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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