Clinical Context

Testosterone stimulates growth of prostate tumors. A mainstay of prostate cancer treatment is to lower production of testosterone or to inhibit its effects with drugs or surgery. Some cases of prostate cancer are castration resistant, meaning that the prostate cancer cells continue to grow even in the presence of low testosterone levels.

The mechanism of action of abiraterone acetate is to reduce testosterone production. The US Food and Drug Administration (FDA) first approved abiraterone acetate in April 2011 as a second-line treatment after docetaxel chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC).

Study Synopsis and Perspective

The FDA has approved the expanded use of abiraterone acetate (Zytiga) to first-line therapy for mCRPC.

The drug, which decreases testosterone production, was approved in April 2011 as a second-line treatment after docetaxel chemotherapy in the same population.

This expanded approval "demonstrates the benefit of evaluating a drug in an earlier disease setting and provides patients and healthcare providers the option of using [abiraterone] earlier in the course of treatment," stated Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA Center for Drug Evaluation and Research, in an FDA news release.

The expanded use of abiraterone was approved by the FDA's priority review program on the basis of a randomized double-blind study, which was published online December 10 in the New England Journal of Medicine.

It comes on the heels of a recommendation made in November 2012 by the Committee for Medicinal Products for Human Use at the European Medicines Agency, which usually means an approval in Europe.

The study results, which were initially reported at the annual meeting of the American Society of Clinical Oncology in June 2012, involved 1088 men with mCRPC who had not previously received chemotherapy.

All subjects received prednisone 5 mg twice daily, and were then randomized to receive either abiraterone 1000 mg daily or placebo.

The coprimary endpoints were radiographic progression-free survival and overall survival.

The data and safety monitoring committee unanimously recommended unblinding the study early, after aggregate efficacy and safety data from the second planned interim analysis showed that 43% of the expected deaths had occurred.

At that time, median follow-up was 22.2 months. Radiographic progression-free survival was significantly longer in the abiraterone group than in the placebo group (16.5 vs 8.3 months; hazard ratio [HR], 0.53; P < .001).

Median overall survival was not reached in the abiraterone group and was 27.2 months in the placebo group. The mortality rate was lower in the abiraterone group than in the placebo group (27% vs 34%). There was a 25% decrease in the risk for death in the abiraterone group (HR, 0.75; P = .01), "indicating a strong trend toward improved survival [with abiraterone]; however, the prespecified boundary for significance (P ≤ .001) was not reached at the observed number of events," write the study authors, led by Charles Ryan, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

For the secondary endpoints, there was a significant benefit with abiraterone in time to initiation of cytotoxic chemotherapy (25.2 vs 16.8 months; HR, 0.58; P < .001), time to opiate use for cancer-related pain (not reached vs 23.7 months; HR, 0.69; P < .001), time to prostate-specific antigen progression (11.1 vs 5.6 months; HR, 0.49; P < .001), and time to decline in Eastern Cooperative Oncology Group performance status of at least 1 point (12.3 vs 10.9 months; HR, 0.82; P = .005).

There were more grade 3 or 4 adverse events in the abiraterone group than in the placebo group (48% vs 42%). Discontinuation of treatment because of adverse events was similar in the 2 groups (10% vs 9%). Adverse events leading to death occurred in 4% of the abiraterone group and 2% of the placebo group.

Adverse events reported more frequently in the abiraterone group included fatigue (39% vs 34%), arthralgia (28% vs 24%), and peripheral edema (28% vs 24%). Mineralocorticoid-related toxic effects were also more common in the abiraterone group, including hypertension (22% vs 13%) and hypokalemia (17% vs 13%).

"Treatment effects were consistently favorable across all prespecified patient subgroups," indicating the magnitude of the survival benefit of abiraterone/prednisone over prednisone alone, the authors write.

More information on the expanded approval of abiraterone is available on the FDA Web site.

The study was funded by Ortho Biotech Oncology Research and Development, which is now part of Janssen Research and Development. Dr. Ryan has received grant funding and consultancy fees from Janssen and other pharmaceutical companies. Some of the study coauthors are employees of Janssen and/or have disclosed relevant financial relationships with industry, as detailed in the disclosure forms contained in the original article.

N Engl J Med. 2013; 368:138-148.

Clinical Implications

• After priority review, the FDA has approved the expanded use of abiraterone acetate as first-line treatment of mCRPC, which offers patients and healthcare providers the option of using abiraterone earlier in the course of treatment. The Committee for Medicinal Products for Human Use at the European Medicines Agency also recommended this expanded indication.
• In the randomized double-blind trial underlying FDA approval for the expanded use of abiraterone, there was a strong trend toward lower mortality rates in the abiraterone group vs the placebo group, and significantly longer radiographic progression-free survival time. There were also significant benefits with abiraterone for the secondary endpoints. Participants in both groups received prednisone 5 mg twice daily.
• The abiraterone group had more grade 3 or 4 adverse events than the placebo group (48% vs 42%), although discontinuation of treatment because of adverse events was similar in both groups (10% vs 9%). Fatal adverse events occurred in 4% of the abiraterone group and in 2% of the placebo group. Fatigue, joint pain, peripheral edema, and mineralocorticoid-related toxic effects were more common in the abiraterone group.

CME Test