The US Food and Drug Administration (FDA) has approved the expanded use of abiraterone acetate (Zytiga, Janssen Biotech Inc) to first-line therapy for metastatic castration-resistant prostate cancer (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," Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA Center for Drug Evaluation and Research, stated 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 last month 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, 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 end points 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 end points, 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 ECOG 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.
The study was funded by Ortho Biotech Oncology Research and Development, which is now part of Janssen Research and Development. Dr. Ryan reports receiving grant funding and consultancy fees from Janssen and other pharmaceutical companies. Some of the study coauthors are employees of Janssen and/or have financial relationships with industry, as detailed in the paper.
N Engl J Med. Published online December 10, 2012. Abstract
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