Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of "hormone-refractory" prostate cancer

Abstract

Background: The best treatment for patients with "hormone-refractory" metastatic prostate cancer is unclear, particularly in patients for whom suramin and hydrocortisone have failed.

Purpose: We investigated a combination of flutamide withdrawal and aminoglutethimide in suramin- and hydrocortisone-pretreated patients with "hormone-refractory" prostate cancer.

Methods: Twenty-nine patients with metastatic prostate cancer were treated with simultaneous flutamide withdrawal and aminoglutethimide (250 mg given orally four times daily). All patients were taking flutamide at the time of entry, and previous treatments with medical or surgical castration, flutamide, suramin, and hydrocortisone had failed in all of these patients. Because of suramin-induced adrenal insufficiency, all patients had previously received, and continued to receive, physiological doses of hydrocortisone. Treatment of all non-surgically castrated patients had previously failed; however, these patients continued to receive depot leuprolide.

Results: In 14 (48%) of 29 patients, the prostate-specific antigen (PSA) decreased by more than 80% for 4 or more weeks. Improvements in anemia, thrombocytopenia, soft-tissue masses, bone scans, and symptoms were also noted. Factors associated with response included prolonged flutamide pretreatment, a markedly elevated pretreatment PSA, and the absence of soft-tissue disease.

Conclusions: Flutamide withdrawal, when combined with the simultaneous administration of aminoglutethimide, is a therapeutically active approach in patients with "hormone-refractory" prostate cancer.

Implications: On the basis of these and additional data, we hypothesize that prolonged exposure to flutamide results in the selective proliferation of cancer cells containing a mutant androgen receptor that aberrantly recognizes flutamide metabolites and nonandrogenic steroids as androgenic stimuli.