FDA Approves Abiraterone for Castration-Resistant Prostate Cancer



In a remarkable expansion of options for men with advanced prostate cancer, on April 28 the Food and Drug Administration issued its fourth approval of a new treatment for use in late-stage disease.

Abiraterone acetate is indicated for treatment of metastatic castration-resistant prostate cancer in men who have already received chemotherapy with docetaxel (Taxotere). An androgen suppressant, abiraterone decreases production of testosterone by inhibiting a protein called CYP17A1.

The new oral drug will be marketed as Zytiga by Johnson & Johnson’s Centocor Ortho Biotech of Horsham, Pa. It is to be used daily in combination with the steroid prednisone in late-stage disease.

The FDA considered abiraterone under its priority review program and acted ahead of its June 20, 2010, regulatory goal date. Approval was widely anticipated, as the abiraterone-prednisone combination was shown to prolong life by about 4 months in a randomized, international, phase III trial that enrolled 1,195 men whose disease was progressing after one or two chemotherapy regimens, including one with docetaxel.

Median overall survival reached 14.8 months with a daily dosage of 1,000 mg of abiraterone plus 5 mg of twice-daily prednisone vs. 10.9 months among late-stage patients who received a placebo with prednisone in the study. Investigators reported a 35% reduction in the risk of death (hazard ratio.646; P less than .0001).

Dr. Johann de Bono

Although more than half of patients had grade 3/4 toxicities, Dr. Johann de Bono of the Royal Marsden NHS Foundation Trust and the U.K. Institute of Cancer Research, both in London, described the drug as well tolerated when he presented the data in fall 2010 at the annual congress of the European Society for Medical Oncology.

The most commonly reported side effects, as listed by the FDA, included: "joint swelling or discomfort, low levels of potassium in the blood, fluid retention (usually of the legs and feet), muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, high blood pressure, heartbeat disorders, urinary frequency, increased nighttime urination, upset stomach or indigestion and upper respiratory tract infection."

The company announcement says abiraterone should be used with caution in patients who have a history of cardiovascular disease or "medical conditions that might be compromised by increases in hypertension, hypokalemia and fluid retention." It also recommends monitoring for adrenocortical insufficiency and hepatotoxicity, and advises that abiraterone should be taken on an empty stomach.

Abiraterone becomes the fourth drug approved for treatment of patients with prostate cancer over the last year. In April 2010, the agency approved the sipuleucel-T (Provenge) vaccine for asymptomatic or minimally symptomatic castration-resistant prostate cancer. This was followed in June 2010, by approval of cabazitaxel (Jevtana), a new injectable taxane that acts as a microtubule inhibitor, for use in combination with prednisone after the failure of a docetaxel-containing therapy.

Then, in November 2010 denosumab (Xgeva) received FDA approval for treatment of skeletal-related events in solid tumors. The indication was based in part on favorable results in a trial that enrolled 1,901 patients with hormone-refractory prostate cancer.

"The last 12 months have been unprecedented in the field of prostate cancer. Between April of 2010 and April of 2011, our field has seen four new therapeutic agents," commented Dr. Judd W. Moul, the James H. Semans, M.D. Professor of Surgery and chief of the Division of Urologic Surgery at Duke University Medical Center in Durham, N.C., in an interview.

"Our toolbox of therapeutic options has grown tremendously in the last year, and it is now more imperative than ever to embrace the multidisciplinary care team of urologists, medical oncologists, radiation oncologists, and other team members to best sequence and strategize for use of these new agents," he added.

Dr. de Bono is employed by the U.K. Institute of Cancer Research, London, which has a commercial interest in the development of abiraterone acetate and has served as a paid consultant of Johnson & Johnson.

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