Elsevier

The Lancet Oncology

Volume 16, Issue 2, February 2015, Pages 152-160
The Lancet Oncology

Articles
Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study

https://doi.org/10.1016/S1470-2045(14)71205-7Get rights and content

Summary

Background

Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies.

Methods

In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily; abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198.

Findings

At a median follow-up of 49·2 months (IQR 47·0–51·8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34·7 months [95% CI 32·7–36·8] vs 30·3 months [28·7–33·3]; hazard ratio 0·81 [95% CI 0·70–0·93]; p=0·0033). The most common grade 3–4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the abiraterone acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [<1%]), and hypertension (25 [5%] vs 17 [3%]).

Interpretation

In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.

Funding

Janssen Research & Development.

Introduction

An overarching feature of the recent management of metastatic castration-resistant prostate cancer is the use of sequential therapies. Before 2010, the only approved systemic treatment associated with improved overall survival was docetaxel.1, 2 Over the past 4 years, five therapeutics with demonstrated survival benefit in randomised clinical studies have become available, and are commonly used in sequence.3, 4, 5, 6, 7, 8, 9, 10, 11 Given the chronicity and heterogeneity of metastatic castration-resistant prostate cancer, administration of such subsequent therapies may confound the measurement of the effect of a particular treatment on overall survival.

Abiraterone acetate is a prodrug of abiraterone, an orally available inhibitor of the cytochrome P450 c17 enzyme complex critical to androgen production. Oral abiraterone acetate plus prednisone demonstrated a significant improvement in survival, compared with placebo plus prednisone, for patients with metastatic castration-resistant prostate cancer with progression of disease after administration of chemotherapy.5, 6 In chemotherapy-naive patients, abiraterone acetate plus prednisone delayed radiographic progression, prevented the onset of symptoms, and preserved quality of life, compared with placebo plus prednisone.9, 10, 12 However, at the interim analyses, overall survival results did not cross the prespecified efficacy boundary for statistical significance as defined by O'Brien and Fleming.13

Here, we present the final overall survival analysis of the COU-AA-302 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer.

Section snippets

Study design and participants

The patient population for this multinational, double-blind, randomised, placebo-controlled phase 3 trial has been described previously.9, 10 Briefly, patients aged 18 years or over with histologically or cytologically confirmed adenocarcinoma of the prostate, prostate-specific antigen (PSA) progression according to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria, or radiographic progression in soft tissue or bone with or without PSA progression, ongoing androgen deprivation

Results

1088 patients were randomly assigned to receive study treatment between April 28, 2009, and June 23, 2010 (figure 1); treatment groups were well balanced.9, 10 The clinical cutoff date for the preplanned final analysis was March 31, 2014. At the time of the final analysis, treatment was ongoing for 42 (8%) patients in the abiraterone acetate group and for no patients in the placebo group. At the final analysis, 238 (44%) patients from the placebo group had subsequently received abiraterone

Discussion

In this final analysis of the COU-AA-302 phase 3 trial, overall survival for men with chemotherapy-naive metastatic castration-resistant prostate cancer was significantly longer with abiraterone acetate and prednisone than with placebo and prednisone, meeting the protocol-specified criterion for statistical significance. Thus both coprimary endpoints—radiographic progression-free survival and overall survival—have been shown to be significantly improved by the addition of abiraterone acetate to

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