Phase II Study of Ketoconazole Plus Granulocyte-Macrophage Colony-Stimulating Factor for Prostate Cancer: Effect of Extent of Disease on Outcome

Purpose: The efficacy of ketoconazole plus the immunostimulatory cytokine granulocyte-macrophage colony-stimulating factor was prospectively evaluated in patients with castration resistant prostate cancer with and without metastases. Materials and Methods: Eligible patients had progressive castration resistant prostate cancer by consensus criteria and had received no prior immunotherapy, chemotherapy or ketoconazole. Patients received 400 mg ketoconazole orally 3 times daily, and 20 mg hydrocortisone orally each morning and 10 mg hydrocortisone orally each evening. Granulocyte-macrophage colony-stimulating factor (250 μg/m²) was administered subcutaneously on days 15 to 28 of each 28-day cycle. Progression was defined as disease progression or toxicity. Results: A total of 49 patients were enrolled, including 37 with radiographically evident metastases and 12 with prostate specific antigen only disease. Median patient age was 68 years (range 52 to 84) and median prostate specific antigen was 23.1 ng/ml (range 5.4 to 306.5). Time to progression, which was the primary study end point, was 9.7 months for all patients. Ten of the 30 treatment failures showed radiographic progression and 6 were due to toxicity, while treatment failure in 14 of 30 patients (47%) consisted only of increasing prostate specific antigen. Median time to progression was 6.9 and 15.4 months in patients with and without metastases, respectively (p = 0.01). Of 48 patients 36 (75%, 95% CI 60-86) experienced a 50% or greater decrease in prostate specific antigen. Four grade 4 events occurred that were unrelated to the study drug. Grade 3 events related to study therapy in more than 1 patient consisted of fatigue in 7 (14%). Conclusions: Combined ketoconazole and granulocyte-macrophage colony-stimulating factor yields a high response rate and it is an option for patients with castration resistant prostate cancer. Time to progression in patients without metastases is significantly longer than in those without metastases.