Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy

Abstract

Background: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design.

Methods: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer).

Results: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events).

Conclusions: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).

Figures

Figure 1. Overall Survival and Failure-free Survival in All Patients and According to Metastatic Status at Randomization (Intention-to-Treat Population).

Combination therapy was androgen-deprivation therapy (ADT) plus abiraterone acetate and prednisolone. Treatment failure was defined as radiologic, clinical, or prostate-specific antigen (PSA) progression or death from prostate cancer.

Figure 2. Forest Plots of Treatment Effect on Overall and Failure-free Survival within Subgroups According to Stratification Factors at Randomization.

In each panel, the dashed vertical line is the point estimate of the hazard ratio for the analysis. Gleason scores range from 3 to 10, with higher scores indicating more aggressive disease, less differentiated tumor, and worse prognosis. The World Health Organization (WHO) performance status was scored on a scale of 0 to 4, with higher numbers indicating greater disability. Time period was defined by corecruiting group; ABCEG corresponds to November 2011 through January 2013, ABCEGH January 2013 through March 2013, and AGH April 2013 through January 2014. NSAID denotes nonsteroidal antiinflammatory drug.

Figure 3. Time until the Initiation of Second-Line Treatment after First Event of Radiologic, Clinical, or PSA Progression.