Pharmacology: Pharmacodynamics: Bicalutamide is a nonsteroidal antiandrogen, devoid of other endocrine activity. It binds to the wild type or normal androgen receptor without activating gene expression, and thus inhibits the androgen stimulus. Regression of prostatic tumors results from this inhibition. Clinically, discontinuation of Casodex/Casodex 150 can result in the "antiandrogen withdrawal syndrome" in a subset of patients.
Casodex 150 was studied as a treatment for patients with localized (T1-T2, N0 or NX, M0) or locally advanced (T3-T4, any N, M0; T1-T2, N+, M0) nonmetastatic prostate cancer in a combined analysis of 3 placebo-controlled double-blind studies in 8113 patients, where Casodex 150 was given as immediate hormonal therapy or as adjuvant to radical prostatectomy or radiotherapy (primarily external beam radiation). At 7.4 years median follow-up, 27.4% and 30.7% of all Casodex 150- and placebo-treated patients, respectively, had experienced objective disease progression.
In the subgroup of patients with locally advanced prostate cancer who did not receive treatment with radical prostatectomy or radiotherapy, immediate therapy with Casodex 150 significantly reduced the risk of objective disease progression [Hazard Ratio (HR)=0.6; 95% CI 0.49-0.73]. A statistically significant reduction in the risk of objective disease progression was also seen in the subgroup of patients with locally advanced disease who received Casodex as adjuvant to radical prostatectomy or radiotherapy (HR=0.69; 95% CI 0.58-0.82). There was no significant difference in progression in patients with localized disease.
A reduction in risk of objective disease progression was seen across most patient groups, but was most evident in those at highest risk of disease progression. Therefore, clinicians may decide that the optimum medical strategy for a patient at low risk of disease progression, particularly in the adjuvant setting following radical postatectomy, may be to defer hormonal therapy until signs that the disease is progressing.
No overall survival difference was seen at 7.4 years median follow-up with 22.9% mortality (HR=0.99; 95% CI 0.91-1.09). However, some trends were apparent in exploratory subgroup analyses of those patients receiving Casodex 150 as immediate therapy alone.
Patients with localized disease receiving Casodex 150 alone showed a trend toward decreased survival compared with placebo patients (HR=1.16; 95% CI 0.99-1.37). In view of this, the benefit-risk profile for the use of Casodex 150 is not considered favorable in this group of patients.
For patients with locally advanced disease receiving Casodex 150 alone, there was a trend toward improved survival with Casodex 150 compared to placebo (HR=0.81; 95% CI 0.66-1.01).
The progression-free survival and overall survival data for patients with locally advanced disease are summarized in the table. (See table.)
Click on icon to see table/diagram/image
In a separate programme, the efficacy of Casodex 150 for the treatment of patients with locally advanced nonmetastatic prostate cancer for whom immediate castration was indicated, was demonstrated in a combined analysis of 2 studies with 480 previously untreated patients with nonmetastatic (M0) prostate cancer. At 56% mortality and a median follow-up of 6.3 years, there was no significant difference between Casodex 150 and castration in survival [hazard ratio=1.05 (CI 0.81-1.36)]; however, equivalence of the 2 treatments could not be concluded statistically.
In a combined analysis of 2 studies with 805 previously untreated patients with metastatic (M1) disease at 43% mortality, Casodex 150 was demonstrated to be less effective than castration in survival time [hazard ratio=1.3 (CI 1.04-1.65)], with a numerical difference in estimated time to death of 42 days (6 weeks) over a median survival time of 2 years.
Bicalutamide is a racemate with its antiandrogen activity being almost exclusively in the R-enantiomer.
Pharmacokinetics: Bicalutamide is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.
The (S)-enantiomer is rapidly cleared relative to the (R)-enantiomer, the latter having a plasma elimination half-life of about 1 week.
On daily administration of Casodex/Casodex 150, the (R)-enantiomer accumulates about 10-fold in plasma as a consequence of its long half-life.
Steady-state plasma concentrations of the (R)-enantiomer, of approximately 9 and 22 mcg/mL are observed during daily administration of Casodex and Casodex 150, respectively. At steady state, the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.
The pharmacokinetics of the (R)-enantiomer is unaffected by age, renal impairment or mild to moderate hepatic impairment. There is evidence that for subjects with severe hepatic impairment, the (R)-enantiomer is more slowly eliminated from plasma.
Bicalutamide is highly protein-bound (racemate 96%, (R)-enantiomer >99%) and extensively metabolized (oxidation and glucuronidation); its metabolites are eliminated via the kidneys and bile in approximately equal proportions.
In a clinical study, the mean concentration of R-bicalutamide in semen of men receiving Casodex 150 was 4.9 mcg/mL. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and equates to approximately 0.3 mcg/kg. This is below that required to induce changes in offspring of laboratory animals.
Toxicology: Preclinical Safety Data Relevant to the Prescriber: Bicalutamide is a potent antiandrogen and a mixed function oxidase enzyme-inducer in animals. Target organ changes, including tumor induction (Leydig cells, thyroid, liver) in animals, are related to these activities. Enzyme induction has not been observed in man and none of these findings is considered to have relevance to the treatment of advanced prostate cancer patients.
Atrophy of seminiferous tubules is a predicted class effect with antiandrogens and has been observed for all species examined. Full reversal of testicular atrophy was 24 weeks after a 12-month repeated-dose toxicity study in rats, although functional reversal was evident in reproduction studies 7 weeks after the end of an 11-week dosing period. A period of subfertility or infertility should be assumed in man.