Follow-up Data Show ZYTIGA® Plus Prednisone Continues to Delay Progression of Metastatic Castration-Resistant Prostate Cancer

Follow-up Data Show ZYTIGA® Plus Prednisone Continues to Delay Progression of
  Metastatic Castration-Resistant Prostate Cancer in Patients without Prior

PR Newswire

ORLANDO, Fla., Feb. 12, 2013

ORLANDO, Fla., Feb. 12, 2013 /PRNewswire/ --Janssen Research & Development,
LLC [Janssen] announced today updated results showing ZYTIGA^® (abiraterone
acetate) plus prednisone continued to provide statistically significant
improvements in disease progression compared to placebo plus prednisone, and
longer overall survival in men with metastatic castration-resistant prostate

The Phase 3, randomized, multicenter, placebo-controlled study (COU-AA-302)
also demonstrated statistically significant improvement compared to placebo in
the secondary endpoints of median time to opiate use for prostate cancer pain
and to initiation of chemotherapy. The data, from the latest pre-specified
interim analysis of the study,were presented today at the annual American
Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU).

"These results show that the benefits of earlier use of abiraterone acetate
are sustained for many patients with metastatic castration-resistant prostate
cancer," said Dana Rathkopf, MD, lead investigator of the study and assistant
attending physician in the Genitourinary Oncology Service at Memorial
Sloan-Kettering Cancer Center in New York City. "We were particularly pleased
with the long median overall survival among patients treated with abiraterone
acetate plus prednisone."

Results from this most recent analysis and earlier interim analyses from
COU-AA-302 were the basis of the December 2012 U.S. Food and Drug
Administration (FDA) approval of an expanded indication for ZYTIGA, in
combination with prednisone, for the treatment of patients with mCRPC. The
European Commission has also approved an expanded indication for ZYTIGA for
the treatment of patients with mCRPC.

"It's important that clinicians have proven treatments to offer patients with
metastatic castration-resistant prostate cancer before chemotherapy," said
Michael L. Meyers, M.D., Ph.D., vice president, compound development team
leader, ZYTIGA, Janssen. "When ZYTIGA was first approved, it provided a
significant option for men with metastatic castration resistant disease after
chemotherapy with docetaxel; now, with its broader indication and supported by
the data presented at ASCO GU, we are pleased that more mCRPC patients may
benefit from this treatment option. The findings also broaden our knowledge
about the therapeutic activity of ZYTIGA." 

The analysis showed a statistically significant 47 percent reduction in risk
of disease progression – measured as radiographic progression-free survival
(rPFS) – in the ZYTIGA plus prednisone arm (ZYTIGA arm) compared to the
placebo plus prednisone arm (control arm). The median rPFS was 16.5 months in
the ZYTIGA arm vs. 8.3 months in the control arm [hazard ratio (HR) 0.53; 95%
confidence interval (CI): 0.45 to 0.62; P<0.0001].

Treatment with ZYTIGA plus prednisone also resulted in an estimated 21 percent
reduction in risk of death [HR=0.79; 95% CI: 0.66, 0.96, P=0.0151]. The median
overall survival (OS) in the ZYTIGA arm was 35.3 months and was 30.1 months in
the control arm. At the time of this interim analysis, conducted when
approximately 55 percent of overall survival events (deaths) occurred, the
pre-specified p-value for statistical significance was not met.

Secondary Endpoints
Treatment with ZYTIGA plus prednisone also resulted in significant
improvements in all secondary study endpoints compared to the control arm,

  o39 percent decrease in the risk of initiation of cytotoxic chemotherapy
    for prostate cancer: a median of 26.5 months for the ZYTIGA arm vs. 16.8
    months for the control arm [HR=0.61 (95% CI: 0.51, 0.72); P<0.0001].
  o29 percent decrease in the risk of opiate use for cancer pain: the median
    time for the ZYTIGA arm was not reached and was 23.7 months for the
    control arm [HR=0.71; 95% CI: (0.59, 0.85); P<0.0002].

Safety Findings
No new safety concerns were identified with the longer treatment with ZYTIGA
compared to previously reported findings with the drug in mCRPC patients who
had prior chemotherapy. In this interim analysis, fatigue, fluid retention,
low blood potassium, hypertension, cardiac disorders and elevated liver
transaminase enzymes were adverse events (AEs) reported more frequently in the
ZYTIGA arm compared to the control arm. Patients in the ZYTIGA arm of the
study experienced more grade 3 and grade 4 AEs than those in the control arm.
Grade 3 or 4 AEs classified as liver toxicity, consisting primarily of
reversible elevations in liver transaminase enzymes, were reported in more
patients in the ZYTIGA arm than in the control arm.

Janssen previously announced that an Independent Data Monitoring Committee
(IDMC) unanimously recommended unblinding this Phase 3 study after an earlier
interim analysis found a statistically significant difference in rPFS and a
trend in the difference in OS. Based on these results, the IDMC also
recommended that patients in the control arm be offered treatment with
abiraterone acetate.

Study Design
Study COU-AA-302 is a Phase 3, randomized, double-blind, multicenter,
placebo-controlled international clinical study, which evaluated ZYTIGA plus
prednisone compared to placebo plus prednisone in 1,088 men with mCRPC who had
failed androgen deprivation therapy and had not received cytotoxic

Patients were randomized either to receive ZYTIGA 1,000 milligrams (mg)
administered orally once daily plus prednisone 5 mg administered orally twice
daily, or placebo orally daily plus prednisone 5 mg administered twice daily.
The co-primary endpoints of the study are rPFS and OS.

Since its first approval in the U.S. in 2011, ZYTIGA has been approved in more
than 65 countries. More than 50,000 men worldwide have received treatment
with ZYTIGA, and it is quickly becoming one of the cornerstones of treatments
with mCRPC.

More information about ZYTIGA can be found at

ZYTIGA^® (abiraterone acetate) is indicated in combination with prednisone for
the treatment of patients with metastatic castration-resistant prostate cancer


Contraindications - ZYTIGA^® (abiraterone acetate) is not indicated for use in
women. ZYTIGA^® can cause fetal harm (Pregnancy Category X) when administered
to a pregnant woman and is contraindicated in women who are or may become

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess
- Use with caution in patients with a history of cardiovascular disease or
with medical conditions that might be compromised by increases in blood
pressure, hypokalemia, or fluid retention. ZYTIGA^® may cause hypertension,
hypokalemia, and fluid retention as a consequence of increased
mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been
established in patients with LVEF <50% or New York Heart Association (NYHA)
Class III or IV heart failure (in study 1) or NYHA Class II to IV heart
failure (in study 2) because these patients were excluded from these
randomized clinical trials. Control hypertension and correct hypokalemia
before and during treatment. Monitor blood pressure, serum potassium, and
symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI) - AI was reported in patients receiving
ZYTIGA^® in combination with prednisone, after an interruption of daily
steroids and/or with concurrent infection or stress. Use caution and monitor
for symptoms and signs of AI if prednisone is stopped or withdrawn, if
prednisone dose is reduced, or if the patient experiences unusual stress.
Symptoms and signs of AI may be masked by adverse reactions associated with
mineralocorticoid excess seen in patients treated with ZYTIGA^®. Perform
appropriate tests, if indicated, to confirm AI. Increased dosages of
corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity - Monitor liver function and modify, withhold, or discontinue
ZYTIGA^® dosing as recommended (see Prescribing Information for more
information). Measure serum transaminases [alanine aminotransferase (ALT) and
aspartate aminotransferase (AST)] and bilirubin levels prior to starting
treatment with ZYTIGA^®, every two weeks for the first three months of
treatment, and monthly thereafter. Promptly measure serum total bilirubin,
AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity
develop. Elevations of AST, ALT, or bilirubin from the patient's baseline
should prompt more frequent monitoring. If at any time AST or ALT rise above
five times the upper limit of normal (ULN) or the bilirubin rises above three
times the ULN, interrupt ZYTIGA^® treatment and closely monitor liver

Increased ZYTIGA^® Exposures with Food - ZYTIGA^® must be taken on an empty
stomach. No food should be eaten for at least two hours before the dose of
ZYTIGA^® is taken and for at least one hour after the dose of ZYTIGA^® is
taken. Abiraterone C[max] and AUC[0-infinity] (exposure) were increased up to
17- and 10-fold higher, respectively, when a single dose of abiraterone
acetate was administered with a meal compared to a fasted state.

Adverse Reactions - The most common adverse reactions (greater than or equal
to 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea,
vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline
phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia,
hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Drug Interactions - ZYTIGA^® is an inhibitor of the hepatic drug-metabolizing
enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a
narrow therapeutic index. If an alternative cannot be used, exercise caution
and consider a dose reduction of the CYP2D6 substrate. In vitro, ZYTIGA^®
inhibits CYP2C8. There are no clinical data on its use with drugs that are
substrates of CYP2C8. Patients should be monitored closely for signs of
toxicity related to the CYP2C8 substrate if used concomitantly with
abiraterone acetate.

Based on in vitro data, ZYTIGA^® is a substrate of CYP3A4. The effects of
strong CYP3A4 inhibitors or inducers on the pharmacokinetics of abiraterone
have not been evaluated, in vivo. Strong inhibitors and inducers of CYP3A4
should be avoided or used with caution during treatment with ZYTIGA^®.

Use in Specific Populations -  Do not use ZYTIGA^® in patients with baseline
severe hepatic impairment (Child-Pugh Class C).

About Janssen Research & Development
Janssen Research & Development is headquartered in Raritan, N.J. and has
affiliated facilities in Europe, the United States and Asia. Janssen Research
& Development is leveraging a combination of internal and external innovation
to discover and develop novel medicines and solutions in five distinct
therapeutic areas: Neuroscience, Oncology, Immunology, Infectious Diseases and
Vaccines, and Cardiovascular and Metabolism. For more information about
Janssen Research & Development visit

Note: Data in this release correspond to ASCO GU Abstract #5.

SOURCE Janssen Research & Development, LLC

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