Progression-free survival doubled in men with metastatic castration-resistant prostate cancer with no chemotherapy exposure who were treated with abiraterone acetate plus prednisone versus prednisone alone.
Fred Saad, MD
Professor, Department of Surgery Head, Urologic Oncology University of Montreal Hospital Center
Progression-free survival (PFS) doubled in men with metastatic castration-resistant prostate cancer (mCRPC) with no chemotherapy exposure who were treated with abiraterone acetate (Zytiga) plus prednisone versus prednisone alone, according to updated clinical trial results presented during the 2013 Annual Meeting of the American Urological Association (AUA).1
The multinational phase III trial, COU-AA-302, ended prematurely when a planned interim analysis showed a median radiographic PFS (rPFS) of 16.5 months with abiraterone versus 8.3 months with prednisone alone. Overall survival (OS) improved by 21% in the abiraterone arm, but the difference did not meet prespecified criteria for statistical significance.
Based on the results, the FDA expanded the label for Zytiga in December 2012, adding an indication for the treatment of men with mCRPC prior to chemotherapy. The change was expected to as much as quadruple the number of men eligible for treatment with abiraterone.
“The results showed that adding abiraterone to prednisone significantly slowed the progression of metastatic castration-resistant prostate cancer in asymptomatic or mildly symptomatic patients who have not previously been treated with chemotherapy,” said Fred Saad, MD, a professor at the University of Montreal Hospital Center, who presented the findings during the AUA meeting, held in San Diego, California, in May. “Overall survival was increased, along with clinically important secondary endpoints, such as time to opiate use and to initiation of chemotherapy.”
Prior use of bone-targeted therapy had no influence on rPFS or OS, he added.
Zytiga gained FDA approval in 2011 for the treatment of mCRPC that has progressed after chemotherapy; when the COU-AA-302 trial began, the drug’s impact on disease with no prior chemotherapy exposure had not been determined. To address that issue, investigators in the United States, Canada, United Kingdom, Europe, and Australia randomly allocated 1088 patients to prednisone plus abiraterone or placebo.
The trial had coprimary endpoints: rPFS and OS. The trial was powered to detect a 33% reduction in the hazard for rPFS, determined on the basis of 378 progression-free events by central radiology review.
A single interim analysis was planned for rPFS after 378 events. Three interim analyses of OS were scheduled to occur after 116 deaths, 311 deaths, and 425 deaths, followed by a final analysis after 773 deaths if the trial continued to conclusion.
After a median follow-up of 27.1 months, the interim analysis for rPFS occurred, revealing a statistically significant hazard ratio (HR) of 0.53 in the abiraterone arm, representing a 47% reduction in the risk of progression (P <.0001).
When the interim analysis for rPFS occurred, the median OS was 35.3 months in the abiraterone arm and 30.1 months in the placebo arm (HR 0.79; P = .0151). However, the results did not reach the required level of significance for that stopping point (P = .0035).
All secondary analyses favored abiraterone: time to opiate use, not reached versus 23.7 months with placebo; time to chemotherapy, 26.5 versus 16.8 months; time to deterioration of performance status, 12.3 versus 10.9 months; and time to PSA progression, 11.1 versus 5.6 months.
Analysis of outcomes by prior use of bone-targeted therapy was prespecified. Saad reported that 38% of patients in the abiraterone arm had received bonetargeted therapy versus 34% in the placebo group. Comparison of patients with and without a history of bone-targeted therapy showed no difference in rPFS (HR = 0.95; P = .565) or OS (HR = 0.92; P = .409).
In general, abiraterone was well tolerated. The most frequent grade 3/4 adverse events in the abiraterone and placebo arms were hypertension, 4.2% versus 3.1%; hypokalemia, 2.6% versus 1.9%; and liver enzyme elevation, 5.5% versus 0.7% for ALT and 3.1% versus 0.9% for AST.
The recent flurry of approvals for drugs used in CRPC stipulates use of the agents in the postchemotherapy setting, Saad noted. Positive data with abiraterone in the prechemotherapy setting, including a favorable safety profile, could help extend the benefits to more patients, he said.
HR (95% CI)
0.53 (0.45, 0.62)
0.79 (0.66, 0.96)
Time to opiate use
0.71 (0.59, 0.85)
Time to chemotherapy
0.61 (0.51, 0.72)
Time to ECOG-PS deterioration
0.83 (0.72, 0.94)
Time to PSA progression
0.50 (0.43, 0.58)
CI, indicates confidence interval; ECOG-PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival; PSA, prostate-specific antigen; rPFS, radiograhic progression-free survival.
aPrespecified alpha level .0035
1. Saad F, Shore ND, Van Poppel H, et al. Abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy: Interim analysis of the COU-AA-302 phase 3 trial. Presented at: the Annual Meeting of the American Urological Association; May 4-8, 2013; San Diego, California. Abstract 713.