An evaluation of high-doses ketoconazole with hydrocortisone substitution in hormone-refractory prostate cancer.

We investigated the efficacy of ketoconazole, an inhibitor of testicular and adrenal biosynthesis, for treating patients with progression of hormone-refractory prostate cancer. The study comprised 35 patients with progressive disease despite salvage treatment with estramustine with or without vinblastine. Treatment consisted high-doses ketoconazole (400 mg three times daily) and hydrocortisone substitution. Patients were monitored clinically and with serial PSA measurements every 3 months. The principal endpoint of the study was PSA response to applied therapy. Of the 35 patients, 18 (51.4%) showed a decrease in PSA 50% with a median duration of 30 weeks (range 6-60 weeks). A PSA reduction 50% was seen in 15 of 31 patients (48.4%) with established metastasis. Twelve patients (34.2%), all of whom had metastasis, exhibited a PSA decrease 80% with median duration of 9 months (range 3-48 months). The median time to progression was 6.3 months (range 0-27 months) and the median survival time was 12.5 months (range 3-48 months). Twelve (34.3%) reported toxicity related to ketoconazole, whereas no patients required discontinuation of therapy. It is apparent from this study that a reasonable percentage of patients failing salvage chemotherapy (estramustine with or without vinblastine) respond favorably to high-dose ketoconazole and that toxicity is mild. In the absence of studies demonstrating better survival with chemotherapy, we believe that a trail of ketoconazole should be considered when progression of PSA occurs, following initial hormonal androgen deprivation.