Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302).

Abstract

BACKGROUND:

Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy.

OBJECTIVE:

Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302.

DESIGN, SETTING, AND PARTICIPANTS:

Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1).

INTERVENTION:

Patients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by mouth versus prednisone.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets α-spending function was used for OS. Adverse events were summarised descriptively.

RESULTS AND LIMITATIONS:

With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p<0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66-0.95]; p=0.0151) but did not reach the prespecified statistical efficacy boundary (α-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p=0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports.

CONCLUSIONS:

The updated IA of study COU-AA-302 in patients with mCRPC without prior chemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ≥24 mo.

TRIAL REGISTRATION:

Study COU-AA-302, ClinicalTrials.gov number, NCT00887198.

PATIENT SUMMARY:

The updated results of this ongoing study showed that disease progression was delayed in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone, and there was a continued trend in prolongation of life compared with patients treated with prednisone alone. Treatment with abiraterone acetate and prednisone was well tolerated by patients who were treated for >2 yr.

• Authors: Dana E Rathkopf, Matthew R Smith, Johann S de Bono, Christopher J Logothetis, Neal D Shore, Paul de Souza, Karim Fizazi, Peter F A Mulders, Paul Mainwaring, John D Hainsworth, Tomasz M Beer, Scott North, Yves Fradet, Hendrik Van Poppel, Joan Carles, Thomas W Flaig, Eleni Efstathiou, Evan Y Yu, Celestia S Higano, Mary-Ellen Taplin, Thomas W Griffin, Mary B Todd, Margaret K Yu, Youn C Park, Thian Kheoh, Eric J Small, Howard I Scher, Arturo Molina, Charles J Ryan, Fred Saad
• Journal: European urology (Eur Urol) Vol. 66 Issue 5 Pg. 815-25 (Nov 2014) ISSN: 1873-7560 [Electronic] Switzerland
• PMID: 24647231 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Chemical References

• Androstenes
• Antineoplastic Agents, Hormonal
• Cytochrome P-450 Enzyme Inhibitors
• Steroid 17-alpha-Hydroxylase
• Abiraterone Acetate
• Prednisone

Topics

• Abiraterone Acetate
• Aged
• Androstenes (administration & dosage, adverse effects)
• Antineoplastic Agents, Hormonal (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Cytochrome P-450 Enzyme Inhibitors (administration & dosage, adverse effects)
• Disease Progression
• Disease-Free Survival
• Double-Blind Method
• Drug Administration Schedule
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Metastasis
• Neoplasms, Hormone-Dependent (drug therapy, enzymology, mortality, pathology)
• Prednisone (administration & dosage)
• Proportional Hazards Models
• Prostatic Neoplasms, Castration-Resistant (drug therapy, enzymology, mortality, pathology)
• Risk Factors
• Steroid 17-alpha-Hydroxylase (antagonists & inhibitors, metabolism)
• Time Factors
• Treatment Outcome