Abiraterone acetate, a selective inhibitor of androgen biosynthesis, prolonged overall survival, reduced mortality risk by 35%, and delayed time to disease progression in men with metastatic castration-resistant prostate cancer who had already undergone chemotherapy.
“These results show that continued androgen-receptor signaling contributes to disease progression, and they provide support for the evaluation of other endocrine therapies in this [advanced] stage of the disease,” wrote Dr. Johann S. de Bono of the Institute of Cancer Research and Royal Marsden Hospital, Sutton (England), and his associates.
Several previous studies have demonstrated that, despite medical or surgical castration, prostate cancers continue to have sufficient levels of androgens, perhaps from synthesis within the tumor itself, to propel tumor growth. In phase I and phase II trials, abiraterone acetate – which potently blocks cytochrome P450 c17 (CYP17), an enzyme critical to testosterone synthesis – has shown promising antitumor activity even in advanced prostate cancer.
Dr. de Bono and his colleagues performed this international phase III randomized double-blind trial at 147 sites to compare daily oral therapy with four 250-mg abiraterone acetate tablets plus low-dose prednisone against placebo plus low-dose prednisone. They enrolled 1,195 men who had previously received docetaxel and showed disease progression despite ongoing androgen deprivation. The primary end point of the study was overall survival.
At a preplanned interim analysis, active treatment was found to reduce the risk of death by 35%, compared with placebo.
Mortality was 42% with active treatment, compared with 55% with placebo. Median overall survival was 14.8 months with abiraterone, compared with 10.9 months with placebo, the investigators reported (N. Engl J. Med. 2011;364:1995-2005).
This survival benefit “was consistent across all subgroups, and … robust after adjustment for stratification factors in a multivariate analysis,” they said. Based on these findings, the trial was unblinded and patients in the placebo group were allowed to switch to active treatment.
“All the secondary end points analyzed provided support for the superiority of abiraterone acetate over placebo,” Dr. de Bono and his associates said. Time to PSA progression was longer (10.2 months vs. 6.6 months), as was median progression-free survival on radiography (5.6 vs. 3.6 months).
Active treatment reduced the risk of disease progression by 42% when assessed by PSA levels and by 33% when assessed by radiographic imaging.
“As our study shows, blocking androgen synthesis by inhibiting CYP17 can produce tumor responses in patients who no longer have a response to standard hormonal therapies and who had received docetaxel-based chemotherapy,” the researchers said.
This study was sponsored by Cougar Biotechnology, with further support provided by the U.K. Medical Research Council, the Experimental Cancer Medical Centre, the National Institute for Health Research Biomedical Research Centre, and the Prostate Cancer Foundation.
Dr. de Bono is employed by the Institute of Cancer Research, where abiraterone was designed and synthesized, and which has a commercial interest in the drug. He and his associates reported ties to numerous drug and biotechnology companies.
'Continued androgen-receptor signaling contributes to disease progression.'
Source DR. DE BONO