EURURO Vol. 71 No. 4

657 692

1. Introduction
Prostate cancer is the most common cancer among men
in industrialized countries and represents one of the
leading causes of cancer deaths The mainstay for
treatment of metastatic castration-resistant prostate
cancer (mCRPC) in the past was docetaxel in combination
with androgen deprivation therapy However, treat-
ment patterns for patients with mCRPC have changed
substantially in the last few years following the approval
of five new agents for mCRPC, including androgen
signaling–directed therapy, immunotherapy, and radio-
pharmaceutical products .
Abiraterone acetate (AA) is a prodrug of abiraterone, a
potent and specific inhibitor of the enzyme 17a-hydroxy-
lase/C17,20-lyase that blocks extragonadal and testicular
androgen biosynthesis . AA (1 g daily) plus prednisone
or prednisolone (5 mg twice daily) is approved for the
treatment of patients with mCRPC on the basis of results
for two pivotal phase 3 trials In patients with
mCRPC who had received prior docetaxel chemotherapy,
treatment with AA improved overall survival (OS) by
4.6 mo (hazard ratio [HR] 0.74, 95% confidence interval
[CI] 0.64–0.86; p < 0.0001) compared to placebo and
prednisone or prednisolone 5 mg twice daily (hereafter
referred to as P) . In COU-AA-302, asymptomatic or
mildly symptomatic men with chemotherapy-naı¨ve mCRPC
had significantly better radiographic progression-free
survival (rPFS; HR 0.52; p < 0.0001) and OS (34.7 vs
30.3 mo; HR 0.81, 95% CI 0.70–0.93; p = 0.0033) with AA
compared to P .
Although the use of sequential therapy is common and
its efficacy is of great interest to clinicians, there is limited
information about subsequent therapy for mCRPC following
treatment with AA. We conducted a post hoc analysis of
COU-AA-302 to evaluate the clinical outcome for docetaxel
as first subsequent therapy (FST) among patients in the AA
treatment arm who experienced disease progression after
protocol-specified treatment with AA and to characterize
subsequent treatment patterns among older ( 75 yr) and
younger (<75 yr) patient subgroups.
2. Patients and methods
COU-AA-302 (ClinicalTrials.gov NCT00887198) is a phase 3, multina-
tional, randomized, double-blind, placebo-controlled study conducted at
151 sites in 12 countries . Patients were enrolled from April 2009 to
June 2010. Patients aged 18 yr with asymptomatic or mildly
symptomatic mCRPC were chemotherapy-naı¨ve and had received
previous anti-androgen therapy. Additional inclusion criteria included
ongoing androgen deprivation with serum testosterone <0.50 ng/ml and
life expectancy of 6 mo. Patients were medically or surgically castrated,
and had tumor progression. Patients with visceral metastases or patients
who had received previous therapy with ketoconazole for >7 d were
excluded.
2.1. Study design
A total of 1088 patients were stratified by Eastern Cooperative Oncology
Group performance status (0 vs 1) and randomized 1:1 to AA (1000 mg
QD plus P 5 mg BID; n = 546) or placebo plus P (n = 542). All study
personnel were blinded to the patient treatment assignments, and
patient treatment assignments remained blinded at the time of disease
progression. The co-primary end points were rPFS and OS. The primary
and secondary end point results obtained at the time of this analysis
have been described in detail previously .
As of March 2014, 365 (67%) patients in the AA treatment arm and
435 (80%) in the P arm received subsequent treatment with one or more
agents approved for mCRPC at the discretion of the investigator after
protocol-specified treatment ) . At the time of data collection,
8% (42/546) of patients continued on AA. The use of a specific subsequent
therapy for mCRPC was not proscribed in the study, but these data were
collected prospectively, while response and discontinuation data on
subsequent therapy were collected retrospectively after patients
discontinued the study drug. Data that could be accessed for these
patients were included in the current analysis. Efficacy analysis was
performed among patients from the AA treatment arm with available
baseline prostate-specific antigen (PSA) within 30 d before the first dose
of docetaxel and at least one post-baseline PSA value. As recommended
by the Prostate Cancer Clinical Trials Working Group (PCWG2) , PSA
response was defined as a 50% PSA decline from baseline with at least
two available PSA values measured 3–4 wk apart. Unconfirmed 50%
PSA declines were defined as a 50% PSA decline from baseline with at
least one available PSA value. Reasons for discontinuation were
investigator reported without specific criteria. Efficacy data for
subsequent therapy were not collected for patients from the P arm.
2.2. Statistical analyses
All data for the current analyses were collected at the final OS analysis
(96% of expected death events). On the basis of the aggregate efficacy and
safety data at the second interim analysis (clinical cutoff December
2011), the independent data-monitoring committee unanimously
recommended unblinding in February 2012, 20 mo after the last patient
was enrolled. To characterize subsequent therapy and treatment
patterns by age subgroup, patients were dichotomized by age at 75 yr.
Conclusions: Patients with mCRPC who progress with AA treatment may still derive benefit
from subsequent docetaxel therapy. These data support further assessment of treatment
patterns following AA treatment for mCRPC, particularly among older patients.
Trial registration: ClinicalTrials.gov NCT00887198.
Patient summary: Treatment patterns for advanced prostate cancer have changed sub-
stantially in the last few years. This additional analysis provides evidence of clinical benefit
for subsequent chemotherapy in men with advanced prostate cancer whose disease
progressed after treatment with abiraterone acetate. Older patients were less likely to
be treated with subsequent therapy.
# 2016 European Association of Urology. Published by Elsevier B.V. This is an open
access article under the CC BY-NC-ND license
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