Abiraterone Acetate

For patients with metastatic castration-resistant prostate

cancer progressing after chemotherapy:
Final analysis of a multicentre, open-label, early-access
protocol trial

Presented by Kamino

Introduction:
Prostate cancer is the second most common cancer in
men worldwide
Highest values in Australia and New Zealand, North
America and western and northern Europe
Most patients with advanced prostate cancer progress
to castration-resistant disease after an initial response
to hormone treatment
`

have a much poorer outlook than do those

with hormone-dependent prostate cancer

Introduction:
Abiraterone acetate is a prodrug of abiraterone
a potent and specific inhibitor of CYP17 that
blocks persistent androgen biosynthesis
Phase 3
randomised
controlled
COU-AA-301
study,
abiraterone acetate plus prednisone was compared
with prednisone alone in patients with metastatic
castration-resistant prostate cancer who were
previously treated with docetaxel
`

significantly prolonged overall survival by 4 - 6 months

Methods:
Patients
Procedures
Outcomes
Statistical Analyses
Role of the funding source
`

Patients
multicentre, open-label, early-access protocol trial at 253 sites in
23 countries
men aged 18 years or older who had metastatic castrationresistant prostate cancer progressing after taxane chemotherapy
and possibly one additional chemotherapy regimen, but without
neuroendocrine differentiation or small-cell histological findings.
PSA progression or radiographic progression in soft tissue or
bone with or without PSA progression;
`

Ongoing androgen deprivation to maintain serum testosterone

lower than 2-0 nmol/L (measured by radioimmunoassay);
and an Eastern Cooperative Oncology Group performance status
of 2 or less.

Procedures
Oral doses of abiraterone acetate (1000 mg per day) and
prednisone (5 mg twice a day) in 28-day cycles.
In regions where prednisone was not available, used
prednisolone.
Allowed two dose reductions of abiraterone acetate (of 250 mg
each) for adverse events related to the drug.
`

Patients could remain in the early-access protocol trial until either

disease progression (both PSA and clinical progression),
unsuccessful adherence to the dosing regimen, sustained side
effects, use of prohibited drugs, or commercial availability of
abiraterone acetate in their respective country

Outcomes
The number of adverse events that arose during treatment
in the early-access protocol trial and within 30 days after
discontinuation of study drugs provided via the earlyaccess protocol trial
Graded all serious adverse events and clinically important
adverse events, and reported them in accordance with the
National Cancer Institutes Common Terminology Criteria
for Adverse Events (CTCAE)
`

Gathered data for the secondary efficacy outcomes of PSA

progression and clinical progression. PSA testing every 3
months

Statistical Analyses

Enrolled patients according to medical need and the dates of commercialisation

and reimbursement of abiraterone acetate in the country in which the patient
was treated.

Used the Kaplan-Meier approach to calculate time to PSA progression and time
to clinical progression, and corresponding two-sided 95% CIs as well as the
median follow-up for PSA and clinical progression.

Summarised all categorical endpoints with frequencies and percentages

Analysed time-to-event endpoints with Kaplan-Meier estimates of survival

distributions

Assessed inference for time-to-event endpoints with a stratified log-rank test

statistic

Estimated hazard ratios and 95% CIs with a stratified proportional hazards
model

Used SAS ver 9.2

Result
Between Nov 17, 2010, and Sept 30, 2013
2314 patients with metastatic castrationresistant prostate cancer progressing after
chemotherapy were enrolled to the early-access
protocol trial
`

Result
Global distribution of the
study population
Of the 23 participating countries
17 were not included in the
COU-AA-301 study
740 (32%) patients were enrolled
from these 17 countries,
enabling collection of safety and
efficacy data from previously
unrepresented regions.

Result
Presents baseline characteristics of
patients in the early-access protocol
trial

2277 (98%) of 2314 patients in the earlyaccess protocol trial had received docetaxel
previously

Duration of exposure to abiraterone acetate

was 4-9 months; received of six cycles of
treatment, and 1226 (53%) were given at least
six cycles of abiraterone acetate

614 (27%) individuals needed temporary dose

interruptions

232 (10%) needed temporary dose

interruptions because of adverse events.

Result
Presents adverse events in the
easy-access protocol population

2314 (100%) enrolled patients received at least

one dose of abiraterone acetate

Provided safety data at the time of clinical cutoff ,

and were assessable for safety

952 (41%) of 2314 patients had grade 3 or 4

adverse events

366 (16%) patients were regarded by the

investigator as drug-related

585 (25%) patients had grade 3 or 4 serious

adverse events

Serious adverse events in 167 (7%) patients were

deemed drug-related

Result
Presents adverse events in the
easy-access protocol population

384 (17%) patients had grade 3 or 4 adverse

events of special interest because they were
potentially associated with raised amounts of
mineralocorticoids due to CYP17 blockade

172 (7%) of 2314 patients discontinued the

study because of adverse events, of which 64
(3%) were drugrelated

171 (7%) patients died. 85 (4%) deaths were

judged by the funder to be caused by disease
progression, 72 (3%) were attributed to an
unrelated adverse experience, and 14 (<1%)
people died for unknown reasons. Of the 86
deaths deemed unrelated to disease
progression

18 (<1%) were attributed to a drug-related

adverse event,

Result
Presents PSA and clinical
progression

683 (30%) patients had PSA progression

and 721 (31%) had clinical progression

PSA progression 8-5 months

Clinical progression 12-7 months

Discussion

Show that abiraterone acetate plus prednisone is safe across a broad

geographical distribution of investigational sites and in a more diverse patient
population

Typically for early-access protocol trials, only serious and grade 3 (or higher)
adverse events are reported, and grade 1 and 2 adverse events are only
reported if they are deemed by the investigator to be medically significant ie,
needing medical intervention or leading to dose reduction or treatment
discontinuation

Have not provided information on grade 1 and 2 adverse events

The estimated median time to PSA progression in the early-access protocol trial
was similar to that reported in COU-AA-301 (8-5 months), and the median time
to clinical progression in the early-access protocol trial was 12-7 months

Discussion

Indicators of clinical progression were significantly improved

On-study exposure to abiraterone acetate plus prednisone in the early-access

protocol trial was shorter than in COU-AA-301, and fewer cycles were given

The results of this early-access protocol trial accord with the safety findings of
the COU-AA-301 study

This study might provide insights more in line with use of abiraterone acetate in
routine clinical practice than would be seen in a randomised controlled trial

Interpretation
This study:

In the context of the COU-AA-301 trial, which provided evidence leading to the
first approval of abiraterone acetate in patients with metastatic castrationresistant prostate cancer who progressed on docetaxel

Provide insights into use of abiraterone acetate in routine clinical practice.

Future work needs to focus on ascertaining the most effective treatment

regimens of abiraterone acetate to optimise patients outcomes