Abiraterone Prolongs Survival in Metastatic Castration-Resistant Prostate Cancer
Elsevier Global Medical News. 2011 May 25, MA Moon
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, according to a report in the May 26 issue of the New England Journal of Medicine.
"The use of hormonal agents is typically not considered in patients who have received 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. Treatment response was greater with abiraterone whether measured by PSA levels (29% response vs. 6%) or Response Evaluation Criteria in Solid Tumors (RECIST) criteria (14% vs. 3%). 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.
Exploratory end points, including pain palliation and time to 25% of patients having a skeletal event, also consistently favored abiraterone over placebo.
"This study validates the hypothesis that the biosyntehsis of steroid hormones downstream of CYP17 contributes to progression of castration-resistant prostate cancer in a subgroup of men for whom this disease remains driven by steroid ligands and should not be described as 'hormone refractory.' Since these men cannot be identified a priori, continuing to call this disease 'androgen independent' or 'hormone refractory' is imprecise," Dr. de Bono and his associates said.
"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," they added.
Compliance with abiraterone acetate therapy was high, "and side effects were easily manageable and reversible, despite the advanced age and level of frailty of the study population," the investigators said.
Toxic effects included hypokalemia, hypertension, and fluid retention, "which were largely abrogated by the use of low-dose prednisone," they wrote.
The rates of drug discontinuation and dose reduction were low, and therapy "did not appear to increase the risk of metabolic changes or symptoms associated with chronic androgen deprivation. Nevertheless, longer follow-up is warranted to evaluate late toxic effects," they noted.
In editorial accompanying the study, Dr. Emmanuel S. Antonarakis and Dr. Mario A. Eisenberger wrote that the findings "provide a proof of principle that metastatic castration-resistant prostate cancer remains androgen-driven" (N. Engl. J. Med. 2011;364:2055-8).
The results of this phase III trial led to Food and Drug Administration approval of abiraterone [Zytiga] in late April for patients who had received docetaxel, but they also "provide sufficient evidence of efficacy to justify the use of abiraterone in all patients with metastatic castration-resistant prostate cancer (i.e., even those with no previous chemotherapy treatment)," said Dr. Antonarakis and Dr. Eisenberger, who are with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.
Moreover, "it is clear ... that our knowledge of the biologic mechanisms involved in the progression of metastatic castration-resistant prostate cancer has reached a level at which the discovery of more effective targeted approaches will probably further improve outcomes," they added.
Johns Hopkins receives funding from Cougar Biotechnology and participated in this clinical trial, but Dr. Antonarakis and Dr. Eisenberger were not involved. They reported ties to Sanofi-Aventis, Millennium, Astellas, and Tokai.
This study was sponsored by Ortho Biotech Oncology Research and Development, a unit of Cougar Biotechnology, with further support provided by the Medical Research Council of the United Kingdom, 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.
