A Randomized, Double-blind, Comparative Study of Abiraterone Acetate Plus Low-dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Subjects With High-Risk, Metastatic Hormone-naive Prostate Cancer (mHNPC).

ZYTIGA® (abiraterone acetate) is a prodrug of abiraterone, an irreversible
inhibitor of
17* hydroxylase/C17, 20-lyase (cytochrome P450c17 [CYP17]), a key enzyme
required for testosterone
synthesis. Marketing authorization for ZYTIGA and prednisone/prednisolone was
granted in April 2011
in the United States and in September 2011 in the European Union. Treatment
with ZYTIGA improves
survival in patients with metastatic castration-resistant prostate cancer. This
study will test whether
ZYTIGA also improves radiographic progression free survival (rPFS) and overall
survival (OS) in patients with newly diagnosed metastatic, hormone-naive
prostate
cancer (mHNPC) who are at an increased risk for rapid disease progression.

OBJECTIVE AND HYPOTHESIS

Primary Objective

The primary objective is to determine whether abiraterone acetate in
combination with low-dose
prednisone and androgen deprivation therapy (ADT) is superior to ADT alone in
improving rPFS and OS in
subjects with mHNPC with high-risk prognostic factors.

Secondary Objective

The secondary objectives are to evaluate the clinically relevant improvements
as well as the safety of
abiraterone acetate plus low-dose prednisone and ADT compared with ADT alone
and to identify
microRNA (miRNA) and mRNA profiles predictive of abiraterone acetate response
or resistance in this
patient population.

Hypothesis

The hypothesis is that addition of abiraterone acetate to ADT as initial
therapy (compared with ADT
alone) will improve rPFS and OS in men with newly-diagnosed, high-risk mHNPC.

OVERVIEW OF STUDY DESIGN

This is a multinational, multicenter, randomized, double-blind,
active-controlled study designed to
determine if newly diagnosed subjects with mHNPC who have high-risk prognostic
factors will benefit
from the addition of abiraterone acetate and low-dose prednisone to ADT. In
this study, ADT refers
specifically to luteinizing hormone releasing hormone (LHRH) agonists or
orchiectomy. Approximately
1200 subjects will be enrolled. The study population includes newly diagnosed
(within 3 months prior to
randomization) adult men with high-risk mHNPC (high-risk prognosis defined
under Subject Selection).
Subjects will be stratified by presence of visceral disease and Eastern
Cooperative Oncology Group
(ECOG) performance grade of 0, 1 vs. 2 prior to randomization. Subjects must
have distant metastatic
disease as documented by positive bone scan or metastatic lesions on CT or MRI
to be eligible. Eligible
subjects may have received ADT or had an orchiectomy within 3 months of
randomization. Subjects may
also receive anti-androgens for up to 3 months prior to randomization but the
continued use of antiandrogens
is to be terminated before randomization. Abiraterone acetate and low-dose
prednisone will be
considered as study drugs.
The study will consist of a Screening Phase of up to 28 days before
randomization to establish study
eligibility and document baseline measurements; a Double-blind Treatment Phase;
and a Follow-up Phase
of up to 60 months to monitor survival status and subsequent prostate cancer
therapy. Each cycle is
28 days. Treatment will continue until disease progression, withdrawal of
consent, or the occurrence of
unacceptable toxicity. Subjects who meet all of the inclusion criteria and none
of the exclusion criteria
will be centrally randomized in a 1:1 ratio to the active group (abiraterone
acetate [1,000 mg once daily]
plus low-dose prednisone [5 mg once daily] plus ADT [LHRH agonist or
orchiectomy]) or the control
group (abiraterone acetate and prednisone placebos plus ADT [LHRH agonist or
orchiectomy]).

In the event of a positive study result (efficacy boundary is crossed) at
either of the interim analyses or at
the time of the final analysis, all subjects will have the opportunity to
enroll in an Open-label Extension
Phase. The Open-label Extension Phase will allow subjects to receive active
drug (abiraterone acetate
plus prednisone) for up to 3 years. Two interim analyses for OS in addition to
the final analysis are planned for
this study after observing 50% (421 events) and 65% (548 events) of the total
number of required (842)
events for the final analysis. It is expected that the rPFS analysis will
likely occur in conjunction with the first interim OS analysis.

Subjects will be monitored for safety throughout the study. Adverse events
including laboratory adverse
events will be graded and summarized using National Cancer Institute Common
Terminology Criteria for
Adverse Events (NCI-CTCAE), Version 4.0. Dose modification guidelines are
provided. An Independent
Data Monitoring Committee (IDMC) will be commissioned for the study to perform
regular safety review
and at the planned interim analyses.

See study design

The risks of this trial are comparable witht the risks associated with standard
of care. Side effects of abiraterone acetate and prednicon are commonly known
and are described in the ICF form, protocl and IB. Addition of abiraterone
acetate to the ADT therapy as initial treatment (compared to ADT alone)
demonstrated an increased OS in patients with newly diagnosed men with high
risk mHNPC.

For side effects of AA and prednisone and risks related to reseach procedures:
see ICF (pg 6-7 and addendum E) and protocol pg 32-34.