(An initial blog was published on this website on Jan. 8th, 2011, describing results from late stage clinical trials of abiraterone acetate in hormone-refractory prostate cancer patients.)
On April 28th, the Food and Drug Administration (FDA) approved abiraterone (Zytiga) for the treatment of men with metastatic castration (hormone)-resistant prostate cancer (meaning the disease progresses despite low levels of tumor growth-promoting hormones) that are no longer responding to the chemotherapy drug docetaxel (taxotere). It should also be noted that in spring, 2010, the FDA approved cabazitaxel (Jevtana) for the same indication. (Cabazitaxel is a member of a class of drugs based on natural products called taxanes. These were originally isolated and identified from yew plants.) In both cases, the FDA approvals were based on findings from large phase III trials in which both drugs improved patient survival as reported in the National Cancer Institute’s Cancer Bulletin, May 3rd, 2011.
The survival improvements produced by abiraterone and cabazitaxel are meaningful but the benefits are still modest: both drugs improve patients’ median overall survival by approximately 2 to 4 months. One advantage is that abiraterone seemingly has fewer side effects and can be taken orally according to Dr. William Dahut of the National Cancer Institute’s Center for Cancer Research.
In the phase III trial, 1,200 patients were randomly assigned to abiraterone administered in combination with the steroid prednisone or to prednisone plus placebo. The median survival time was 14.8 months in patients who received abiraterone and prednisone compared to 10.9 months in those receiving prednisone alone. In addition to testosterone, abiraterone affects production of other hormones that can lead to side effects such as hypertension. Therefore steroids like prednisone are used to protect against or minimize such side effects. Steroids can have their own long-term side effects, though, so the need to combine abiraterone with steroids could limit use of abiraterone in men with earlier-stage disease and longer life expectancies.
Abiraterone’s target is the production of testosterone. It works by inhibiting an enzyme, CYP17, that plays a central role in allowing the body to produce testosterone from cholesterol. However, studies have shown that tumor cells adapt to a low-androgen (such as testosterone) environment, in part by increasing the expression of the androgen receptors on their cell surfaces. So, while the overall amount of testosterone in the body may be very low, it is still being produced, and tumor cells develop the ability to take in as much as they can get. For more information, see the following link to WebMD.
With these newly-approved drugs and several others in clinical trials, more research is needed to determine the best sequence of therapies, or which combination of multiple therapeutic agents might be more effective to benefit the individual patient. In addition to abiraterone, two other drugs, TAK-700 and MDV-3100, are in phase III clinical trials in men with castration (hormone)-resistant prostate cancer that is no longer responding to docetaxel. TAK-700 also targets the production of testosterone but it could potentially be used at doses that would not require concomitant steroid supplementation and the resulting side effects of steroids such as prednisone. MDV3100 works differently, disrupting tumor cells’ ability to use testosterone. It does this in part by clogging up androgen receptors on cells which bind testosterone. Because of its mechanism of action, MDV3100 does not have to be used in combination with steroids.
The overall good news is that newer therapies which perform their functions differently are progressing through the pipeline for use in combating prostate cancer.