Bicalutamide (Casodex®) in the treatment of prostate cancer: History of clinical development

Abstract

BACKGROUND Bicalutamide (Casodex®) is a new nonsteroidal antiandrogen developed for use in patients with prostate cancer. The efficacy and tolerability of bicalutamide as monotherapy and as combination therapy for patients with advanced prostate cancer have been evaluated in randomized clinical trials. Clinical trials are currently in progress to further evaluate bicalutamide as monotherapy in patients with advanced stages of disease and as adjuvant or first‐line therapy in patients with early‐stage disease. METHODS A review of published trials of bicalutamide focusing on dose‐ranging investigations, phase II and phase III monotherapy trials, a phase III trial of combined androgen blockade, and a safety overview. RESULTS In dose‐ranging trials, bicalutamide doses of 10‐200 elicited biochemical, objective, and subjective responses; higher bicalutamide doses (up to 600 mg) have also been evaluated. A 50‐mg daily dose of bicalutamide was initially evaluated as monotherapy in phase II and phase III trials; in subsequent trials, a 150‐mg daily dose was investigated. A 150‐mg daily dose is considered to provide equivalent survival outcome compared with castration in patients with locally advanced prostate cancer, whereas the benefits of a better quality of life and better palliation with the 150‐mg daily bicalutamide dose relative to castration in patients with metastatic disease needs to be balanced against the small shortfall (median difference, 42 days) in survival. In combination with a luteinizing hormone‐releasing hormone agonist analogue (LHRH‐A), a 50‐mg daily dose of bicalutamide has equivalent efficacy to a corresponding flutamide (250 mg three times daily) combination regimen. Treatment with the bicalutamide combination regimen resulted in a longer median survival than with the flutamide combination regimen. Bicalutamide is well tolerated when used as monotherapy or in combination with a LHRH‐A. The benefits of bicalutamide as monotherapy include retention of libido and sexual potency and as combination therapy a lower incidence of diarrhea relative to flutamide. CONCLUSIONS A 50‐mg daily dose of bicalutamide is sufficient when given in combination with an agent, such as a LHRH‐A, that lowers serum testosterone, but higher doses of bicalutamide may be needed when the drug is given as monotherapy. Bicalutamide, 50‐mg daily, is a logical first choice for antiandrogen therapy when used in combination with an LHRH‐A for the treatment of patients with advanced prostate cancer. Bicalutamide 150‐mg daily is considered an effective monotherapy for use in patients with locally advanced disease. Additional clinical trials are currently in progress to further evaluate bicalutamide as a monotherapy for advanced prostate cancer and to assess its value as adjuvant or first‐line therapy for early‐stage prostate cancer. Prostate 34:61–72, 1998. © 1998 Wiley‐Liss, Inc.

Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer

“…CWR-22-BMSLD1 was marginally sensitive to 150 mg/kg bicalutamide, which yields 3-fold higher steady-state exposures in mice than in humans (150 versus 52 Amol/L; ref. 45). Furthermore, tumors treated with bicalutamide grew progressively during treatment.…”

Development of β-amino-carbonyl compounds as androgen receptor antagonists

“…The final result was imaged using the Chimera program. 3 , the mice were divided into 5 groups of 10 mice per group (vehicle, 2 mg/kg compound 6012-4, 10 mg/kg compound 6012-4, 10 mg/kg compound 6012-3 and 10 mg/kg Casodex). The compounds and vehicle were injected intraperitoneally daily for 28 d. All compounds were dissolved in vehicle (5% DMSO, 15% Cremophor EL, 30% PEG-400 and 50% water).…”

“…Bicalutamide, which is marketed as Casodex, is an orally available agent widely used in the treatment of prostate cancer [2][3][4] and hirsutism [5] . The drug was first introduced in 1995 as part of a combination therapy (with surgical or medical castration) for advanced prostate cancer and was subsequently employed as monotherapy for earlier stages of the disease [4] .…”

MDV3100 for the treatment of prostate cancer

“…For patients with biochemical progression on CAB, antiandrogen withdrawal has been shown to result in biological responses in 15 --30% of cases [21]. Cyproterone acetate, flutamide, nilutamide and bicalutamide are reversible inhibitors of the AR and have a several-fold lower affinity for the androgen receptor compared with androgens [22]. Increased AR protein expression or mutations in the AR can cause these drugs to behave as partial agonists, resulting in the 'antiandrogen withdrawal syndrome' [23].…”