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.

Keywords: Abiraterone acetate; Chemotherapy-naive; Efficacy; Metastatic castration-resistant prostate cancer; Safety.

Fig. 1

Co–primary end point: (a,b) radiographic progression-free survival assessed by investigator review at prespecified interim analysis. (b) The size of the circle reflects the number of patients affected. For hazard ratio (HR) <1, the result favours abiraterone. AA = abiraterone; ALK-P = alkaline phosphatase; BPI = Brief Pain Inventory; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase; N.A. = North America; P = prednisone; PSA = prostate-specific antigen.

Fig. 2

Co–primary end point: (a,b) overall survival. Prespecified significance level by the O’Brien-Fleming boundary = 0.0035. (b) The size of circle reflects the number of patients affected. For hazard ratio (HR) <1, the result favours abiraterone. AA = abiraterone; ALK-P = alkaline phosphatase; BPI = Brief Pain Inventory; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase; N.A. = North America; NE = not estimable; P = prednisone; PSA = prostate-specific antigen.

Fig. 3

Secondary end points: (a) time to opiate use for cancer-related pain; (b) time to initiation of chemotherapy; (c) time to deterioration in the Eastern Cooperative Oncology Group (ECOG) score; (d) time to prostate-specific antigen (PSA) progression. AA = abiraterone; CI = confidence interval; HR = hazard ratio; NR = not reached; P = prednisone.

Fig. 4

Maximal prostate-specific antigen (PSA) decline from baseline. A negative percentage indicates a decline in PSA. A positive percentage indicates that the patient never has a decline in PSA.