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| Title: High-dose bicalutamide monotherapy for the treatment
of prostate cancer. |
| Title Abreviation: Urology |
Date of Pub: 1996 Jan |
| Author: Blackledge GR; |
| Issue/Part/Supplement: 1A Suppl |
Volume Issue: 47 |
Pagination: 44-7; discussion 48-53 |
| MESH Headings: Androgen Antagonists (*AD); Anilides (*AD); Human;
Male; Prostatic Neoplasms (*DT); -RN-; |
| Journal Title Code: WSY |
Publication Type: CLINICAL TRIAL |
| Date of Entry: 960226N |
Entry Month: 9605 |
| Country: UNITED STATES |
Index Priority: 2 |
| Language: Eng |
Unique Identifier: 96149766 |
| Unique Identifier: 96149766 |
ISSN: 0090-4295 |
| Abstract: OBJECTIVES. Bicalutamide is a nonsteroidal
competitive inhibitor of androgens at the androgen receptor. The level of blockade that
can be achieved is dependent on the relative numbers of molecules of the agonist and the
competitive antagonist around the receptor. Increasing the dose of a competitive
inhibitor, therefore, should potentially increase the level of blockade. Bicalutamide
has been investigated extensively at daily doses up to 150 mg, and there is evidence of
increasing blockade at doses up to this point, as evidenced by increasing suppression of
prostate-specific antigen (PSA) and also improvement in response rate, both subjective and
objective. At doses of up to 150 mg, increases 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 with the use of bicalutamide
as monotherapy. METHODS. A number of studies 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
primary treatment for advanced prostate cancer and also as a second-line treatment option
for patients who have demonstrated a flutamide withdrawal response. RESULTS. In
noncomparative trials, the decline in PSA value associated with daily doses of 200 mg bicalutamide
was greater than that observed with daily doses of 150 mg, and there was also a slightly
higher response rate. When 200 mg daily doses were used as therapy following failure of
flutamide in combination with castration, and also following evidence of a flutamide
withdrawal response, further responses 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 evaluated 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 evidence of PSA suppression and responses were seen that
were at least equivalent to those observed at lower doses. Pharmacokinetics evaluation has
been carried out at this dose, and there is now evidence of nonlinearity of plasma
concentrations, suggesting that further dose escalation is unlikely to confer major
additional benefit over the 150- and 200-mg doses. To confirm the evidence of nonlinearity
of plasma concentrations at doses > 200 mg, a randomization between 450 mg bicalutamide
and medical castration is currently being carried out. Patients are still being recruited
into this trial, but there has been no evidence of any change in the tolerability profile
of bicalutamide at any dose > 150 mg. CONCLUSIONS. In summary, bicalutamide
has shown increasing evidence of activity as a competitive blocker of the androgen
receptor at daily doses of up to 200 mg. At daily doses > 200 mg, there is evidence of
nonlinearity of plasma concentrations, and therefore further benefit is unlikely to be
seen as a result of further escalating the dose of bicalutamide. |
| Abstract By: Author |
| Address: Zeneca Pharmaceuticals, Macclesfield, Cheshire, United
Kingdom. |
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