The evidence supporting the use of this protocol comes from two phase III randomised, double-blind, placebo-controlled trials, COU-AA-301r (patients who have received prior chemotherapy) and COU-AA-302r (chemotherapy naïve patients).
Post chemotherapy population
The COU-AA-301 trial was designed to evaluate whether abiraterone plus prednisone compared with placebo plus prednisone prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received docetaxel. Between May 2008 through July 2009, 1195 patients who had previously received docetaxel were randomly assigned to receive prednisone 5 mg twice daily with either abiraterone acetate 1000 mg or placebo.
The primary end point was overall survival (OS) and the secondary endpoints included time to prostate-specific antigen (PSA) progression and progression-free survival (PFS).r
Chemotherapy naive population
The COU-AA-302 trial was designed to evaluate whether abiraterone plus prednisolone compared with placebo plus prednisone prolongs radiographic progression free survival and overall survival, among patients with progressive metastatic castrate resistant prostate cancer who had not been previously treated with chemotherapy and with no or mild cancer-related symptoms. Between April 2009 and June 2010, 1088 patients ECOG 0-1, were randomised to receive abiraterone 1000mg (n=546) or placebo (n=542) and prednisolone 5 mg twice daily.
The co-primary endpoints were independently evaluated radiographic progression free survival and overall survival. The secondary end points were patient reported outcomes including, time to opiate use for cancer-related pain, to cytotoxic chemotherapy initiation, to decline in ECOG status and PSA progression.r
Efficacy
Post chemotherapy population
Median overall survival was 14.8 months in the abiraterone acetate group and 10.9 months in the placebo group (hazard ratio, 0.65; 95% confidence interval CI, 0.54 to 0.77; P<0.001). Time to PSA progression was 10.2 months in the abiraterone acetate group versus 6.6 months in the placebo group. Median progression free survival on the basis of radiographic evidence was 5.6 months in the abiraterone acetate group versus 3.6 months in the placebo group. Abiraterone acetate significantly increased overall survival compared to placebo.r
Kaplan-Meier curve for overall survival
© New Engl J Med 2011
Chemotherapy naive population
Radiographic progressionr
At first interim analysis (when 13% of deaths had occurred) treatment with abiraterone plus prednisolone compared with placebo plus prednisolone, resulted in a 57% reduction in the risk of radiographic progression or death (median not reached v median of 8.3 months; HR for abiraterone/prednisolone -v- prednisolone alone, 0.43; 95% CI 0.35 to 0.52; P<0.001)). By second interim analysis (when 43% of deaths had occurred) the median time to radiographic progression free survival was 16.5 months in the abiraterone plus prednisolone group compared with 8.3 months in the prednisolone only group (HR, 0.53; 95% CI, 0.45 to 0.62; p<0.001).
Overall Survivalr
At second interim analysis (22.2 months), more deaths occurred in the prednisolone alone group (186 of 542 patients [34%] -v- 147 of 546 patients [27%]). Median OS was not reached in the abiraterone/prednisolone group -v- 27.2 (95% CI 26.0 to not yet reached) in the prednisolone only group. The risk of death was 25% less in the abiraterone/prednisolone group (HR, 0.75; 95% CI, 0.61 to 0.93; P=0.01).
Final analysis showed a median overall survival of 34.7 months (95% CI 32.7-36.8) in the abiraterone group and 30.3 months (28.7-33.3) in the placebo group. With a significant decrease in risk of death in the abiraterone group compared with the placebo group (HR 0.81, 95% CI 0.70-0.93; p=0.0033).
© New Engl J Med 2013
Secondary endpoints were reported separately.r
Toxicity
The adverse events seen in both trials were minimal and majority occurred at a similar frequency to the control arm – placebo. These adverse events can be attributed to disease or con-current or past therapy such as androgen deprivation therapy (ADT).
Those adverse events seen more frequently in the abiraterone acetate arm included diarrhoea, urinary tract infection, fluid retention and oedema, hypokalemia, hypertension and arthralgia.r
© N Engl J Med 2011
© N Engl J Med 2013