FDA Approves Abiraterone for Advanced Prostate Cancer
For the second time in a year, the Food and Drug Administration (FDA) has approved a new treatment for men with advanced prostate cancer who, until recently, have had few effective treatment options.
Last Thursday, the agency approved abiraterone (Zytiga) for the treatment of men with metastatic castration-resistant prostate cancer (meaning the disease progresses despite low levels of tumor-fueling hormones) that are no longer responding to the chemotherapy drug docetaxel. Last spring, the agency approved cabazitaxel (Jevtana) for the same indication. In both cases, the approvals were based on findings from large phase III trials in which the drugs improved patient survival.
The availability of these two new drugs—as well as the immunotherapy sipuleucel-T (Provenge), which the FDA approved last April as an alternative to docetaxel for some men with metastatic castration-resistant prostate cancer—has altered the treatment landscape for advanced prostate cancer, several researchers said.
With a number of other experimental drugs in clinical trials also showing promise for the treatment of metastatic prostate cancer, it’s almost “an embarrassment of riches” at the moment, said Dr. Ian Thompson, of the University of Texas Health Science Center at San Antonio.
But although the survival improvements produced by abiraterone and cabazitaxel are meaningful, he cautioned, the benefits are still modest: both drugs improve patients’ median overall survival by approximately 2 to 4 months.
In addition, the availability of multiple treatment options creates new—albeit welcome—problems, as researchers and clinicians must now try to make difficult decisions about which drugs to use in which patients and when. Some of these decisions, however, involve so-called “off-label” uses of the available therapies.
Androgens Are Still Important
Abiraterone’s approval was based on findings from a clinical trial, funded by the drug’s manufacturer, Cougar Biotechnology, in which nearly 1,200 patients were randomly assigned to abiraterone in combination with the steroid prednisone or to prednisone plus placebo. The median overall survival was 14.8 months in patients who received abiraterone and prednisone and 10.9 months in those who received prednisone alone, researchers reported last December at a major European cancer conference. Patients treated with abiraterone experienced few serious side effects. (Findings from the trial that led to cabazitaxel approval were reported in March 2010).
Abiraterone and cabazitaxel haven’t been compared in a head-to-head trial, but abiraterone has fewer serious side effects and can be taken orally, which may make it the preferred first option for these patients, said Dr. William Dahut of NCI’s Center for Cancer Research.
“The ease of administration [of abiraterone] and the favorable side-effect profile will obviously play a role in which treatment clinicians and patients choose,” agreed Dr. Maha Hussain of the University of Michigan Comprehensive Cancer Center.
Patients who have already been treated with the drug ketoconazole may be an exception. (Although not approved by the FDA for use in men with advanced prostate cancer, ketoconazole has proven beneficial for some patients.) “Patients with prior exposure to ketoconazole probably don’t respond as well to abiraterone” as those who haven’t received it, Dr. Dahut explained.
Whereas cabazitaxel is a next-generation drug in the class of chemotherapy agents called taxanes, abiraterone is the first in an approaching wave of new agents for prostate cancer that, directly or indirectly, target testosterone—a wave that represents a “paradigm shift” in the treatment of this disease, according to Dr. Dahut. (See the box at the bottom of the page.) Abiraterone works by inhibiting an enzyme, CYP17, that plays a central role in allowing the body to produce testosterone from cholesterol.
Drug-induced castration with luteinizing hormone-releasing hormone agonists—which rob prostate tumor cells of the testosterone they need to grow—has been a standard and successful treatment for prostate cancer for several decades. But in many patients the disease eventually progresses despite very low levels of available testosterone.
“Fifteen years ago, it was largely believed that once a patient's disease progressed on hormone therapy, he was hormone refractory and there was really no point going on to second- and third-line hormonal therapies,” Dr. Dahut said. But tumor cells, studies have shown, adapt to a low-androgen environment, in part by increasing the expression of the androgen receptors on their surfaces. So, while the overall amount of testosterone in the body may be very low, it’s still being produced, and tumor cells develop the ability to take in as much as they can get.
Abiraterone’s efficacy, he added, signals “the importance of targeting testosterone” even in patients in whom the hormone “is at castrate levels.”
Which Drugs, Combinations, or Sequences?
The availability of several new treatment options for advanced prostate cancer has created a situation in which patients and their doctors may need to make difficult clinical decisions when there isn’t necessarily sufficient clinical evidence. For example, some doctors will likely want to use abiraterone in patients with advanced disease who are no longer responding to standard hormonal therapies but who have not yet been treated with docetaxel.
Patients are likely to have responses to abiraterone at this point in their disease, Drs. Dahut and Hussain agreed, although, Dr. Dahut cautioned, there is no evidence yet that this treatment approach will improve survival. And, Dr. Hussain added, insurance coverage of this off-label indication is unlikely at this time. A phase III trial testing this approach is under way.
If the FDA eventually approves abiraterone for use in patients with castration-resistant disease who have not yet been treated with docetaxel, there will also be questions about whether abiraterone or sipuleucel-T should be used first.
More research is needed to determine the best sequence of therapies, or which combination of therapies might be more effective, Dr. Thompson said. The goal is to “conduct adaptive trials that use multiple agents that are most likely to benefit the individual patient,” he added.
Efforts in this area need to proceed with serious deliberation and care, Dr. Hussain stressed, particularly when it comes to testing combinations of drugs. “Smart, rational approaches supported by scientific mechanistic data to justify testing these agents in combination are needed,” she said, “not just because they’re available and we can do it.”