TOKYO and SAN FRANCISCO, March
24, 2015 /PRNewswire/ -- Astellas Pharma Inc.
(Tokyo: 4503) and Medivation, Inc.
(Nasdaq: MDVN) today announced new data from the Phase 2 TERRAIN
trial of enzalutamide compared to bicalutamide in metastatic
castration-resistant prostate cancer (CRPC), as well as an updated
overall survival analysis from the placebo-controlled Phase 3
PREVAIL trial of enzalutamide in chemotherapy-naive metastatic
CRPC. The data were presented during a plenary session at the
2015 European Association of Urology (EAU) Congress in Madrid, Spain.
"The late breaking data presented at this year's EAU Congress
further demonstrate the breadth and depth of the enzalutamide
development program and is reflective of the many potential
benefits enzalutamide may offer to men with metastatic prostate
cancer," said Claire Thom, Pharm.D.,
senior vice president and Oncology therapeutic head, Astellas
Pharma Global Development, Inc. "We are excited to see that
enzalutamide continues to generate promising data for men with
advanced prostate cancer and their loved ones."
Highlights of Key Enzalutamide Data
Title: A randomized, double-blind, phase 2, efficacy and
safety study of enzalutamide vs. bicalutamide in metastatic
castrate resistant prostate cancer: 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 progression-free survival (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.
"The results of the TERRAIN trial, if confirmed, have the
potential to impact the treatment landscape of metastatic
castration-resistant prostate cancer," said Axel Heidenreich, M.D., Ph.D., professor and
director, Department of Urology, University hospital, Aachen,
Germany. "The study demonstrated
an improvement with enzalutamide over the standard practice of
the addition of bicalutamide to a luteinizing hormone-releasing
hormone therapy."
- The study achieved its primary objective of a statistically
significant increase in PFS for enzalutamide compared to
bicalutamide. The median PFS in the enzalutamide arm was 9.9 months
longer compared to that in the bicalutamide arm (15.7 vs. 5.8
months, respectively) with a Hazard Ratio (HR) of 0.44 (95%
confidence interval [CI], 0.34-0.57; p<0.0001);
- The median time to PSA progression was 13.6 months longer with
enzalutamide (19.4 months) relative to bicalutamide treatment (5.8
months) with an HR of 0.28 (p<0.0001);
- 82% of enzalutamide-treated patients achieved ≥ 50% PSA
reduction from baseline by week 13 vs. 21% of bicalutamide-treated
patients;
- The median time on enzalutamide treatment was 11.7 months
compared to 5.8 months on bicalutamide;
- The safety profile of the enzalutamide-treated patients in
TERRAIN is consistent with the known safety profile of
enzalutamide.
- Serious adverse events (AEs) were reported in 31.1% of
enzalutamide vs. 23.3% of bicalutamide patients and Grade 3 or
higher cardiac AEs were observed in 5.5% of enzalutamide vs. 2.1%
of bicalutamide patients. Two seizures were reported with
enzalutamide and one with bicalutamide;
- The common (≥10%) AEs reported more frequently with
enzalutamide vs. bicalutamide were fatigue (27.9% vs. 20.1%), back
pain (19.1% vs. 18.0%), hot flush (14.8% vs. 11.1%), hypertension
(14.2% vs. 7.4%), diarrhea (11.5% vs. 9.0%), weight decreased
(10.9% vs. 7.9%) and pain in extremities (10.9% vs. 5.3%).
Title: Enzalutamide in men with chemotherapy-naive metastatic
castration-resistant prostate cancer (mCRPC): Final overall
survival analysis of the phase 3 PREVAIL study
The Phase 3 PREVAIL trial, a randomized, double-blind,
placebo-controlled, multi-national trial, enrolled 1,717 patients
at sites in the United States,
Canada, Europe, Australia, Russia, Israel and Asia, including Japan. The trial enrolled patients with
chemotherapy-naive metastatic prostate cancer whose disease
progressed on androgen deprivation therapy (i.e., a LHRH therapy or
after bilateral orchiectomy). The co-primary endpoints of the trial
were overall survival (OS) and radiographic PFS. The trial was
designed to evaluate enzalutamide at a dose of 160 mg taken orally
once daily versus placebo.
"This study demonstrates that starting patients on enzalutamide
at the point when their castration-resistant prostate cancer
becomes metastatic has the potential to prolong survival," said
Bertrand Tombal, M.D., Ph.D.,
professor and chairman, Department of Urology, Universite
catholique de Louvain, Cliniques universitaires Saint-Luc,
Brussels, Belgium. "The overall
survival analysis from the PREVAIL trial confirms significant
overall survival benefit despite many patients receiving subsequent
treatments."
- An updated overall survival analysis was conducted at 784
deaths and found a statistically significant overall survival
benefit with a 23% reduction in risk of death (OS: HR 0.77; 95% CI
0.67–0.88; p=0.0002) and a 4-month improvement in median survival
with enzalutamide (35.3 months [95% CI 32.2 – not yet reached])
over placebo (31.3 months [95% CI 28.8 – 34.2]). As of the
June 2014 cut-off date with a median
follow-up duration of 31 months:
- 52% of enzalutamide and 81% of placebo patients received ≥1
subsequent life-extending prostate cancer therapy.
For Full Prescribing Information for XTANDI (enzalutamide)
capsules, please visit www.XtandiHCP.com/PI
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 three
different steps in the androgen receptor signaling pathway.
Important Safety Information
Contraindications: XTANDI (enzalutamide) capsules can cause
fetal harm when administered to a pregnant woman based on its
mechanism of action and findings in animals. XTANDI is not
indicated for use in women. XTANDI is contraindicated in women who
are or may become pregnant.
Warnings and Precautions: In Study 1, conducted in
patients with metastatic castration-resistant prostate cancer
(CRPC) who previously received docetaxel, seizure occurred in 0.9%
of patients who were treated with XTANDI and 0% treated with
placebo. In Study 2, conducted in patients with chemotherapy-naive
metastatic CRPC, seizure occurred in 0.1% of patients who were
treated with XTANDI and 0.1% treated with placebo. Patients
experiencing a seizure were permanently discontinued from therapy
and all seizure events resolved. There is no clinical trial
experience readministering XTANDI to patients who experienced a
seizure, and limited clinical trial experience in patients with
predisposing factors for seizure. Study 1 excluded the use of
concomitant medications that may lower threshold, whereas 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.
Adverse Reactions: The most common adverse reactions (≥
10%) reported from the two combined clinical trials that occurred
more commonly (≥ 2% over placebo) in the XTANDI-treated 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.
Other Adverse Reactions include:
- Laboratory Abnormalities: In the two studies, Grade 14
neutropenia occurred in 15% of patients treated with XTANDI (1%
Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade
3-4). The incidence of Grade 14 thrombocytopenia was 6% of patients
treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo
(0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of
patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients
treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in
bilirubin occurred in 3% of patients treated with XTANDI (0.1%
Grade 3-4) and 2% of patients treated with placebo (no Grade
3-4).
- Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo
patients and in Study 2, 1 patient in each treatment group (0.1%)
had an infection resulting in death.
- Falls: In the two studies, falls including fall-related
injuries occurred in 9% of XTANDI patients vs 4% treated with
placebo. 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: In the two studies, hypertension was reported in
11% of patients receiving XTANDI and 4% of patients receiving
placebo. No patients experienced hypertensive crisis. Medical
history of hypertension was balanced between arms. Hypertension led
to study discontinuation in < 1% of XTANDI or placebo treated
patients.
Drug Interactions:
- Effect of Other Drugs on XTANDI: Administration of strong
CYP2C8 inhibitors can increase the plasma exposure to XTANDI.
Co-administration of XTANDI with strong CYP2C8 inhibitors should be
avoided if possible. If co-administration of XTANDI cannot be
avoided, reduce the dose of XTANDI. Co-administration of XTANDI
with strong or moderate CYP3A4 and CYP2C8 inducers may alter the
plasma exposure of XTANDI and should be avoided if possible.
- Effect of XTANDI on Other Drugs: XTANDI is a strong CYP3A4
inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. 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.
For Full Prescribing Information for XTANDI (enzalutamide)
capsules, please visit www.XtandiHCP.com
About Astellas Pharma Inc.
Astellas Pharma Inc. is a
pharmaceutical company dedicated to improving the health of people
around the world through provision of innovative and reliable
pharmaceuticals. The organization is committed to being a global
category leader in Oncology and Urology, and has several oncology
compounds in development in addition to enzalutamide. For more
information on Astellas Pharma Inc., please visit our website at
www.astellas.com/en.
About Medivation Inc.
Medivation, Inc. is a
biopharmaceutical company focused on the rapid development 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 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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