HIGH-DOSE BICALUTAMIDE MONOTHERAPY FOR THE TREATMENT OF PROSTATE-CANCER

Objectives. Bicalutamide is a nonsteroidal competitive inhibitor of an drogens at the androgen receptor. The level of blockade that can be ac hieved is dependent on the relative numbers of molecules of the agonis t and of the competitive antagonist around the receptor. Increasing th e dose of a competitive inhibitor, therefore, should potentially incre ase the level of blockade. Bicalutamide has been investigated extensiv ely at daily doses up to 150 mg, and there is evidence of increasing b lockade at doses up to this point, as evidenced by increasing suppress ion of prostate-specific antigen (PSA) and also improvement in respons e rate, both subjective and objective. At doses of up to 150 mg, incre ases in plasma concentration of bicalutamide were approximately linear , and all doses were equally well tolerated. It was thought, therefore , that there was a case for investigating higher doses of bicalutamide to determine whether increased androgen blockade could be achieved wi th the use of bicalutamide as monotherapy. Methods. A number of studie s have now been carried out evaluating bicalutamide in daily doses of 200 mg, 300 mg, and 450 mg. The 200-mg dose has been evaluated as a pr imary treatment for advanced prostate cancer and also as a second-line treatment option for patients who have demonstrated a flutamide withd rawal response. Results. In noncomparative trials, the decline in PSA value associated with daily doses of 200 mg bicalutamide was greater t han that observed with daily doses of 150 mg, and there was also a sli ghtly higher response rate. When 200 mg daily doses were used as thera py following failure of flutamide in combination with castration, and also following evidence of a flutamide withdrawal response, further re sponses were seen, perhaps suggesting the theory that in some prostate cancer cell mutations, bicalutamide acts as a pure antagonist rather than as a partial agonist. More recently, bicalutamide has been evalua ted at higher doses: 20 patients have been exposed for periods up to 6 months at daily doses of 300 mg. This dose was well tolerated, and ev idence of PSA suppression and responses were seen that were at least e quivalent to those observed at lower doses. Pharmacokinetics evaluatio n has been carried out at this dose, and there is now evidence of nonl inearity of plasma concentrations, suggesting that further dose escala tion is unlikely to confer major additional benefit over the 150- and 200-mg doses. To confirm the evidence of nonlinearity of plasma concen trations at doses >200 mg, a randomization between 450 mg bicalutamide and medical castration is currently being carried out. Patients are s till being recruited into this trial, but there has been no evidence o f any change in the tolerability profile of bicalutamide at any dose > 150 mg. Conclusions. In summary, bicalutamide has shown increasing evi dence of activity as a competitive blocker of the androgen receptor al daily doses of up to 200 mg. At daily doses >200 mg, there is evidenc e of nonlinearity of plasma concentrations, and therefore further bene fit is unlikely to be seen as a result of further escalating the dose of bicalutamide.