Elsevier

European Urology

Volume 74, Issue 1, July 2018, Pages 17-23
European Urology

Platinum Priority – Prostate Cancer
Editorial by Stéphane Culine on pp. 24–25 of this issue
The Phase 3 COU-AA-302 Study of Abiraterone Acetate Plus Prednisone in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Stratified Analysis Based on Pain, Prostate-specific Antigen, and Gleason Score

https://doi.org/10.1016/j.eururo.2017.08.035Get rights and content

Abstract

Background

In the COU-AA-302 study (NCT00887198), abiraterone acetate plus prednisone (AAP) significantly improved outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) versus prednisone alone. Baseline clinical parameters predicting that treatment response could help inform clinical decisions were explored.

Objective

To identify patients who derive the greatest clinical benefit from AAP treatment.

Design, setting, and participants

A total of 1088 mCRPC patients treated with either AAP or prednisone in the first-line setting in COU-AA-302 were included in this post hoc analysis.

Intervention

Abiraterone acetate1000 mg daily versus placebo, both plus prednisone 10 mg daily.

Outcome measurements and statistical analysis

Univariate and multivariable Cox regression analyses were performed, including clinical and pathological parameters for the primary end points overall survival (OS) and radiographic progression-free survival (rPFS), and secondary study end points. Tumor-associated baseline parameters independently impacting OS were applied to stratify patients according to possible treatment effects.

Results and limitations

Baseline prostate-specific antigen (PSA), tumor-related pain as assessed by the Brief Pain Inventory-Short Form (BPI-SF), and Gleason score (GS) at primary diagnosis were identified as tumor-associated variables that independently impacted OS. AAP significantly improved outcomes versus prednisone in both group 1 (BPI-SF 0–1 and PSA <80 ng/ml and GS <8; p = 0.006; hazard ratio [HR]: 0.61) and group 2 (BPI-SF 2–3 and/or PSA ≥80 ng/ml and/or GS ≥8; p = 0.03; HR: 0.84). The differences observed for treatment effects between groups 1 and 2 for OS (HR: 0.61 vs 0.84), rPFS (HR: 0.41 vs 0.59), and time to chemotherapy (HR: 0.64 vs 0.71) were not statistically significant.

Conclusions

AAP significantly improved outcomes in mCRPC patients compared with prednisone alone regardless of baseline pain and PSA level, and GS at primary diagnosis with no significant differences between observed treatment effects in groups 1 and 2.

Patient summary

Treatment with abiraterone acetate and prednisone (compared with treatment with prednisone only) for metastatic castration-resistant prostate cancer increased survival in all patients in the study regardless of pain, prostate-specific antigen levels at the start of treatment, and Gleason score at primary diagnosis.

Introduction

The therapeutic landscape in metastatic castration-resistant prostate cancer (mCRPC) has expanded in recent years with the introduction of several novel anticancer drugs prolonging overall survival (OS), including the CYP17 inhibitor abiraterone acetate (AA), the androgen-receptor antagonist enzalutamide, the radioisotope alpharadin (radium-223), the taxane cabazitaxel, and the vaccine sipuleucel-T (marketing authorization withdrawn in the European Union) [1], [2], [3]. These treatment options exploit different mechanisms of action; therefore, different biomarkers and prognostic variables are most relevant to measuring and predicting treatment response for different agents.

Independent predictors of OS previously identified include, but are not limited to, tumor-associated markers such as prostate-specific antigen (PSA) and Gleason score (GS), bone turnover markers such as alkaline phosphatase (ALP), patient-related factors such as cancer-related pain and performance status, metastatic distribution (eg, presence or absence of visceral metastases), and laboratory parameters, including hemoglobin, lactate dehydrogenase (LDH), albumin, and neutrophil-to-lymphocyte ratio [1], [4]. Further research into predictors of patient response to different treatments would benefit physicians, supporting evidence-based clinical decision making on initial treatment selection and optimal sequential treatments [1].

AA in combination with prednisone (AAP) was initially approved in 2011 for the treatment of mCRPC patients after chemotherapy, and subsequently for the first-line treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients based on results from the pivotal phase 3 COU-AA-302 study (NCT00887198) [5], [6]. In COU-AA-302, AAP significantly improved median radiographic progression-free survival (rPFS) and median OS versus placebo plus prednisone (PP) [6], and delayed clinical deterioration and initiation of chemotherapy [5]. Similar survival benefit from AAP was observed across several predefined patient subgroups, regardless of baseline Eastern Cooperative Oncology Group performance status(ECOG PS) (0 vs 1), tumor-associated pain assessed by the Brief Pain Inventory-Short Form (BPI-SF) score (0–1 vs 2–3), metastatic sites (bone only or bone and other sites), age (<65, ≥65, or ≥75 yr), and PSA, LDH, and ALP levels [5], [6].

More in-depth analysis of outcomes across patient subgroups may reveal differential treatment effects and point to clinical characteristics with prognostic value in predicting treatment response. Here, we report a post hoc analysis of COU-AA-302 with patients stratified according to baseline characteristics, with the aims of identifying patients deriving the greatest clinical benefit from AAP treatment and describing prostate cancer–related parameters identified at initiation of therapy to inform further clinical decisions.

Section snippets

Patients and methods

COU-AA-302 was a phase 3, double-blind, placebo-controlled, randomized clinical trial in which 1088 asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients received prednisone 5 mg twice daily plus AA 1000 mg once daily or placebo (Fig. 1). Details of the study design have been reported previously [5]. Patients had mCRPC after PSA progression according to Prostate Cancer Clinical Trials Working Group 2 criteria [7] or radiographic progression under ongoing androgen-deprivation

Univariate and multivariable analyses of OS

Univariate analysis identified several variables with a significant association with OS (Table 1). Significance was maintained on multivariable analysis for baseline BPI-SF score, PSA, hemoglobin, LDH, ALP, age, and GS at primary diagnosis (Table 1).

Discussion

This post hoc analysis of the COU-AA-302 study revealed that both patient groups achieved significantly improved outcomes with AAP versus PP, including improvements in OS and rPFS as well as in secondary study end points, regardless of pain and PSA levels at study entry and GS at primary diagnosis. While OS, rPFS, and time to chemotherapy and opiate use were longer in asymptomatic mCRPC patients, defined as patients with lacking or very minimal prostate cancer–related pain, PSA levels <80 ng/ml

Conclusions

This post hoc analysis of the COU-AA-302 study revealed that all patients regardless of baseline characteristics achieved significantly improved outcomes with AAP versus PP. OS, rPFS, and time to chemotherapy and opiate use were longer in asymptomatic mCRPC patients with PSA levels <80 ng/ml at the start of treatment and a GS of <8 at primary diagnosis compared with patients with advanced PSA or pain levels or a GS of ≥8. Since there was no significantly different treatment effect between both

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