NORTHBROOK, Ill. and
SAN FRANCISCO, JUNE 1, 2014 /PRNewswire/ -- Astellas Pharma
US, Inc., a U.S. subsidiary of Tokyo-based Astellas Pharma Inc. (Tokyo: 4503) and Medivation, Inc. (Nasdaq:
MDVN) today announced the online publication in the New England
Journal of Medicine of the results from the Phase 3 PREVAIL
trial, an international, randomized, double-blind,
placebo-controlled clinical study of enzalutamide. The study
evaluated the benefit and safety of enzalutamide in men with
metastatic prostate cancer, who had few or no symptoms, that had
progressed on luteinizing hormone-releasing hormone (LHRH) therapy
or after bilateral orchiectomy. The paper, "Enzalutamide in Men
with Metastatic Prostate Cancer Before Chemotherapy," appears in
the June 1 online issue and the
companies anticipate publication in a future print issue of the
Journal.
"The PREVAIL study results demonstrate that treatment with
enzalutamide in men with metastatic castration resistant prostate
cancer can decrease the risk of death, delay the growth or spread
of metastatic prostate cancer, and delay the time to initiation of
chemotherapy," said Tomasz M. Beer,
M.D., F.A.C.P., professor of medicine and deputy director of the
Knight Cancer Institute at Oregon Health & Science University,
and co-principal investigator of the PREVAIL study. "We are
delighted that the New England Journal of Medicine has
chosen to publish these important results."
A supplemental New Drug Application (sNDA) based on the PREVAIL
results received a priority review designation from the U.S. Food
and Drug Administration (FDA). The Prescription Drug User Fee
Act (PDUFA) goal date is September 18,
2014. A variation application to amend the European
Marketing Authorization Application based on the results of PREVAIL
was validated for review by the European Medicines Agency on
April 24, 2014.
About the PREVAIL Trial
The Phase 3 PREVAIL trial is a
randomized, double-blind, placebo-controlled, multi-national trial
that enrolled more than 1,700 patients at sites in the United States, Canada, Europe, Australia, Russia, Israel and Asia including Japan. The trial enrolled patients with
chemotherapy-naive metastatic prostate cancer whose disease
progressed on androgen deprivation therapy (i.e., a luteinizing
hormone-releasing hormone (LHRH) therapy or after bilateral
orchiectomy). The co-primary endpoints of the trial were overall
survival and radiographic progression-free survival. The trial was
designed to evaluate enzalutamide at a dose of 160 mg taken orally
once daily versus placebo.
In the PREVAIL trial, men treated with enzalutamide demonstrated
a statistically significant delay in cancer progression and
reduction in the risk of death compared with placebo.
Enzalutamide reduced the risk of radiographic progression or
death by 81% (HR=0.19; p < 0.0001), compared with
placebo. The rate of radiographic progression-free survival at 12
months of follow up was 65% among patients treated with
enzalutamide, as compared with 14% among patients receiving
placebo.
Enzalutamide reduced the risk of death by 29% (HR=0.71; p <
0.0001), compared with placebo. A total of 626 patients (72%)
in the enzalutamide group, as compared with 532 patients (63%) in
the placebo group, were alive at the September 16, 2013 data cutoff
date.
The most common clinically relevant adverse events associated
with enzalutamide treatment as compared with placebo-treated
patients in the PREVAIL trial included fatigue, hot flush and
hypertension; hypertension was observed in 13.4% of enzalutamide
versus 4.1% of placebo-treated patients. Grade 3 or higher cardiac
adverse events were reported in 2.8% of enzalutamide versus 2.1% of
placebo-treated patients. One patient experienced a seizure in each
treatment group.
Enzalutamide Mechanism of Action
Enzalutamide
is an androgen receptor inhibitor that acts on different steps in
the androgen receptor signaling pathway. Enzalutamide has been
shown to competitively inhibit androgen binding to androgen
receptors, and inhibit androgen receptor nuclear translocation and
interaction with DNA.
About XTANDI® (enzalutamide) capsules
XTANDI
was approved by the FDA on August 31, 2012 and is indicated for the
treatment of patients with metastatic castration-resistant prostate
cancer (mCRPC) who have previously received docetaxel. In March
2014, Astellas and Medivation submitted a sNDA to the FDA
seeking approval of XTANDI for the treatment of men with metastatic
prostate cancer that has progressed on LHRH therapy or after
bilateral orchiectomy. In May 2014, the FDA granted the sNDA
application Priority Review designation with a PDUFA date of
September 18, 2014.
Important Safety Information for XTANDI (from the approved
prescribing information) Contraindications:
XTANDI can cause fetal harm when administered to a pregnant woman
based on its mechanism of action. XTANDI is not indicated for use
in women. XTANDI is contraindicated in women who are or may become
pregnant.
Warnings and Precautions: In the randomized
clinical trial, seizure occurred in 0.9% of patients on XTANDI. No
patients on the placebo arm experienced seizure. Patients
experiencing a seizure were permanently discontinued from therapy.
All seizures resolved. Patients with a history of seizure, taking
medications known to decrease the seizure threshold, or with other
risk factors for seizure were excluded from the clinical trial.
Because of the risk of seizure associated with XTANDI use, patients
should be advised of the risk of engaging in any activity where
sudden loss of consciousness could cause serious harm to themselves
or others.
Adverse Reactions: The most common adverse drug
reactions (>/= 5%) reported in patients receiving XTANDI in the
randomized clinical trial were asthenia/fatigue, back pain,
diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal
pain, headache, upper respiratory infection, muscular weakness,
dizziness, insomnia, lower respiratory infection, spinal cord
compression and cauda equina syndrome, hematuria, paresthesia,
anxiety, and hypertension. Grade 1-4 neutropenia occurred in 15% of
XTANDI patients (1% Grade 3-4) and in 6% on placebo (no Grade 3-4).
Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients
and 2% on placebo. One percent of XTANDI patients compared to 0.3%
on placebo died from infections or sepsis. Falls or injuries
related to falls occurred in 4.6% of XTANDI patients versus 1.3% on
placebo. Falls were not associated with loss of consciousness or
seizure. Fall-related injuries were more severe in XTANDI patients
and included non-pathologic fractures, joint injuries, and
hematomas. Grade 1 or 2 hallucinations occurred in 1.6% of XTANDI
patients and 0.3% on placebo, with the majority on
opioid-containing medications at the time of the event.
Drug Interactions - Effect of Other Drugs on
XTANDI: Administration of strong CYP2C8 inhibitors can
increase the plasma exposure to XTANDI. Co-administration of XTANDI
with strong CYP2C8 inhibitors should be avoided if possible. If
co-administration of XTANDI cannot be avoided, reduce the dose of
XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4
and CYP2C8 inducers can alter the plasma exposure of XTANDI and
should be avoided if possible.
Effect of XTANDI on Other Drugs: XTANDI is a
strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in
humans. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow
therapeutic index, as XTANDI may decrease the plasma exposures of
these drugs. If XTANDI is co-administered with warfarin (CYP2C9
substrate), conduct additional INR monitoring.
For Full Prescribing Information for XTANDI (enzalutamide)
capsules, please visit www.XtandiHCP.com.
About Astellas Pharma Inc.
Astellas Pharma
Inc. is a pharmaceutical company dedicated to improving the health
of people around the world through provision of innovative and
reliable pharmaceuticals. The organization is committed to being a
global category leader in Oncology and Urology, and has several
oncology compounds in development in addition to enzalutamide. For
more information on Astellas Pharma Inc., please visit our website
at www.astellas.com/en.
About Medivation
Medivation, Inc. is a
biopharmaceutical company focused on the rapid development of novel
small molecule drugs to treat serious diseases for which there are
limited treatment options. Medivation aims to transform the
treatment of these diseases and offer hope to critically ill
patients and their families. For more information, please visit us
at www.medivation.com.
About the Astellas/Medivation Collaboration
In
October 2009, Medivation and Astellas
entered into a global agreement to jointly develop and
commercialize enzalutamide. The companies are collaborating on a
comprehensive development program that includes studies to develop
enzalutamide across the full spectrum of advanced prostate cancer
as well as advanced breast cancer. The companies jointly
commercialize XTANDI in the United
States and Astellas will have responsibility for
manufacturing and all additional regulatory filings globally, as
well as commercializing XTANDI outside the United States.
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SOURCE Astellas Pharma US, Inc.
