Abiraterone versus Placebo before Chemotherapy for Patients with Metastatic Prostate Cancer
Metastatic castration-resistant prostate cancer (mCRPC) is associated with rapid deterioration and leads to mortality in this patient population within 2 to 4 years. The treatment options available for patients with mCRPC who have not received chemotherapy have been proved to produce response in these patients, but new options are needed that could prolong life or lead to tumor regression. A recent study compared the benefit of abiraterone acetate (Zytiga) with prednisone versus placebo plus prednisone for patients with mCRPC before chemotherapy (Ryan CJ, et al. N Engl J Med. 2013;368:138-148).
Previous studies have shown that the use of abiraterone plus low-dose prednisone in patients with mCRPC who have received chemotherapy improves survival; this combination was subsequently approved by the US Food and Drug Administration (FDA) for this patient population. Early-phase clinical trials in patients with mCRPC who have not received chemotherapy have shown increased response rates with this combination.
Consequently, this phase 3 clinical trial was designed to evaluate the effects of the combination of abiraterone plus low-dose prednisone on radiographic progression-free survival (PFS) and overall survival (OS) and other measures of disease progression in patients with advanced or metastatic disease before chemotherapy.
Between April 2009 and June 2012, a total of 1088 patients were randomized in a 1:1 ratio to receive 1000 mg of abiraterone plus prednisone 5 mg twice daily (ie, low-dose) or placebo plus prednisone. The primary end points were radiographic PFS and OS.
By the time of the first interim analysis on December 20, 2010, the combination of abiraterone plus low-dose prednisone resulted in a 57% reduction in the risk of radiographic PFS. The study was unblinded after this analysis, when 43% of the expected deaths occurred. The median radiographic PFS was 16.5 months with the combination versus 8.3 months with placebo plus prednisone. The median OS was not reached with the combination versus reaching 27.2 months with the placebo plus prednisone. In addition, a 25% reduction in mortality risk was seen with the combination (hazard ratio, 0.75; 95% confidence interval, 0.61-0.93; P = .01), showing a strong trend of improved survival. The PFS was favorable across all subgroups with the combination.
The addition of abiraterone to low-dose prednisone was associated with favorable PFS across all subgroups compared with prednisone and placebo. Furthermore, the abiraterone plus prednisone combination was superior to prednisone plus placebo in terms of time to initiation of cytotoxic chemotherapy, pain medication use, prostate-specific antigen progression, and performance status. As can be expected, grade 3 or grade 4 adverse events and abnormalities on liver function were more common with the abiraterone plus prednisone combination. Based on these results, in November 2012, the FDA approved the combination of abiraterone plus low-dose prednisone for the treatment of patients with mCRPC before chemotherapy.