FDA Approves Abiraterone for Metastatic Prostate Cancer

April 28, 2011 — The US Food and Drug Administration (FDA) has approved abiraterone acetate (Zytiga, Cougar Biotechnology) in combination with prednisone for the treatment of metastatic, castration-resistant prostate cancer in men who have received prior docetaxel chemotherapy.

The application was reviewed under the FDA's priority review program, and the new oral agent is being approved ahead of the product's June 20, 2011, regulatory goal date, according to the FDA.

In the pivotal COU-AA-301 trial, patients who received abiraterone acetate plus prednisone had a median overall survival duration of 14.8 months, compared with 10.9 months for patients receiving prednisone plus placebo. The difference was statistically significant.

"Zytiga prolonged the lives of men with late-stage prostate cancer who had received prior treatments and had few available therapeutic options," said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research.

Abiraterone treatment also resulted in significant differences between the 2 treatment groups for all the COU-AA-301 trial's secondary endpoints, including time to prostate-specific antigen (PSA) progression, radiographic progression-free survival, and PSA response rate. These results and the survival data were presented this year at the 35th European Society for Medical Oncology (ESMO) Congress and reported by Medscape Medical News at the time.

Abiraterone investigator Johann de Bono, MBBS, PhD, suggested that the modest improved survival was impressive in light of the efforts to date in the field. "While 3.9 months may not seem like much, in the history of prostate cancer, only 4 drugs have ever shown a survival benefit," he noted at ESMO.

The new drug targets the protein cytochrome P450 17A1 (CYP17A1), which plays an important role in the production of testosterone, according to the FDA. Abiraterone works by decreasing the production of testosterone, which stimulates prostate cancer cell growth.

Abiraterone is being marketed by Centocor Ortho Biotech.

More Details on Efficacy, Adverse Events

In the COU-AA-301 study, Dr. de Bono and colleagues randomly assigned 1195 patients with castration-resistant metastatic prostate cancer who had been previously treated with docetaxel to receive abiraterone, 1000 mg, plus prednisone, 5 mg, twice daily (n = 797) or placebo plus prednisone (n = 398) at 147 centers in 13 countries.

Primary and Secondary Endpoints

Response	Abiraterone Acetate Group	Placebo Group	P Value
Median overall survival (mo)	14.8	10.9	< .0001
Time to PSA progression (mo)	10.2	6.6	< .0001
Radiographic progression-free survival (mo)	5.6	3.6	< .0001
PSA response (%)	38	10	< .0001

Adverse events were more commonly observed in the abiraterone group. Fluid retention was more common (30.5% vs 22.3%), as was hypokalemia (17.1% vs 8.4%), but grade 3/4 hypokalemia (3.8% vs 0.8%) and grade 3/4 hypertension (1.3% vs 0.3%) were infrequent.

Liver function test abnormalities were reported in 10.4% of the patients who received the investigational agent compared with 8.1% in the placebo group. Cardiac problems were also more common in the abiraterone group compared with placebo, at 12.5% vs 9.4%.

However, overall, Dr. de Bono believes that the drug is not terribly toxic. "It is an oral agent and does not have the toxicity of chemotherapy, and it is well tolerated in my experience," he said at ESMO.

Multiple New Treatments on Horizon in This Setting

In addition to the newly approved abiraterone, 2 other new agents have been approved for men with advanced prostate cancer in the past year.

Sipuleucel-T (Provenge, Dendreon) is an immunotherapy indicated for asymptomatic or minimally symptomatic men with castration-resistant metastatic prostate cancer. It improved overall survival duration by a median of 4.1 months compared with survival in a control group.

Candidates for this vaccine should have a good performance status, an estimated life expectancy of more than 6 months, and no visceral disease, according the 2011 National Comprehensive Cancer Network guidelines.

Another new second-line option in this setting — cabazitaxel (Jevtana, Sanofi-Aventis) — has also been shown in a phase 3 trial to prolong overall survival; median survival duration was 15.1 months in the cabazitaxel group and 12.7 months in the mitoxantrone group.

For more information on abiraterone, contact the FDA Office of Oncology Drug Products or visit the FDA Web site.