XTANDI becomes the first and only androgen
receptor signaling inhibitor approved for use with or without a
GnRH analog therapy* in nonmetastatic castration-sensitive prostate
cancer
TOKYO and NEW
YORK, Nov. 16, 2023 /PRNewswire/ -- Astellas
Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") and Pfizer Inc.
(NYSE: PFE) today announced that the companies received an approval
by the U.S. Food and Drug Administration (FDA) of a supplemental
New Drug Application for XTANDI® (enzalutamide),
following FDA expedited development and review programs (Priority
Review designation, Fast Track designation, Real-time Oncology
Review), based on results from the Phase 3 EMBARK trial. With this
approval, XTANDI becomes the first and only androgen receptor
signaling inhibitor approved by the FDA for the treatment of
patients with nonmetastatic castration-sensitive prostate cancer
(nmCSPC) with biochemical recurrence at high risk for metastasis
(high-risk BCR). Patients with nmCSPC with high-risk BCR may be
treated with XTANDI with or without a gonadotropin-releasing
hormone (GnRH) analog therapy.
Of men who have undergone definitive prostate cancer treatment,
including radical prostatectomy, radiotherapy, or both, an
estimated 20-40% will experience biochemical recurrence (BCR)
within 10 years.1 About nine out of 10 men with
high-risk BCR will develop metastatic disease, and one in
three will die as a result of their metastatic prostate
cancer.2
"For patients who were previously treated for prostate cancer
and had achieved remission, only to later receive the distressing
news of disease recurrence with a risk of metastasis, the emotional
toll can be profound," said Courtney
Bugler, President and CEO of ZERO Prostate Cancer. "This
approval of XTANDI is a promising treatment option for the
community, offering a ray of hope to patients and their caregivers
during these challenging times."
"Having had the privilege of taking care of patients with
prostate cancer for nearly 40 years, I have been fortunate to have
participated in many of the prostate cancer landscape changing
trials; notably, we have not progressed our evidenced-based care
for patients with biochemical recurrence (BCR), also known as
nmCSPC, until the completion of the EMBARK trial," said
Neal Shore, MD, FACS, Chief Medical
Officer of Strategic Innovation and Pharmacy, GenesisCare
USA, Director, CPI, Carolina
Urologic Research Center, and Primary Investigator for the EMBARK
trial. "Previously, treatment options for these BCR patients,
especially those who have a high likelihood of developing
metastases were limited. The FDA approval of XTANDI for patients
with nmCSPC with BCR at high risk of metastasis represents an
important advancement whereby an androgen deprivation signaling
inhibitor, enzalutamide, has achieved standard of care discussion
for patient-physician decision-making."
The approval is based on results from the Phase 3 EMBARK trial,
which evaluated XTANDI plus leuprolide, placebo plus leuprolide,
and XTANDI (single agent) in patients with nonmetastatic hormone-
(or castration-) sensitive prostate cancer (nmHSPC or nmCSPC) with
high-risk BCR. Detailed results from the trial were presented as a
plenary session during the 2023 American Urological Association
Annual Meeting and subsequently published in the New England
Journal of Medicine.
"Today's FDA approval is the culmination of over a decade of
research and development as we've worked to bring XTANDI forward
for as many patients with prostate cancer as possible who may
benefit," said Ahsan Arozullah, M.D., MPH, Senior Vice President
and Head of Oncology Development, Astellas. "With every milestone,
our clinical development program has played an instrumental role in
changing the course of patients' lives. We are proud that XTANDI
can now be offered to a subset of men with nonmetastatic
castration-sensitive prostate cancer with biochemical recurrence
and at high risk for metastases."
"More than 300,000 men in the U.S. have been prescribed XTANDI,
and we are excited to have this approval expand the indication for
the first time into an earlier setting of the disease," said
Chris Boshoff, M.D., Ph.D., Chief
Oncology Research and Development Officer and Executive Vice
President at Pfizer. "This milestone is a testament to XTANDI's
legacy and robust clinical profile, with overall survival
demonstrated for patients with metastatic castration-resistant
prostate cancer, nonmetastatic castration-resistant prostate
cancer, and metastatic castration-sensitive prostate cancer.
With today's approval, we look forward to bringing this
therapy to even more patients who have nonmetastatic
castration-sensitive prostate cancer at high risk for their cancer
metastasizing."
XTANDI is currently under review with other regulatory
authorities around the world, including the European Medicines
Agency, to support an expanded indication in nmHSPC (or nmCSPC)
with high-risk BCR based on the results of EMBARK.
About EMBARK
The Astellas- and Pfizer-led Phase 3,
randomized, double-blind, placebo-controlled, multi-national trial
enrolled 1,068 patients with nonmetastatic hormone- (or
castration-) sensitive prostate cancer (nmHSPC or nmCSPC) with
high-risk BCR at sites in the U.S., Canada, Europe, South
America, and the Asia-Pacific region. Patients who were
considered to experience high-risk BCR had a prostate-specific
antigen doubling time (PSA-DT) ≤ 9 months; serum testosterone ≥ 150
ng/dL (5.2 nmol/L); and screening PSA by the central laboratory ≥ 1
ng/mL if they had a radical prostatectomy (with or without
radiotherapy) as primary treatment for prostate cancer, or at least
2 ng/mL above the nadir if they had radiotherapy only as primary
treatment for prostate cancer. Patients in the EMBARK trial were
randomized to receive enzalutamide 160 mg daily plus leuprolide
(n=355), enzalutamide 160 mg as a single agent (n=355), or placebo
plus leuprolide (n=358). Leuprolide 22.5 mg was administered every
12 weeks.
EMBARK met its primary endpoint of metastasis-free survival
(MFS) for the XTANDI plus leuprolide arm, demonstrating a
statistically significant reduction in the risk of metastasis or
death over placebo plus leuprolide. MFS is defined as the duration
of time in months between randomization and the earliest objective
evidence of radiographic progression by central imaging or death
due to any cause, whichever occurred first.
The study also met a key secondary endpoint, by demonstrating
that patients treated with XTANDI (single agent) had a
statistically significant reduction in the risk of metastasis or
death versus placebo plus leuprolide, meeting its MFS endpoint.
In EMBARK, Grade 3 or higher adverse events (AEs) were reported
in 46% of XTANDI plus leuprolide patients, 50% of patients treated
with XTANDI (single agent), and 43% of patients receiving placebo
plus leuprolide. Permanent discontinuation due to AEs as the
primary reason was reported in 21% of XTANDI plus leuprolide
patients, 18% in XTANDI (single agent) patients, and 10% in placebo
plus leuprolide patients.
For more information on the EMBARK trial (NCT02319837) go to
www.clinicaltrials.gov.
About Nonmetastatic Castration-Sensitive Prostate Cancer with
High-Risk Biochemical Recurrence
In nonmetastatic
castration- (or hormone-) sensitive prostate cancer (nmCSPC or
nmHSPC), no evidence of the cancer spreading to distant parts of
the body (metastases) is detectable with conventional radiological
methods (CT/MRI), and the cancer still responds to medical or
surgical treatment designed to lower testosterone
levels.3,4 Of men who have undergone definitive
prostate cancer treatment, including radical prostatectomy,
radiotherapy, or both, an estimated 20-40% will experience a BCR
within 10 years.1 About 9 out of 10 men with high-risk BCR will
develop metastatic disease, and 1 in 3 will die as a result of
their metastatic prostate cancer.2 The EMBARK trial focused on men
with high-risk BCR. Per the EMBARK protocol, patients with nmCSPC
and high-risk BCR are those initially treated by radical
prostatectomy or radiotherapy, or both, with a PSA-DT ≤ 9 months.
High-risk BCR patients with a PSA-DT of ≤ 9 months have a higher
risk of metastases and death.5 In the U.S., it is
estimated that 12,000-16,000 patients are diagnosed
with nmCSPC with high-risk BCR annually.6
About
XTANDI® (enzalutamide)
XTANDI®
(enzalutamide) is an androgen receptor signaling inhibitor. XTANDI
is a standard of care and has received regulatory approvals in one
or more countries around the world for use in men with metastatic
castration-sensitive prostate cancer (mCSPC; also known as
metastatic hormone-sensitive prostate cancer or mHSPC), metastatic
castration-resistant prostate cancer (mCRPC), non-metastatic
castration-resistant prostate cancer (nmCRPC) and nonmetastatic
castration-sensitive prostate cancer (nmCSPC) with biochemical
recurrence at high risk for metastasis (high-risk BCR). XTANDI is
currently approved for one or more of these indications in more
than 90 countries, including in the U.S., European Union and
Japan. Over one million patients
have been treated with XTANDI globally.6
U.S. Important Safety Information
XTANDI
(enzalutamide) is indicated in the U.S. for the treatment of
patients with castration-resistant prostate cancer (CRPC),
metastatic castration-sensitive prostate cancer (mCSPC) and
nonmetastatic castration-sensitive prostate cancer (nmCSPC) with
biochemical recurrence at high risk for metastasis (high-risk
BCR).
Warnings and Precautions
Seizure occurred in 0.6% of patients receiving
XTANDI in eight randomized clinical trials. In a study of patients
with predisposing factors for seizure, 2.2% of XTANDI-treated
patients experienced a seizure. It is unknown whether
anti-epileptic medications will prevent seizures with XTANDI.
Patients in the study had one or more of the following predisposing
factors: use of medications that may lower the seizure threshold,
history of traumatic brain or head injury, history of
cerebrovascular accident or transient ischemic attack, and
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. 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) There have been reports of PRES in patients
receiving XTANDI. PRES is a neurological disorder that 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 eight randomized 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 combined data of five
randomized, placebo-controlled clinical studies, ischemic heart
disease occurred more commonly in patients on the XTANDI arm
compared to patients on the placebo arm (3.5% vs 2%). Grade 3-4
ischemic events occurred in 1.8% of patients on XTANDI versus 1.1%
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 occurred in patients receiving
XTANDI. 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. In
the combined data of five randomized, placebo-controlled clinical
studies, falls occurred in 12% of patients treated with XTANDI
compared to 6% of patients treated with placebo. Fractures occurred
in 13% of patients treated with XTANDI and in 6% of patients
treated with placebo.
Embryo-Fetal Toxicity The 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.
Adverse Reactions (ARs)
In the data from the five
randomized placebo-controlled trials, the most common ARs (≥ 10%)
that occurred more frequently (≥ 2% over placebo) in XTANDI-treated
patients were musculoskeletal pain, fatigue, hot flush,
constipation, decreased appetite, diarrhea, hypertension,
hemorrhage, fall, fracture, and headache. In the
bicalutamide-controlled study, the most common ARs (≥ 10%) reported
in XTANDI-treated patients were asthenia/fatigue, back pain,
musculoskeletal pain, hot flush, hypertension, nausea,
constipation, diarrhea, upper respiratory tract infection, and
weight loss.
In AFFIRM, the placebo-controlled study of metastatic CRPC
(mCRPC) patients who previously received docetaxel, Grade 3 and
higher ARs were reported among 47% of XTANDI-treated patients.
Discontinuations due to ARs were reported for 16% of XTANDI-treated
patients. In PREVAIL, the placebo-controlled study of
chemotherapy-naive mCRPC patients, Grade 3-4
ARs were reported in 44% of XTANDI patients and 37% of
placebo patients. Discontinuations due to ARs were reported for 6%
of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled
study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and
38% of bicalutamide patients. Discontinuations with an AR as the
primary reason were reported for 8% of XTANDI patients and 6% of
bicalutamide patients.
In PROSPER, the placebo-controlled study of nonmetastatic CRPC
(nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of
XTANDI patients and 23% of placebo patients. Discontinuations with
an AR as the primary reason were reported for 9% of XTANDI patients
and 6% of placebo patients.
In ARCHES, the placebo-controlled study of metastatic CSPC
(mCSPC) patients, Grade 3 or higher ARs were reported in 24% of
XTANDI-treated patients. Permanent discontinuation due to ARs as
the primary reason was reported in 5% of XTANDI patients and 4% of
placebo patients.
In EMBARK, the placebo-controlled study of nonmetastatic CSPC
(nmCSPC) with high-risk biochemical recurrence (BCR) patients,
Grade 3 or higher adverse reactions during the total duration of
treatment were reported in 46% of patients treated with XTANDI plus
leuprolide, 50% of patients receiving XTANDI as a single agent, and
43% of patients receiving placebo plus leuprolide. Permanent
treatment discontinuation due to adverse reactions during the total
duration of treatment as the primary reason was reported in 21% of
patients treated with XTANDI plus leuprolide, 18% of patients
receiving XTANDI as a single agent, and 10% of patients receiving
placebo plus leuprolide.
Lab Abnormalities: Lab abnormalities that occurred in
≥ 5% of patients, and more frequently (> 2%) in the
XTANDI arm compared to placebo in the pooled, randomized,
placebo-controlled studies are hemoglobin decrease, neutrophil
count decreased, white blood cell decreased, hyperglycemia,
hypermagnesemia, hyponatremia, hyperphosphatemia, and
hypercalcemia.
Hypertension: In the combined data from five
randomized placebo-controlled clinical trials, hypertension was
reported in 14.2% of XTANDI patients and 7.4% of placebo patients.
Hypertension led to study discontinuation in < 1% of patients in
each arm.
Drug Interactions
Effect of Other Drugs on
XTANDI Avoid coadministration with strong CYP2C8
inhibitors. If coadministration cannot be avoided, reduce the
dosage of XTANDI.
Avoid coadministration with strong CYP3A4 inducers. If
coadministration cannot be avoided, increase the dosage of
XTANDI.
Effect of XTANDI on Other Drugs Avoid
coadministration with certain CYP3A4, CYP2C9, and CYP2C19
substrates for which minimal decrease in concentration may lead to
therapeutic failure of the substrate. If coadministration cannot be
avoided, increase the dosage of these substrates in accordance with
their Prescribing Information. In cases where active metabolites
are formed, there may be increased exposure to the active
metabolites.
Please see Full Prescribing Information for additional safety
information.
About Astellas
Astellas Pharma Inc. is a
pharmaceutical company conducting business in more than 70
countries around the world. We are promoting the Focus Area
Approach that is designed to identify opportunities for the
continuous creation of new drugs to address diseases with high
unmet medical needs by focusing on Biology and Modality.
Furthermore, we are also looking beyond our foundational Rx focus
to create Rx+® healthcare solutions that combine our
expertise and knowledge with cutting-edge technology in different
fields of external partners. Through these efforts, Astellas stands
on the forefront of healthcare change to turn innovative science
into VALUE for patients. For more information, please visit our
website at https://www.astellas.com/en.
About Pfizer Oncology
At Pfizer Oncology, we are
committed to advancing medicines wherever we believe we can make a
meaningful difference in the lives of people living with cancer.
Today, we have an industry-leading portfolio of 24 approved
innovative cancer medicines and biosimilars across more than 30
indications, including breast, genitourinary, colorectal, blood and
lung cancers, as well as melanoma.
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 commercial agreement to jointly develop and commercialize
XTANDI® (enzalutamide) in the
United States, while Astellas has responsibility for
manufacturing and all additional regulatory filings globally, as
well as commercializing the product outside the United States. Pfizer receives alliance
revenues as a share of U.S. profits and receives royalties on sales
outside the U.S.
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 November 16,
2023. 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 a new indication in the U.S.
for the treatment of patients with nonmetastatic
castration-sensitive prostate cancer with biochemical recurrence at
high risk for metastasis (high-risk BCR), 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; the uncertainties inherent in research and
development, including the ability to meet anticipated clinical
endpoints, commencement and/or completion dates for clinical
trials, regulatory submission dates, regulatory approval dates
and/or launch dates, as well as the possibility of unfavorable new
clinical data and further analyses of existing clinical data;
whether the EMBARK trial will meet the secondary endpoint of
overall survival; the risk that clinical trial data are subject to
differing interpretations and assessments by regulatory
authorities; whether regulatory authorities will be satisfied with
the design of and results from the clinical studies; whether and
when drug applications for XTANDI may be filed in other
jurisdictions; whether and when regulatory authorities in any
jurisdictions may approve any such applications that may be pending
or filed for XTANDI (including the application pending with the
European Medicines Agency), which will depend on a myriad of
factors, including making a determination as to whether the
product's benefits outweigh its known risks and determination of
the product's efficacy and, if approved, whether XTANDI for any
potential indication will be commercially successful; decisions by
regulatory authorities impacting labeling, manufacturing processes,
safety, and/or other matters that could affect the availability or
commercial potential of XTANDI, including for the new indication;
dependence on the efforts and funding by Astellas Pharma Inc. for
the development, manufacturing and commercialization of XTANDI;
uncertainties regarding the impact of COVID-19 on Pfizer's
business, operations and financial results; 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, 2022 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.
*leuprolide
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2 Antonarakis, Emmanuel S et al. "The natural history of
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3 Cancer.net. Prostate Cancer: Types of Treatment
(12-2022).
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Accessed March 16, 2023.
4 American Society of Clinical Oncology. ASCO
Answers: Prostate Cancer (2021).
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Accessed March 16, 2023.
5 Paller, Channing J et al. "Management of patients with
biochemical recurrence after local therapy for prostate cancer."
Hematology/oncology clinics of North
America vol. 27,6 (2013): 1205-19, viii.
doi:10.1016/j.hoc.2013.08.005
6 Astellas. Data on File. XTANDI patient.
January 2023.
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