SURPRISING ACTIVITY OF FLUTAMIDE WITHDRAWAL, WHEN COMBINED WITH AMINOGLUTETHIMIDE, IN TREATMENT OF HORMONE-REFRACTORY PROSTATE-CANCER

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'' p rostate cancer. Methods: Twenty-nine patients with metastatic prostate cancer were treated with simultaneous flutamide withdrawal and aminog lutethimide (250 mg given orally four times daily). All patients were taking flutamide at the time of entry, and previous treatments with me dical or surgical castration, flutamide, suramin, and hydrocortisone h ad 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 nons urgically castrated patients had previously failed; however, these pat ients continued to receive depot leuprolide. Results: In 14 (48%) of 2 9 patients, the prostate-specific antigen (PSA) decreased by more than 80% for 4 or more weeks. Improvements in anemia, thrombocytopenia, so ft-tissue masses, bone scans, and symptoms were also noted. Factors as sociated with response included prolonged flutamide pretreatment, a ma rkedly elevated pretreatment PSA, and the absence of soft-tissue disea se. Conclusions: Flutamide withdrawal, when combined with the simultan eous administration of aminoglutethimide, is a therapeutically active approach in patients with ''hormone-refractory'' prostate cancer. Impl ications: On the basis of these and additional data, we hypothesize th at prolonged exposure to flutamide results in the selective proliferat ion of cancer cells containing a mutant androgen receptor that aberran tly recognizes flutamide metabolites and nonandrogenic steroids as and rogenic stimuli.