Prostate cancer is a progressive disease. Over time, the cancer cells start to become resistant to hormonal therapies that are designed to block the release and/or uptake of androgen. In the past, patients were considered to have reached the state of metastatic CRPC after failing first-line hormonal therapy and were often immediately started on chemotherapy. However, we’ve learned over the last decade or so that demonstrating resistance to one kind of hormonal therapy does not mean these patients cannot be successfully treated with a second or even third trial of hormonal manipulation. Clinical trials with 2 new oral agents have shown them to be effective in patients who have failed conventional hormonal therapy. The first is an antiandrogen, developed by Dr. Charles Sawyers, called MDV3100. An antiandrogen given in concert with gonadotropin-releasing hormone (GnRH) analogues has been the standard of care for a long time; MDV3100 is a novel antiandrogen that has a much higher binding affinity to the androgen receptor compared with other antiandrogens. So far, data show that patients who already failed treatment with a GnRH analogue in concert with bicalutamide or nilutamide respond well to MDV3100 with only minimal toxicities. We’ve seen significant declines in prostate-specific antigen (PSA) levels with this agent, and although it’s too early to determine whether it will have an effect on survival outcomes, any oral agent that provides an immediate biochemical response without significantly affecting quality of life in patients who have already failed standard hormonal therapy is very promising. The second new agent in this area of research is called abiraterone; it is being developed by Dr. Johann de Bono. Ketoconazole is an antifungal agent that is often used as a second- or third-line hormonal treatment in metastatic prostate cancer. It works at the level of the adrenal gland, which plays an important role in the manufacture of estrogen or testosterone via steroidogenesis. Although the drug can be effective in some patients, it causes significant nausea, vomiting, rash, and fatigue. Abiraterone is an oral medication that also targets steroidogenesis by the adrenal glands, but by a different pathway. Dr. de Bono and colleagues have seen some dramatic declines in PSA as well as on radiographic scans in patients who have failed prior hormonal therapy, including those who failed ketoconazole and/or docetaxel, but with considerably lower rates of toxicity compared with ketoconazole. There is great interest in moving this agent into phase 3 trials, especially considering its ability to elicit a response in patients who have already failed multiple hormonal therapies. ### Susan F. Slovin, MD, PhD