TOKYO and
NEW YORK, Oct. 21, 2016 /PRNewswire/ -- Astellas Pharma
Inc. (TSE: 4503) and Pfizer Inc. (NYSE:PFE) today announced the
U.S. Food and Drug Administration (FDA) approved a supplemental New
Drug Application (sNDA) to update the U.S. product labeling for
XTANDI® (enzalutamide) capsules to include new clinical data versus
bicalutamide from the TERRAIN study. The data demonstrate
improvement in radiographic progression-free survival (rPFS) in
patients with metastatic castration-resistant prostate cancer
(CRPC) who were treated with enzalutamide compared to patients who
were treated with bicalutamide.
The TERRAIN study evaluated men with
metastatic CRPC and the results from this study were published in
the Lancet Oncology. The updated label includes data that
enzalutamide reduces the risk of radiographic progression or
death by 40% compared with bicalutamide, showing
a median rPFS of 19.5 months for the enzalutamide
group versus a median of 13.4 months for the bicalutamide group
(hazard ratio = 0.60 [0.43, 0.83]; 95% confidence interval) based
on an analysis recommended by the FDA. The safety
profile of enzalutamide was consistent with results of earlier
enzalutamide trials.
"The addition of data from the TERRAIN trial continues to
build the body of evidence that demonstrates the clinical impact
XTANDI can have for patients living with metastatic CRPC,"
said Steven Benner,
M.D., senior vice president, therapeutic area head for oncology
development, Astellas. "Advances in scientific
knowledge as seen through clinical trials like TERRAIN would not be
possible without the participation of hundreds of patients, family
members and clinical investigators, and we thank them for their
valuable contributions."
According to the American Cancer Society, each year
approximately 181,000 new cases of prostate cancer will be
diagnosed and an estimated 26,000 men will die of the disease in
2016.1 Up to 40 percent of men diagnosed with prostate
cancer who undergo therapy develop metastatic, or advanced,
prostate cancer.2 In the U.S., the five-year relative
survival rate for prostate cancer patients with metastatic disease
is 28 percent, compared with 100 percent for prostate cancer
patients with non-metastatic disease.3
"We are pleased with the FDA's decision to
update the XTANDI label with these data from the first
and largest comparative trial that demonstrated safety
and efficacy of enzalutamide compared to bicalutamide,"
said Mohammad Hirmand, M.D.,
interim chief medical officer at Medivation, Inc., which is now
part of Pfizer. "We believe these data will help physicians better
understand the differences between enzalutamide and bicalutamide
for their patients living with metastatic CRPC."
The Committee for Medicinal Products for Human Use (CHMP)
of the European Medicines Agency (EMA) issued a positive opinion on
April 1, 2016 recommending approval
of a type II variation to include data from the TERRAIN trials in
the European label for XTANDI.
About the TERRAIN trial
The Phase II TERRAIN trial enrolled 375 chemotherapy-naïve
patients with metastatic CRPC in North
America and Europe. Radiographic progression-free
survival was defined as the time from randomization to the first
objective evidence of radiographic progression as assessed by
Independent Central Review or death, whichever occurred first. The
trial was designed to evaluate patients who were randomized 1:1 to
receive enzalutamide at a dose of 160 mg taken orally once daily
versus bicalutamide at a dose of 50 mg taken once
daily.
Grade 3-4 adverse reactions were reported in 38.8% of
enzalutamide-treated patients and 37.6% of bicalutamide-treated
patients. Individual Grade 3 or higher adverse events largely
occurred at a similar rate (<1% difference) between the
enzalutamide vs. bicalutamide treatment groups, with the exception
of hypertension (7.1% vs. 4.4%), diarrhea (0% vs. 1.1%) and back
pain (2.7% vs. 1.6%). Two seizures were reported in the
enzalutamide group and one in the bicalutamide group. The most
common Grade 1-4 adverse reactions (incidence ≥10%) occurring
during treatment and more common in the enzalutamide-treated versus
bicalutamide-treated patients included asthenic conditions, back
pain, musculoskeletal pain, hot flush, hypertension, diarrhea,
upper respiratory tract infection, and weight loss.
About
XTANDI® (enzalutamide)
capsules
XTANDI (enzalutamide) capsules is an androgen receptor
inhibitor that blocks 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. The clinical
significance of this mechanism of action (MOA) is
unknown.
XTANDI is approved by the U.S. Food and Drug
Administration for the treatment of patients with metastatic
castration-resistant prostate cancer (mCRPC).
Important Safety Information
Contraindications
XTANDI is not indicated for women. XTANDI can cause fetal
harm and potential loss of pregnancy.
Warnings and Precautions
Seizure occurred in 0.5% of patients
receiving XTANDI in clinical studies. In placebo-controlled
studies, 8 of 1671 (0.5%) patients treated with XTANDI and 1 of
1243 (0.1%) patients treated with placebo experienced a seizure. In
patients who previously received docetaxel, 7 of 800 (0.9%)
patients treated with XTANDI experienced a seizure and no patients
treated with placebo experienced a seizure. In a placebo-controlled
study in chemotherapy-naïve patients, 1 of 871 (0.1%) treated with
XTANDI and 1 of 844 (0.1%) patients treated with placebo
experienced a seizure. In bicalutamide-controlled studies conducted
in chemotherapy-naïve patients, 3 of 380 (0.8%) patients treated
with XTANDI and 1 of 387 (0.3%) patients treated with bicalutamide
experienced a seizure. 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 (≥ 10%) that occurred more commonly (≥ 2% over
placebo) in the XTANDI patients from the two placebo-controlled
clinical trials 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 the bicalutamide-controlled
study of chemotherapy naïve patients, the
most common adverse reactions (≥ 10%) reported in XTANDI patients
were asthenia/fatigue, back pain, musculoskeletal pain, hot flush,
hypertension, nausea, constipation, upper respiratory tract
infection, diarrhea, and weight loss.
In the study of patients taking XTANDI who previously
received docetaxel, 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 the
placebo-controlled study of chemotherapy-naïve patients, 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. In the
bicalutamide-controlled study of chemotherapy naïve patients, Grade
3-4 adverse reactions were reported in 38.8% of XTANDI patients and
37.6% of bicalutamide patients. Discontinuations due to adverse
events were reported for 7.6% of XTANDI patients and 6.3% of
bicalutamide patients.
Lab Abnormalities: In the two placebo-controlled trials
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 a study of patients taking XTANDI who
previously received docetaxel, 1% of XTANDI patients compared to
0.3% of placebo patients died from infections or sepsis. In the
placebo-controlled study of chemotherapy-naïve patients, 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 in the two
placebo-controlled trials. 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 in the two placebo-controlled trials. No patients
experienced hypertensive crisis. Medical history of hypertension
was balanced between arms. Hypertension led to study
discontinuation in < 1% of all patients in each arm.
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.
Please see Full Prescribing
Information at
https://www.astellas.us/docs/us/12A005-ENZ-WPI.pdf?v=1 for
additional safety information.
You are encouraged to report negative side effects of
prescription drugs to the FDA.
Visit
www.fda.gov/medwatch or call
1‐800‐FDA‐1088.
About Astellas
Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to
improving the health of people around the world through the
provision of innovative and reliable pharmaceutical products. We
focus on Urology, Oncology, Immunology, Nephrology and Neuroscience
as prioritized therapeutic areas while advancing new therapeutic
areas and discovery research leveraging new
technologies/modalities. We are also creating new value by
combining internal capabilities and external expertise in the
medical/healthcare business. Astellas is on the forefront of
healthcare change to turn innovative science into value for
patients. For more information, please visit our website at
www.astellas.com/en.
About Pfizer Oncology
Pfizer Oncology is committed to pursuing innovative
treatments that have a meaningful impact on those living with
cancer. As a leader in oncology speeding cures and accessible
breakthrough medicines to patients, Pfizer Oncology is helping to
redefine life with cancer. Our strong pipeline of biologics, small
molecules and immunotherapies, one of the most robust in the
industry, is studied with precise focus on identifying and
translating the best scientific breakthroughs into clinical
application for patients across a wide range of cancers. By working
collaboratively with academic institutions, individual researchers,
cooperative research groups, governments and licensing partners,
Pfizer Oncology strives to cure or control cancer with its
breakthrough medicines. Because Pfizer Oncology knows that success
in oncology is not measured solely by the medicines you
manufacture, but rather by the meaningful partnerships you make to
have a more positive impact on people's lives. Learn more about how
Pfizer Oncology is applying innovative approaches to improve the
outlook for people living with cancer
at http://www.pfizer.com/research/therapeutic_areas/oncology.
Pfizer Disclosure Notice
The information contained in this release is as of
October 21, 2016. Pfizer assumes no
obligation to update forward-looking statements contained in this
release as the result of new information or future events or
developments.
This release contains forward-looking information about
XTANDI® (enzalutamide) capsules and a label update to include the
results of the TERRAIN study, including their potential benefits,
that involves substantial risks and uncertainties that could cause
actual results to differ materially from those expressed or implied
by such statements. Risks and uncertainties include, among other
things,uncertainties regarding the commercial impact of the label
update; the uncertainties inherent in research and development,
including the ability to meet anticipated clinical trial
commencement and completion dates and regulatory submission dates,
as well as the possibility of unfavorable clinical trial results,
including unfavorable new clinical data and additional analyses of
existing clinical data; whether and when any drug applications may
be filed for any potential additional indications for XTANDI;
whether and when any such applications may be approved by
regulatory authorities, which will depend on the assessment by such
regulatory authorities of the benefit-risk profile suggested by the
totality of the efficacy and safety information submitted;
decisions by regulatory authorities regarding labeling and other
matters that could affect the availability or commercial potential
of XTANDI; risks related to the ability to sustain and increase the
rate of growth in revenues for XTANDI despite increasing
competitive, reimbursement and economic challenges; dependence on
the efforts and funding by Astellas Pharma Inc. for the
development, manufacturing and commercialization of XTANDI; and
competitive developments.
A further description of risks and uncertainties can be
found in Pfizer's Annual Report on Form 10-K for the fiscal year
ended December 31, 2015 and in its
subsequent reports on Form 10-Q, including in the sections thereof
captioned "Risk Factors" and "Forward-Looking Information and
Factors That May Affect Future Results", as well as in its
subsequent reports on Form 8-K, all of which are filed with the
U.S. Securities and Exchange Commission and available
at www.sec.gov
and www.pfizer.com.
Astellas Forward-Looking Statement
In this press release, statements made with respect to
current plans, estimates, strategies and beliefs and other
statements that are not historical facts are forward-looking
statements about the future performance of Astellas. These
statements are based on management's current assumptions and
beliefs in light of the information currently available to it and
involve known and unknown risks and uncertainties. A number of
factors could cause actual results to differ materially from those
discussed in the forward-looking statements. Such factors include,
but are not limited to: (i) changes in general economic conditions
and in laws and regulations, relating to pharmaceutical markets,
(ii) currency exchange rate fluctuations, (iii) delays in new
product launches, (iv) the inability of Astellas to market existing
and new products effectively, (v) the inability of Astellas to
continue to effectively research and develop products accepted by
customers in highly competitive markets, and (vi) infringements of
Astellas' intellectual property rights by third parties.
Information about pharmaceutical products (including
products currently in development), which is included in this press
release is not intended to constitute an advertisement or medical
advice.
References
- American Cancer Society. "Cancer Facts and Figures:
2016."
- "Current and emerging treatments in the management of
castration-resistant prostate cancer." David Shapiro and Basir
Tareen. Expert Rev Anticancer Ther.
2012;12(7):951-964.
- National Cancer Institute. SEER Cancer Statistics
Factsheets: Prostate Cancer. Available at
seer.cancer.gov/statfacts/html/prost.html. Accessed October 5, 2016.
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