches are needed to antagonize AR expression and function more efficiently. The AR associates with a number of proteins, coactivators and corepressors. There are indications that expression of some of these proteins is altered in prostate cancer, a fact which might be important for improvement of endocrine therapy.

J Clin Oncol. 2004 Jul 1;22(13):2546-53.
Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition.
Smith MR, Goode M, Zietman AL, McGovern FJ, Lee H, Finkelstein JS.
Massachusetts General Hospital, Boston, MA 02114, USA. smith.matthew@mgh.harvard.edu

PURPOSE: Gonadotropin-releasing hormone agonists decrease bone mineral density, lean mass, and muscle size and increase fat mass in men with prostate cancer. Less is known about the effects of bicalutamide monotherapy on bone mineral density and body composition. PATIENTS AND METHODS: In a 12-month, open-label study, we randomly assigned 52 men with prostate cancer and no bone metastases to receive either leuprolide or bicalutamide (150 mg by mouth daily). Bone mineral density and body composition were measured by dual energy x-ray absorptiometry and quantitative computed tomography. RESULTS: Mean (+/- standard error) bone mineral density of the posterior-anterior lumbar spine decreased by 2.5% +/- 0.5% in the leuprolide group and increased by 2.5 +/- 0.5 in the bicalutamide group from baseline to 12 months (P <.001). Mean changes in bone mineral density of the total body, total hip, femoral neck, and trabecular bone of the lumbar spine also differed significantly between groups (P < or =.003 for each comparison). Fat mass increased by 11.1% +/- 1.3% in the leuprolide group and by 6.4% +/- 1.1% in the bicalutamide group (P =.01). Changes in lean mass, muscle size, and muscle strength were similar between the groups. Breast tenderness and enlargement were more common in the bicalutamide group than in the leuprolide group. Fatigue, loss of sexual interest, and vasomotor flushing were less common in the bicalutamide group than in the leuprolide group. CONCLUSION: In men with prostate cancer, bicalutamide monotherapy increases bone mineral density, lessens fat accumulation, and has fewer bothersome side effects than treatment with a gonadotropin-releasing hormone agonist.

Ann Oncol. 2004 Jun;15(6):974-8.
Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate.
Tay MH, Kaufman DS, Regan MM, Leibowitz SB, George DJ, Febbo PG, Manola J, Smith MR, Kaplan ID, Kantoff PW, Oh WK.
Lank Center for Genitourinary Oncology, Division of Solid Tumor Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

BACKGROUND: Medical or surgical castration is effective in advanced prostate cancer but with profound side-effects, particularly on sexual function. Effective, less toxic therapies are needed. This study examined whether the addition of finasteride to high-dose bicalutamide enhanced disease control, as measured by additional decreases in serum prostate-specific antigen (PSA). PATIENTS AND METHODS: Forty-one patients with advanced prostate cancer received bicalutamide (150 mg/day). Finasteride (5 mg/day) was added at first PSA nadir. Serum PSA was measured every 2 weeks until disease progression. Questionnaires were administered to assess sexual function. RESULTS: Median follow-up is 3.9 years. At the first PSA nadir, median decrease in PSA from baseline was 96.5%. Thirty of 41 patients (73%) achieved a second PSA nadir and median decrease of 98.5% from baseline. Median time to each nadir was 3.7 and 5.8 weeks, respectively. Median time to treatment failure was 21.3 months. Toxicities were minor, including gynecomastia. Seventeen of 29 (59%) and 12 of 24 (50%) men had normal sex drive at baseline and at second PSA nadir, respectively. One-third of men had spontaneous erection at both time points. CONCLUSION: Finasteride provides additional intracellular androgen blockade when added to bicalutamide. Duration of control is comparable to castration, with preserved sexual function in some patients.

J Urol. 2004 Jun;171(6 Pt 1):2272-6, quiz 2435.
Bicalutamide 150 mg maintains bone mineral density during monotherapy for localized or locally advanced prostate cancer.
Sieber PR, Keiller DL, Kahnoski RJ, Gallo J, McFadden S.
Urological Associates of Lancaster Ltd, Lancaster, Pennsylvania 17604-3200, USA. psieber610@aol.com

PURPOSE: We evaluated changes in bone mineral density (BMD), fat-free mass (FFM) and serum lipid levels during bicalutamide 150 mg monotherapy compared with medical castration for 2 years. MATERIALS AND METHODS: A total of 103 men with localized or locally advanced prostate cancer (T1-T4, Nx, M0) for whom immediate androgen deprivation was indicated were enrolled in this prospective, multicenter, open-label, parallel group study. Patients were randomized to bicalutamide 150 mg once daily (51) or medical castration with a luteinizing hormone releasing hormone analogue (52) for 96 weeks. Primary end points were mean percent change from baseline in lumbar spine BMD, hip BMD and FFM at 96 weeks. Mean changes in lipid parameters with time were also evaluated. RESULTS: BMD was maintained during bicalutamide 150 mg monotherapy (+2.42% for lumbar spine BMD and +1.13% for hip BMD at week 96), while castration was associated with a progressive loss in BMD (-5.40% and -4.39% at week 96, respectively, both p <0.0001 at week 96). There was no significant difference between bicalutamide 150 mg and castration in mean percent change from baseline in FFM (-1.56% and -3.86%, respectively, at week 96, p = 0.31), although there was a trend for greater progressive loss over time with castration. Mean changes in lipid parameters were small and similar in the 2 groups. CONCLUSIONS: Bicalutamide 150 mg monotherapy may offer an important advantage compared to castration in terms of bone loss and body composition for patients who require long-term androgen deprivation for localized or locally advanced prostate cancer.

Clin Prostate Cancer. 2004 Mar;2(4):213-9.
An evaluation of bicalutamide in the treatment of prostate cancer.
Schellhammer PF, Davis JW.
Department of Urology, Eastern Virginia Medical School and Virginia Prostate Center, Norfolk, VA 25502, USA. schellpf@evmsmail.evms.edu

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.

Urol Int. 2004;72(2):91-8.
Antiandrogen monotherapy: recommendations for the treatment of prostate cancer.
Sciarra A, Cardi A, Di Silverio F.
Department of Urology, University La Sapienza, Rome, Italy. sciarrajr@hotmail.com

OBJECTIVE: The concept of antiandrogens as monotherapy for the treatment of prostate cancer is discussed. METHODS: Both Medline and Current Contents were used to identify studies on antiandrogen monotherapy in prostate cancer. We tried to analyze this database critically to establish whether or not there is evidence for using this monotherapy. RESULTS: In particular, bicalutamide in monotherapy has been compared with castration in large international trials. Results show that antiandrogen monotherapy is inferior to castration in patients with metastatic tumour but the difference in median survival is limited. In locally advanced M0 prostate cancer bicalutamide 150 mg monotherapy seems equivalent to castration in terms of overall survival and time to progression. Analysis of quality of life showed that there is evidence of some benefits from bicalutamide when compared to castration in both sexual interest and physical capacity. CONCLUSION: Antiandrogens in monotherapy can be effective and well tolerated. However, more research is needed because none of the available compounds have definitively been proven to be equivalent to castration.

Expert Rev Anticancer Ther. 2004 Feb;4(1):37-48.
Bicalutamide (Casodex) in the treatment of prostate cancer.
Fradet Y.
Laval University, Cancer Research Center, CHUQ - L'Hotel-Dieu de Quebec, 11 Cote du Palais, Quebec, QC G1R 2J6, Canada. fradet@attglobal.net

Prostate cancer is an important healthcare issue in men worldwide. With the advent of prostate-specific antigen screening and improved diagnostic techniques, prostate cancer is now being diagnosed in younger men and at earlier disease stages. As a result, patients often live with their disease for many years after diagnosis. This shift in the patient profile has focused attention to the impact of treatment on quality of life. Medical/surgical castration has traditionally been the mainstay of hormonal therapy but is associated with side effects including loss of libido and impotence. Nonsteroidal antiandrogens such as bicalutamide (Casodex) offer an effective alternative to castration with potential quality-of-life benefits. This paper reviews the evidence concerning the use of bicalutamide at all stages of the disease. Copyright Future Drugs Ltd.

J Urol. 2003 Dec;170(6 Pt 2):S48-52; discussion S52-4.
Bicalutamide monotherapy for early stage prostate cancer: an update.
Iversen P.
Department of Urology, Rigshospitalet, University of Copenhagen, Denmark. piv@rh.dk

PURPOSE: The current evidence is considered to support 150 mg of the nonsteroidal antiandrogen bicalutamide for early stage prostate cancer. MATERIALS AND METHODS: Data from phase III trials of 150 mg bicalutamide monotherapy for locally advanced disease are discussed. In addition, the first overall results are examined from the bicalutamide early prostate cancer program conducted at a median followup of 3 years, in which patients with localized or locally advanced disease were randomized to receive 150 mg bicalutamide or placebo as well as standard care. RESULTS: Mature data from phase III studies have shown that 150 mg bicalutamide monotherapy provide similar survival outcome to that observed with castration in patients with locally advanced (M0) disease. Moreover, 150 mg bicalutamide have benefits over castration in terms of quality of life, particularly sexual interest and physical capacity, and preservation of bone mineral density. In the bicalutamide early prostate cancer program 150 mg significantly reduced the risk of objective progression in patients with localized or locally advanced disease at 3 years of median followup, with the greatest benefit seen in patients with poorer prognosis. Followup is ongoing to further determine the benefit of 150 mg bicalutamide in early prostate cancer. CONCLUSIONS: Bicalutamide is emerging as a useful treatment option for early prostate cancer.

Eur Urol. 2003 Nov;44(5):512-7; discussion 517-8.
Immediate treatment with bicalutamide 150mg as adjuvant therapy significantly reduces the risk of PSA progression in early prostate cancer.
See W, Iversen P, Wirth M, McLeod D, Garside L, Morris T.
Division of Urology, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital, 9200 W. Wisconsin Avenue, Milwaukee, WI, USA.

OBJECTIVE: To evaluate the effect of bicalutamide ('Casodex') 150mg (in addition to standard care), on the risk of prostate-specific antigen (PSA) progression, in patients with early prostate cancer. METHODS: The bicalutamide 150mg Early Prostate Cancer (EPC) programme is the largest clinical trial programme in the treatment of prostate cancer to date. This paper reports the PSA progression data from the EPC programme at a median of 3years' follow-up, for the overall study population, and across the radical prostatectomy and radiotherapy primary therapy strategies. PSA progression was predefined as the earliest occurrence of PSA doubling from baseline, objective progression, or death from any cause. RESULT: Overall, bicalutamide 150 mg in addition to standard care significantly reduced the risk of PSA progression by 59% compared with standard care alone (HR 0.41; 95% CI 0.38, 0.45; p<<0.0001). Significant reductions were observed following radical prostatectomy (51%; HR 0.49; 95% CI 0.43, 0.56; p<<0.0001) and radiotherapy (58%; HR 0.42; 95% CI 0.33, 0.53; p<<0.0001). Further exploration of the data by disease stage, nodal status, Gleason score and pre-treatment PSA level revealed significant reductions in the risk of PSA progression across most prognostic risk factor subgroups. CONCLUSIONS: Bicalutamide 150mg significantly reduces the risk of PSA progression, irrespective of whether patients received radical prostatectomy or radiotherapy as standard care. The EPC programme is ongoing and further progression and survival data are awaited.

Clin Oncol (R Coll Radiol). 2003 Sep;15(6):318-21.
Is bicalutamide equivalent to goserelin for prostate volume reduction before radiation therapy? A prospective, observational study.
Henderson A, Langley SE, Laing RW.
Department of Urology, St Luke's Cancer Centre, Guildford, UK.

INTRODUCTION: We compare the cytoreductive efficacy of bicalutamide or goserelin with no hormonal manipulation in prostate cancer before brachytherapy. MATERIALS AND METHODS: Transrectal ultrasound volume estimations were performed in clinic and during the brachytherapy-planning scan. Between volume estimations, patients received no hormonal treatment, bicalutamide 150 mg once daily or goserelin 3.6 mg every 28 days. RESULTS: Patients receiving no hormonal manipulation had a volume increase of 8% compared with an 8% volume reduction in the bicalutamide group and a 26% reduction in the goserelin group. As initial prostate volume was not equivalent in the three groups, a subgroup analysis was performed on patients who received active treatment for more than 3 months who had initial prostate volume less than 55 cm3. In this subgroup, a mean fall in prostate volume of 7%, occurred in the bicalutamide group compared with 21% in the goserelin group. In both the original and subgroup analysis, the cytoreductive efficacy of goserelin was significantly greater than bicalutamide (P < 0.0001). CONCLUSION: In the absence of data from randomised trials, comparing the efficacy of these agents, luteinising hormone-releasing hormone (LHRH) analogues remain the gold standard for cytoreduction before prostate brachytherapy. If the neoadjuvant efficacy of hormonal manipulation in external beam radiotherapy is dependent on prostate volume reduction, then LHRH analogues may also prove more effective in this neoadjuvant role.

CASODEX generic Substance: bicalutamide

CASODEX generic
Substance: bicalutamide