Elsevier

The Lancet Oncology

Volume 13, Issue 10, October 2012, Pages 983-992
The Lancet Oncology

Articles
Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study

https://doi.org/10.1016/S1470-2045(12)70379-0Get rights and content

Summary

Background

Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events).

Methods

Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00638690.

Findings

Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4–22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8–17·0] vs 11·2 months [10·4–13·1]; hazard ratio [HR] 0·74, 95% CI 0·64–0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3–11·1, in the abiraterone group vs 6·6 months, 5·6–8·3, in the placebo group; HR 0·63, 0·52–0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6–6·5, vs 3·6 months, 2·9–5·5; HR 0·66, 0·58–0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3–4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]).

Interpretation

This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up.

Funding

Janssen Research & Development.

Introduction

Androgen-deprivation therapy is the standard of care for advanced prostate cancer.1, 2 Although most men initially respond to castration with treatment with luteinising hormone-releasing analogues or bilateral orchiectomy, progression eventually occurs, and the median overall survival after chemotherapy is consistently less than 2 years in patients with metastatic disease.3, 4 Incontrovertible evidence now exists that tumour progression after androgen-deprivation therapy, previously thought to be androgen-independent or hormone-refractory, commonly remains hormone driven.5, 6, 7, 8, 9 Postulated mechanisms of resistance include increased intratumoral steroid synthesis, increased expression of androgen receptor, splice variants of androgen receptor, and mutations leading to increased androgen receptor ligand promiscuity.9 This disease state is consequently more precisely described as castration-resistant prostate cancer.5, 9 All patients ultimately progress to metastatic castration-resistant prostate cancer.1 Patients who fail primary androgen-deprivation therapy are often treated with secondary hormonal therapies, including second-line antiandrogens, antiandrogen withdrawal, glucocorticoids, oestrogens, and ketoconazole. None of these treatments, however, have been assessed in definitive phase 3 trials and therefore, none have shown significant benefit in overall survival.1 Docetaxel was the first systemic therapy to show an improvement in overall survival in patients with metastatic castration-resistant prostate cancer, but patients invariably die of progressive disease.10, 11 Recently, sipuleucel-T and cabazitaxel were approved for castration-resistant prostate cancer treated before and after chemotherapy on the basis of survival benefits in phase 3 trials.12, 13

Abiraterone acetate is a selective inhibitor of androgen biosynthesis that potently and irreversibly blocks CYP17, a crucial enzyme in testosterone and oestrogen synthesis, resulting in virtually undetectable serum and intratumoral androgens14, 15 and antitumour activity in both chemotherapy-naive and chemotherapy-treated patients with metastatic castration-resistant prostate cancer.16, 17, 18, 19 In the prespecified interim analysis of the present phase 3 study of men with metastatic castration-resistant prostate cancer who had disease progression after docetaxel chemotherapy, treatment with abiraterone acetate plus prednisone was associated with median survival of 14·8 months versus 10·9 months for men treated with placebo plus prednisone.20 The most common adverse events were associated with increased concentrations of mineralocorticoids and included hypokalaemia, fluid retention, and hypertension, which were mitigated by administration of prednisone as concomitant treatment. At the time of the initial analysis, 552 participants in the trial had died.20

On the basis of these results, on Aug 25, 2010, the Independent Data Monitoring Committee (IDMC) recommended that the study be unmasked and the study protocol amended to allow all remaining patients in the placebo group to receive treatment with abiraterone acetate if they met prespecified criteria for crossover treatment.20 We describe the final analysis of the COU-AA-301 study at 775 death events, before crossover of patients from placebo to abiraterone acetate.

Section snippets

Patients

Full details of the COU-AA-301 study are provided in the initial report.20 Briefly, in this phase 3, multinational, double-blind, randomised placebo-controlled trial, we enrolled patients from 147 sites in 13 countries. Men with histologically or cytologically confirmed metastatic castration-resistant prostate cancer were eligible if they had had previous treatment with docetaxel and a maximum of two previous chemotherapies; prostate-specific antigen (PSA) progression according to Prostate

Results

Patients were enrolled between May 8, 2008, and July 28, 2009. The clinical cutoff date for the analyses presented here was Sept 20, 2010. Overall, 1195 patients were randomly assigned to receive either abiraterone acetate plus prednisone or placebo plus prednisone (figure 1). With a median follow-up of 12·8 months (IQR 10·9–14·4) at the time of data cutoff for the interim analysis, 552 death events had occurred. The present analysis was done at a median follow-up of 20·2 months (IQR 18·4–22·1

Discussion

This final analysis of the COU-AA-301 study in patients with metastatic castration-resistant prostate cancer who had progressed after docetaxel confirms that abiraterone acetate plus prednisone improves overall survival relative to placebo plus prednisone. In general, the survival benefit for patients assigned to the abiraterone group compared with the placebo group favoured abiraterone acetate across most of the subgroups analysed, providing proof of principle that metastatic

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    Other COU-AA-301 investigators are listed in the appendix

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