U.S. FDA Approves XTANDI (enzalutamide) for the Treatment of Men with Non-Metastatic Castration-Resistant Prostate Cancer (CRPC)

Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa,
Ph.D., “Astellas”) and Pfizer Inc. (NYSE: PFE) today announced the U.S.
Food and Drug Administration (FDA) approved a supplemental New Drug
Application (sNDA) for XTANDI® (enzalutamide), following FDA
Priority Review designation, based on results from the Phase 3 PROSPER
trial. The FDA action broadens the indication for XTANDI to men with
castration-resistant prostate cancer (CRPC), now including men with
non-metastatic CRPC. This approval makes XTANDI the first and only oral
medication FDA-approved for both non-metastatic and metastatic CRPC.
XTANDI was first approved by the FDA in 2012 for the treatment of
patients with metastatic CRPC who had previously received docetaxel, and
was granted approval in 2014 for chemotherapy-naïve men with metastatic
CRPC.

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“With today’s approval, there is now a new option for men with
non-metastatic CRPC, who are in between the failure of androgen
deprivation therapy resulting in CRPC and the onset of metastatic
disease,” said Jonathan Simons, M.D., Prostate Cancer Foundation
President and CEO. “As a foundation that drives research aimed at
improving patient outcomes, it is exciting to see approvals like this,
which are vital to help address unmet patient needs.”

The updated label is based on results from the Phase 3 PROSPER trial,
which demonstrated that the use of XTANDI plus androgen deprivation
therapy (ADT) significantly reduced the risk of developing metastasis or
death compared to ADT alone in men with non-metastatic CRPC. The median
for the primary endpoint, metastasis-free survival (MFS), was 36.6
months for men who received XTANDI plus ADT compared to 14.7 months with
ADT alone (N=1401; HR=0.29 [95% CI: 0.24-0.35]; p<0.0001). The most
common adverse reactions (greater than or equal to 10%) that occurred
more frequently (greater than or equal to 2% over placebo) in XTANDI
plus ADT-treated patients were: asthenic conditions (40% vs 20%), hot
flush (13% vs 7.7%), hypertension (12% vs 5.2%), dizziness (12% vs
5.2%), nausea (11% vs 8.6%) and fall (11% vs 4.1%). Grade 3 or higher
adverse reactions were reported in 31 percent of men treated with XTANDI
plus ADT and in 23 percent of men treated with ADT alone. Data from the
PROSPER study were presented at the 2018 Genitourinary Cancers Symposium
(ASCO GU) in February and published in the New England Journal of
Medicine in June.

“Reducing the risk of disease progression is an important treatment goal
in castration-resistant prostate cancer, since the disease becomes
harder to treat as it advances,” said Andy Schmeltz, global president,
Oncology, Pfizer. “With XTANDI, men with CRPC now have a clinically
proven treatment option that reduces the risk of metastasis. This
approval delivers on the potential for XTANDI to help men at an earlier
stage of the disease, and we are continuing to evaluate the medicine in
an extensive development program across additional prostate cancer
populations.”

“This approval is important progress for men with CRPC, who now have
XTANDI as a treatment option regardless of whether or not they have
detectable metastatic disease,” said Steven Benner, M.D., senior vice
president and global therapeutic area head, Oncology Development,
Astellas. “XTANDI is a standard of care in the treatment of men with
metastatic CRPC and has been prescribed to more than 250,000 men
worldwide since its initial approval in 2012. The expanded indication
based on the PROSPER data builds on the body of evidence for XTANDI.”

Pfizer and Astellas are committed to helping patients access XTANDI by
providing them with access and reimbursement support resources
regardless of their situation. Patients can visit www.XTANDI.com
or call 1-855-898-2634 to learn more.

PROSPER Trial Results

The Phase 3 PROSPER trial enrolled 1,401 patients with non-metastatic
CRPC. Patients were randomized 2:1 and received either XTANDI plus ADT
or placebo plus ADT (ADT alone). Data in the updated XTANDI label
demonstrates that the use of XTANDI plus ADT significantly reduced the
risk of developing metastases or death compared to ADT alone. The median
for the primary endpoint, MFS, was 36.6 months for men who received
XTANDI compared to 14.7 months with ADT alone (HR=0.29 [95% CI:
0.24-0.35]; p<0.0001).

The primary efficacy outcome was supported by a statistically
significant delay in the time to first use of new antineoplastic therapy
(TTA) for patients who received XTANDI plus ADT compared to those who
received ADT alone (median 39.6 months vs 17.7 months; HR=0.21 [95% CI:
0.17-0.26]; p < 0.0001). Overall survival (OS) data were not mature at
the time of final MFS analysis.

The most common adverse reactions (greater than or equal to 10%) that
occurred more frequently (greater than or equal to 2% over placebo) in
XTANDI plus ADT-treated patients compared to the ADT alone patients
were: asthenic conditions (40% vs 20%), hot flush (13% vs 7.7%),
hypertension (12% vs 5.2%), dizziness (12% vs 5.2%), nausea (11% vs
8.6%) and fall (11% vs 4.1%). Grade 3 or higher adverse reactions were
reported in 31 percent of men treated with XTANDI plus ADT and in 23
percent of men treated with ADT alone. In the study, 3.4 percent of
patients in the XTANDI plus ADT arm and 0.6 percent in the ADT alone arm
died from adverse events. Discontinuations with an adverse event as the
primary reason were reported for 9.4 percent of patients treated with
XTANDI plus ADT vs 6 percent treated with ADT alone.

About Prostate Cancer

Prostate cancer is the second most common cancer in men worldwide.1
More than 164,000 men in the United States are estimated to be newly
diagnosed with prostate cancer in 2018.2 In the European
Union, the estimated number of new prostate cancer cases in 2015 was
365,000.3

Castration-resistant prostate cancer (CRPC) refers to the subset of men
whose prostate cancer progresses despite castrate levels of testosterone
(i.e., less than 50 ng/dL).4 Non-metastatic CRPC means there
is no clinically detectable evidence of the cancer spreading to other
parts of the body (metastases), and there is a rising prostate-specific
antigen (PSA) level.5 Many men with non-metastatic CRPC and a
rapidly rising PSA level go on to develop metastatic CRPC.6

About XTANDI® (enzalutamide) capsules

XTANDI (enzalutamide) is an androgen receptor inhibitor indicated for
the treatment of patients with castration-resistant prostate cancer.

Important Safety Information for XTANDI®

Warnings and Precautions

Seizure occurred in 0.4% of patients receiving XTANDI in
clinical studies. In a study of patients with predisposing factors for
seizure, 2.2% of XTANDI-treated patients experienced a seizure. Patients
in the study had one or more of the following pre-disposing factors: use
of medications that may lower the seizure threshold; history of
traumatic brain or head injury, cerebrovascular accident or transient
ischemic attack, Alzheimer’s disease, meningioma, or leptomeningeal
disease from prostate cancer, unexplained loss of consciousness within
the last 12 months, history of seizure, presence of a space occupying
lesion of the brain, history of arteriovenous malformation, or history
of brain infection. It is unknown whether anti-epileptic medications
will prevent seizures with XTANDI. Advise patients of the risk of
developing a seizure while taking XTANDI and of engaging in any activity
where 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.

Hypersensitivity reactions, including edema of the face (0.5%),
tongue (0.1%), or lip (0.1%) have been observed with XTANDI in clinical
trials. Pharyngeal edema has been reported in post-marketing cases.
Advise patients who experience any symptoms of hypersensitivity to
temporarily discontinue XTANDI and promptly seek medical care.
Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease In the placebo-controlled clinical
studies, ischemic heart disease occurred more commonly in patients on
the XTANDI arm compared to patients on the placebo arm (2.7% vs 1.2%).
Grade 3-4 ischemic events occurred in 1.2% of patients on XTANDI versus
0.5% on placebo. Ischemic events led to death in 0.4% of patients on
XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of
ischemic heart disease. Optimize management of cardiovascular risk
factors, such as hypertension, diabetes, or dyslipidemia. Discontinue
XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures In the placebo-controlled clinical studies,
falls occurred in 10% of patients treated with XTANDI compared to 4% of
patients treated with placebo. Fractures occurred in 8% of patients
treated with XTANDI and in 3% of patients treated with placebo. Evaluate
patients for fracture and fall risk. Monitor and manage patients at risk
for fractures according to established treatment guidelines and consider
use of bone-targeted agents.

Embryo-Fetal Toxicity Safety and efficacy of XTANDI have not been
established in females. XTANDI can cause fetal harm and loss of
pregnancy when administered to a pregnant female. Advise males with
female partners of reproductive potential to use effective contraception
during treatment with XTANDI and for 3 months after the last dose of
XTANDI. XTANDI should not be handled by females who are or may become
pregnant.

Adverse Reactions

The most common adverse reactions (? 10%) that occurred more frequently
(? 2% over placebo) in the XTANDI patients from the randomized
placebo-controlled trials were asthenia/fatigue, decreased appetite, hot
flush, arthralgia, dizziness/vertigo, hypertension, headache and weight
decreased. In the bicalutamide-controlled study, the most common adverse
reactions (? 10%) reported in XTANDI patients were asthenia/fatigue,
back pain, musculoskeletal pain, hot flush, hypertension, nausea,
constipation, diarrhea, upper respiratory tract infection, and weight
loss.

In the placebo-controlled study of metastatic CRPC (mCRPC) 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 mCRPC 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 placebo-controlled study of
non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher adverse
reactions were reported in 31% of XTANDI patients and 23% of placebo
patients. Discontinuations with an adverse event as the primary reason
were reported for 9% of XTANDI patients and 6% of placebo patients. In
the bicalutamide-controlled study of chemotherapy-naïve mCRPC patients,
Grade 3-4 adverse reactions were reported in 39% of XTANDI patients and
38% of bicalutamide patients. Discontinuations with an AE as the primary
reason were reported for 8% of XTANDI patients and 6% of bicalutamide
patients.

Lab Abnormalities: In the two placebo-controlled trials in
patients with mCRPC, Grade 1-4 neutropenia occurred in 15% of XTANDI
patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). In
the placebo-controlled trial in patients with nmCRPC, Grade 1-4
neutropenia occurred in 8% of patients receiving XTANDI (0.5% Grade 3-4)
and in 5% of patients receiving placebo (0.2% Grade 3-4).

Hypertension: In the two placebo-controlled trials in patients
with mCRPC, hypertension was reported in 11% of XTANDI patients and 4%
of placebo patients. Hypertension led to study discontinuation in <1% of
patients in each arm. In the placebo-controlled trial in patients with
nmCRPC, hypertension was reported in 12% of patients receiving XTANDI
and 5% of patients receiving placebo.

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 for additional safety information.

About the Enzalutamide Development Program

Pfizer and Astellas are collaborating on a comprehensive development
program that includes studies of enzalutamide across the full spectrum
of advanced prostate cancer. Ongoing studies of enzalutamide in prostate
cancer include the ARCHES trial in metastatic hormone-sensitive prostate
cancer and the EMBARK trial in non-metastatic hormone-sensitive prostate
cancer.

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. For more information,
please visit our website at https://www.astellas.com/en.

About Pfizer Oncology

Pfizer Oncology is committed to pursuing innovative treatments that have
a meaningful impact on people living with cancer. Our growing pipeline
of biologics, small molecules, and immunotherapies is focused on
identifying and translating the best scientific breakthroughs into
clinical application for patients across a diverse array of solid tumors
and hematologic cancers. Today, we have 10 approved oncology medicines
and 14 assets currently in clinical development. By maximizing our
internal scientific resources and collaborating with other companies,
government and academic institutions, as well as patients and non-profit
and professional organizations, we are bringing together the brightest
and most enterprising minds to take on the toughest cancers. Together we
can accelerate breakthrough treatments to patients around the world and
work to redefine life with cancer.

About the Pfizer/Astellas Collaboration

In October 2009, Medivation, Inc., which is now part of Pfizer
(NYSE:PFE), and Astellas (TSE: 4503) entered into a global agreement to
jointly develop and commercialize enzalutamide. 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.

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.

Pfizer Disclosure Notice

The information contained in this release is as of July 13, 2018. 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) and an expanded indication in the U.S. to include men
with non-metastatic castration-resistant prostate cancer, 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
success of XTANDI in the expanded indication; 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; the risk that clinical trial data
are subject to differing interpretations, and, even when we view data as
sufficient to support the safety and/or effectiveness of a product
candidate, regulatory authorities may not share our views and may
require additional data or may deny approval altogether; whether
regulatory authorities will be satisfied with the design of and results
from our clinical studies; the risks associated with interim data;
whether and when drug applications for any other potential indications
for XTANDI will be filed in any jurisdictions; whether and when
regulatory authorities in any jurisdictions may approve any such other
applications, 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 and, if approved, whether
XTANDI for any such indications will be commercially successful;
decisions by regulatory authorities regarding labeling, safety, and
other matters that could affect the availability or commercial potential
of XTANDI; risks related to 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, 2017 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.

______________________1 American Cancer Society. Global
Cancer Facts and Figures (2015). https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-3rd-edition.pdf.
Accessed 01-11-2018.2 American Cancer Society. Key
Statistics for Prostate Cancer. https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html.
Accessed 01-08-2018.3 European Commission. Epidemiology
of prostate cancer in Europe (03-17-2017). https://ec.europa.eu/jrc/en/publication/epidemiology-prostate-cancer-europe.
Accessed 01-19-2018.4 Kirby M, Hirst C, Crawford ED.
Characterising the castration-resistant prostate cancer population: a
systematic review. Int J Clin Pract 2011;65(11):1180-92.5
Luo J, Beer T, Graff J. Treatment of nonmetastatic castration-resistant
prostate cancer. Oncology 2016;30(4):336-44.6
Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum
prostate-specific antigen in men with castrate nonmetastatic prostate
cancer. J Clin Oncol 2005;23(13):2918-25.

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