The purpose of this study is to test the safety of ketoconazole and how well it works after chemotherapy has been used. Ketoconazole at lower doses has been used for fungal infections however has not yet been approved by the Food and Drug Administration for use in prostate cancer. Ketoconazole has been used for many years at high doses for prostate cancer, and this study will be to look at use of lower dose ketoconazole after someone has received chemotherapy. Ketoconazole works by halting the production of steroids in your body, including testosterone, and is thought to work directly on prostate cancer cells in published lab studies.

The aim of the study is to research the response of low dose ketoconazole in hormone refractory prostate cancer (HRPC) patients who have already undergone chemotherapy as part of their prostate cancer treatment. The hypothesis of the study is that HRPC patients who have been previously treated with chemotherapy will demonstrate objective PSA response rates to low dose ketoconazole, comparable to historical response rates reported in chemotherapy-naïve patients. This is a single arm trial, with all participants given ketoconazole 200mg TID, along with hydrocortisone given at 20mg in the morning, 10mg at night daily. Each cycle will consist of 28 days. The subject's study participation will continue until subject experiences disease progression, unacceptable toxicities, withdraws consent from the study or dies.

Inclusion Criteria:

• Patients must have histologically or cytologically proven prostate cancer with a Gleason score available or interpretable.
• Patients must have prostate cancer deemed to be hormone refractory, by progression of measurable or evaluable disease or rising PSA.
• Patients must be >18 years old
• Patients must have received at least one prior chemotherapy regimen >3 weeks prior to initiation of study and patients must have recovered from the side effects of the therapy
• Patients must have an ECOG status of 0-3
• Patients must have normal organ and marrow function, determined within 14 days of registration.
• Patients must have been surgically or medically castrated. If the method of castration was LHRH agonists (leuprolide or goserelin), then the patient must be willing to continue the use of LHRH agonists.
• Patients must have a serum total testosterone level <50 ng/dl
• If the patient has been treated with non-steroidal anti-androgens (flutamide, bicalutamide or nilutamide) or other hormonal treatment (megace or steroids), the patient must have stopped these agents at least 28 days prior to enrollment for flutamide, megace or steroids and at least 42 days prior to enrollment for bicalutamide or nilutamide; and the patients must have demonstrated progression of disease since the agents were suspended.

Exclusion Criteria:

• Patients with any condition that impairs the ability to swallow medications orally
• Patients who are unable to give informed consent
• Patients who have received ketoconazole treatment for prostate cancer in the past
• Patients with other active malignancies in the past 3 years except nonmelanoma skin cancer
• Patients may not be receiving any other investigational agents
• Patients with known hypersensitivity to ketoconazole
• Patients may not be taking certain medications, including terbinafine, astemizole, triazolam, statins (except pravastatin and fluvastatin) and acid suppressive agents (antacids, H2 blockers, PPI) while on ketoconazole, and patients on these medications must agree to discontinue these medications and consider alternative therapies.

From the start of treatment until 8-12 weeks after removal from study, assessed for up to 2 years.