CASODEX^® (bicalutamide)

Indications

CASODEX 50 mg daily is indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate.

CASODEX 150 mg daily is not approved for use alone or with other treatments.

Mechanism of Action

CASODEX is a non-steroidal androgen receptor inhibitor. It competitively inhibits the actions of androgens by binding to cytosol androgen receptors in target tissues. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of the androgen.

When CASODEX is combined with luteinizing hormone-releasing hormone (LHRH) analog therapy, the suppression of serum testosterone induced by the LHRH analog is not affected. However, in trials with CASODEX as a single agent for prostate cancer, rises in serum testosterone and estradiol have been noted.

In a subset of patients who have been treated with an LHRH agonist, and who discontinue CASODEX therapy due to progressive advanced prostate cancer, reduction in Prostate Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.

Safety

Serum transaminase levels should be measured prior to starting treatment with CASODEX, at regular intervals for the first four months of treatment, and periodically thereafter.

Development of diabetes has been reported in men receiving LHRH-As. Consider monitoring blood glucose in patients receiving CASODEX with an LHRH-A.

The most commonly reported adverse events regardless of causality for CASODEX plus an LHRH-A were hot flashes (53%), pain (35%), back pain (25%), asthenia (22%), constipation (22%), pelvic pain (21%), infection (18%), nausea (15%), dyspnea (13%), peripheral edema (13%), diarrhea (12%), hematuria (12%), and nocturia (12%).

Dosing

The recommended dose for CASODEX therapy in combination with an LHRH analog therapy is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that CASODEX be taken at the same time each day. Treatment with CASODEX should be started at the same time as treatment with an LHRH analog.

Efficacy

CASODEX 50 mg Daily in Combination with an LHRH-A
In a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive CASODEX 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with LHRH analogs (either goserelin acetate implant or leuprolide acetate depot). In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) patients treated with CASODEX-LHRH analog therapy and 235 (57.5%) patients treated with flutamide-LHRH analog therapy had died. There was no significant difference in survival between treatment groups (see Figure 1). The hazard ratio for time to death (survival) was 0.87 (95% confidence interval 0.72 to 1.05).

Enlarge

There was no significant difference in time to objective tumor progression between treatment groups (see Figure 2). Objective tumor progression was defined as the appearance of any bone metastases or the worsening of any existing bone metastases on bone scan attributable to metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal metastases. The hazard ratio for time to progression of CASODEX plus LHRH analog to that of flutamide plus LHRH analog was 0.93 (95% confidence interval, 0.79 to 1.10).

Enlarge

Quality of life was assessed with self-administered patient questionnaires on pain, social functioning, emotional well being, vitality, activity limitation, bed disability, overall health, physical capacity, general symptoms, and treatment-related symptoms. Assessment of the Quality of Life questionnaires did not indicate consistent significant differences between the two treatment groups.

Safety Data from Clinical Studies using CASODEX 150 mg CASODEX 150 mg is not approved for use either alone or with other treatments.
Two identical multicenter, randomized, open-label trials comparing CASODEX 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, MO) or metastatic (M1) prostate cancer.

Monotherapy — M1 Group
CASODEX 150 mg daily is not approved for use in patients with M1 cancer of the prostate. Based on an interim analysis of the two trials for survival, the Data Safety Monitoring Board recommended that CASODEX treatment be discontinued in the M1 patients because the risk of death was 25% (HR 1.25, 95% CI 0.87 to 1.81) and 31% (HR 1.31, 95% CI 0.97 to 1.77) higher in the CASODEX-treated group compared to that in the castrated group, respectively.

Locally Advanced (T3-4, NX, MO) Group
CASODEX 150 mg daily is not approved for use in patients with locally advanced (T3-4, NX, M0) cancer of the prostate. Following discontinuation of all M1 patients, the trials continued with the T3-4, NX, MO patients until study completion. In the larger trial (N=352), the risk of death was 25% (HR 1.25, 95% CI 0.92 to 1.71) higher in the CASODEX group and in the smaller trial (N=140), the risk of death was 36% (HR 0.64, 95% CI, 0.39 to 1.03) lower in the CASODEX group.

In addition to the above two studies, there are three other ongoing clinical studies that provide additional safety information for CASODEX 150 mg, a dose that is not approved for use. These are three multicenter, randomized, double-blind, parallel group trials comparing CASODEX 150 mg daily monotherapy (adjuvant to previous therapy or under watchful waiting) with placebo, for death or time to disease progression, in a population of 8113 patients with localized or locally advanced prostate cancer.

CASODEX 150 mg daily is not approved for use as therapy for patients with localized prostate cancer who are candidates for watchful waiting. Data from a planned subgroup analysis of two of these trials in 1627 patients with localized prostate cancer who were under watchful waiting, revealed a trend toward decreased survival in the CASODEX arm after a median follow-up of 7.4 years. There were 294 (37.7%) deaths in the CASODEX-treated patients versus 279 (32.9%) deaths in the placebo-treated patients (localized watchful waiting group) for a hazard ratio of 1.16 (95% CI 0.99 to 1.37).