NORTHBROOK, Ill. and
SAN FRANCISCO, Jan. 13, 2016 /PRNewswire/ -- Astellas US
LLC, a subsidiary of Tokyo-based
Astellas Pharma Inc. (TSE:4503), and Medivation, Inc. (Nasdaq:
MDVN), today announced that results from the Phase 2 TERRAIN trial
of enzalutamide compared to bicalutamide in metastatic
castration-resistant prostate cancer (CRPC) were published in the
Lancet Oncology. The article, titled, " Efficacy and Safety
of enzalutamide Versus bicalutamide for Patients with Metastatic
Prostate Cancer (TERRAIN)," appears in the January 13th online issue and will be published
in a future print issue of the journal.
The TERRAIN study achieved its primary endpoint demonstrating a
statistically significant increase in progression-free survival
(PFS) for enzalutamide compared to bicalutamide (Hazard Ratio =
0.44; 95% Confidence Interval, 0.34-0.57; p<0.0001). Median PFS,
defined as time from randomization to centrally confirmed
radiographic progression, skeletal-related event, initiation of new
anti-neoplastic therapy or death, whichever occurred first, was
15.7 months in the enzalutamide group compared to 5.8 months in the
bicalutamide group. The observed adverse event profile of
enzalutamide in TERRAIN appeared consistent with that from Phase 3
enzalutamide trials.
"TERRAIN is the first and largest head-to-head trial comparing
enzalutamide with bicalutamide that evaluated both the efficacy and
safety of these agents in the treatment of men with mCRPC," said
Claire Thom, Pharm D., senior vice
president and oncology therapeutic head, Astellas. "We are pleased
Lancet Oncology has chosen to publish these results."
The median time on treatment in TERRAIN was 11.7 months in the
enzalutamide group versus 5.8 months in the bicalutamide
group. Serious adverse events were reported in 31.1% of
enzalutamide-treated patients and 23% of bicalutamide-treated
patients. Individual Grade 3 or higher adverse events largely
occurred at a similar rate (<1% difference) between treatment
groups, with the exception of hypertension (7.1% vs. 4.2%) and back
pain (2.7% vs. 1.6%), which occurred more frequently in the
enzalutamide treatment group. Grade 3 or higher cardiac events were
reported in 5.5% of enzalutamide-treated patients versus 2.1% of
bicalutamide-treated patients. Two seizures were reported in the
enzalutamide group and one in the bicalutamide group. The most
common side effects occurring during treatment and more common in
the enzalutamide-treated versus bicalutamide-treated patients
included fatigue, back pain, hot flush, hypertension, diarrhea,
weight decreased and pain in extremity.
About the TERRAIN trial
The Phase 2 TERRAIN trial
enrolled 375 patients in North
America and Europe. The
trial enrolled patients with metastatic prostate cancer whose
disease progressed despite treatment with a luteinizing
hormone-releasing hormone (LHRH) analogue therapy or following
surgical castration. The primary endpoint of the trial was PFS,
defined as time from randomization to centrally confirmed
radiographic progression, skeletal-related event, initiation of new
anti-neoplastic therapy or death, whichever occurred first. The
trial was designed to evaluate enzalutamide at a dose of 160 mg
taken orally once daily versus bicalutamide at a dose of 50 mg
taken once daily, the approved dose in combination with an LHRH
analogue.
About XTANDI® (enzalutamide) capsules
XTANDI is approved by the U.S. Food and Drug Administration for the
treatment of patients with metastatic castration-resistant prostate
cancer (CRPC).
Enzalutamide Mechanism of Action
Enzalutamide is an androgen receptor inhibitor that acts on
multiple steps in the androgen receptor signaling pathway within
the tumor cell. In preclinical studies, enzalutamide has been shown
to competitively inhibit androgen binding to androgen receptors,
and inhibit androgen receptor nuclear translocation and interaction
with DNA.
Important Safety Information
Contraindications
XTANDI is not indicated for women and is contraindicated in women
who are or may become pregnant. XTANDI can cause fetal harm when
administered to a pregnant woman.
Warnings and Precautions
Seizure In Study 1,
conducted in patients with metastatic castration-resistant prostate
cancer (CRPC) who previously received docetaxel, seizure occurred
in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2,
conducted in patients with chemotherapy-naive metastatic CRPC,
seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo
patients. There is no clinical trial experience re-administering
XTANDI to patients who experienced a seizure, and limited safety
data are available in patients with predisposing factors for
seizure. Study 1 excluded the use of concomitant medications that
may lower threshold; Study 2 permitted the use of these
medications. Because of the risk of seizure associated with XTANDI
use, patients should be advised of the risk of engaging in any
activity during which sudden loss of consciousness could cause
serious harm to themselves or others. Permanently discontinue
XTANDI in patients who develop a seizure during treatment.
Posterior Reversible Encephalopathy Syndrome (PRES) In
post approval use, there have been reports of PRES in patients
receiving XTANDI. PRES is a neurological disorder which can present
with rapidly evolving symptoms including seizure, headache,
lethargy, confusion, blindness, and other visual and neurological
disturbances, with or without associated hypertension. A diagnosis
of PRES requires confirmation by brain imaging, preferably MRI.
Discontinue XTANDI in patients who develop PRES.
Adverse Reactions
The most common adverse reactions
(greater than or equal to 10%) reported from two combined clinical
studies that occurred more commonly (greater than or equal to 2%
over placebo) in XTANDI patients were asthenia/fatigue, back pain,
decreased appetite, constipation, arthralgia, diarrhea, hot flush,
upper respiratory tract infection, peripheral edema, dyspnea,
musculoskeletal pain, weight decreased, headache, hypertension, and
dizziness/vertigo.
In Study 1, Grade 3 and higher adverse reactions were reported
among 47% of XTANDI patients and 53% of placebo patients.
Discontinuations due to adverse events were reported for 16% of
XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4
adverse reactions were reported in 44% of XTANDI patients and 37%
of placebo patients. Discontinuations due to adverse events were
reported for 6% of both study groups.
- Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of
XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5%
Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI
patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade
3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI
patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade
3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI
patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade
3-4).
- Infections: In Study 1, 1% of XTANDI patients compared to 0.3%
of placebo patients died from infections or sepsis. In Study 2, 1
patient in each treatment group (0.1%) had an infection resulting
in death.
- Falls (including fall-related injuries), occurred in 9% of
XTANDI patients and 4% of placebo patients. 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.
- Hypertension occurred in 11% of XTANDI patients and 4% of
placebo patients. No patients experienced hypertensive crisis.
Medical history of hypertension was balanced between arms.
Hypertension led to study discontinuation in < 1% of all
patients.
Drug Interactions
Effect of Other Drugs on
XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the
plasma exposure to XTANDI. If co-administration is necessary,
reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can
decrease the plasma exposure to XTANDI. If co-administration is
necessary, increase the dose of XTANDI.
Effect of XTANDI on Other Drugs 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. 076-1123-PM 10/15 warfarin (CYP2C9
substrate), conduct additional INR monitoring.
For Full Prescribing Information for XTANDI (enzalutamide)
capsules, please visit www.XtandiHCP.com
You are encouraged to report negative side effects of
prescription drugs to the FDA. Visit
www.fda.gov/medwatch or call
1800FDA1088.
About Astellas
Astellas is a pharmaceutical company
dedicated to improving the health of people around the world
through provision of innovative and reliable pharmaceuticals. For
more information on Astellas, please visit our website
at www.astellas.us, follow us on Twitter
at www.twitter.com/AstellasUS or like our Facebook page
at www.facebook.com/AstellasUS.
About Medivation Inc.
Medivation, Inc. is a
biopharmaceutical company focused on the development and
commercialization of medically innovative therapies 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 http://www.medivation.com
About the Medivation/Astellas Collaboration
In
October 2009, Medivation (NASDAQ:
MDVN) and Astellas (TSE: 4503) 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 has
responsibility for manufacturing and all additional regulatory
filings globally, as well as commercializing XTANDI outside
the United States.
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