LYNPARZA Reduced the Risk of Disease
Progression or Death by 47% Compared to Placebo in Patients Whose
Disease Had Not Progressed On at Least 16 Weeks of a First-Line
Platinum-Based Chemotherapy Regimen
Only PARP Inhibitor Approved in Germline
BRCA-mutated Advanced Pancreatic Cancer
AstraZeneca and Merck (NYSE:
MRK), known as MSD outside the United States and Canada, today
announced that the U.S. Food and Drug Administration (FDA) has
approved LYNPARZA for the maintenance treatment of adult patients
with deleterious or suspected deleterious germline BRCA-mutated
(gBRCAm) metastatic pancreatic adenocarcinoma whose disease has not
progressed on at least 16 weeks of a first-line platinum-based
chemotherapy regimen. Patients will be selected for therapy based
on an FDA-approved companion diagnostic for LYNPARZA.
The approval follows the
recommendation by the U.S. FDA Oncologic Drugs Advisory Committee
on Dec. 17 for LYNPARZA in this indication and was based on results
from the pivotal Phase 3 POLO trial published in the New England
Journal of Medicine and
presented at the 2019 American Society of Clinical Oncology (ASCO)
Annual Meeting.
Results showed a statistically
significant and clinically meaningful improvement in
progression-free survival (PFS) where LYNPARZA nearly doubled the
time patients with gBRCAm metastatic pancreatic cancer lived
without disease progression or death to a median of 7.4 months vs.
3.8 months on placebo (HR 0.53 [95% CI 0.35-0.81]
p=0.0035).
The most common adverse
reactions (ARs) ≥10% were fatigue/asthenia (60%), nausea (45%),
abdominal pain (34%), diarrhea (29%), anemia (27%), decreased
appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia
(15%), rash (15%), thrombocytopenia (14%), dyspnea (13%),
neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and
stomatitis (10%). The most common ≥ grade 3 ARs were anemia (11%),
fatigue/asthenia (5%), decreased appetite (3%), abdominal pain
(2%), vomiting (1%) and arthralgia (1%). Among patients taking
LYNPARZA, dose interruptions due to an adverse reaction of any
grade occurred in 35% and dose reductions due to an adverse
reaction occurred in 17%. Discontinuation due to adverse reactions
occurred in 6% of patients receiving LYNPARZA.
Dave Fredrickson, executive
vice president, head of the oncology business unit, AstraZeneca,
said, “Patients with advanced pancreatic cancer historically have
faced poor outcomes due to the aggressive nature of the disease and
limited treatment advances over the last few decades. LYNPARZA is
now the only approved targeted medicine in biomarker-selected
patients with advanced pancreatic cancer.”
Dr. Roy Baynes, senior vice
president and head of global clinical development, chief medical
officer, Merck Research Laboratories, said, “LYNPARZA embodies
Merck’s and AstraZeneca’s commitment to advance the treatment of
challenging types of cancer, including metastatic pancreatic
cancer. The expanded approval of LYNPARZA represents a significant
milestone for patients and supports the value of germline BRCA
testing in patients with this disease.”
Dr. Hedy L. Kindler,
co-principal investigator of the POLO trial and professor of
medicine, University of Chicago Medicine, said, “Today’s approval
of olaparib based on the POLO results gives clinicians an important
first-line maintenance treatment option which nearly doubled the
progression-free survival benefit in patients with germline
BRCA-mutated metastatic pancreatic cancer.”
Julie Fleshman, president and
CEO, Pancreatic Cancer Action Network, said, “Metastatic pancreatic
cancer patients have been waiting a long time for new therapy
options for their devastating disease. Today’s approval of LYNPARZA
provides an exciting new treatment option for patients with
germline BRCA-mutated metastatic pancreatic cancer.”
The Pancreatic Cancer Action
Network (PanCAN) is a U.S.-based organization that supports and
advocates on behalf of the patients, caregivers and communities
affected by pancreatic cancer.
LYNPARZA is currently approved
in 65 countries for the maintenance treatment of platinum-sensitive
relapsed ovarian cancer, regardless of BRCA status. It is approved
in the U.S., the EU, Japan and several other countries as
first-line maintenance treatment of BRCA-mutated advanced ovarian
cancer following response to platinum-based chemotherapy. It is
also approved in 44 countries, including the U.S. and Japan, for
gBRCAm, HER2-negative metastatic breast cancer, previously treated
with chemotherapy; in the EU, this includes locally advanced breast
cancer.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS There are no contraindications for
LYNPARZA.
WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute
Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients
exposed to LYNPARZA monotherapy, and the majority of events had a
fatal outcome. The duration of therapy in patients who developed
secondary MDS/AML varied from <6 months to >2 years. All of
these patients had previous chemotherapy with platinum agents
and/or other DNA-damaging agents, including radiotherapy, and some
also had a history of more than one primary malignancy or of bone
marrow dysplasia.
Do not start LYNPARZA until patients have recovered from
hematological toxicity caused by previous chemotherapy (≤Grade 1).
Monitor complete blood count for cytopenia at baseline and monthly
thereafter for clinically significant changes during treatment. For
prolonged hematological toxicities, interrupt LYNPARZA and monitor
blood count weekly until recovery.
If the levels have not recovered to Grade 1 or less after 4
weeks, refer the patient to a hematologist for further
investigations, including bone marrow analysis and blood sample for
cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.
Pneumonitis: Occurred in <1% of patients exposed to
LYNPARZA, and some cases were fatal. If patients present with new
or worsening respiratory symptoms such as dyspnea, cough, and
fever, or a radiological abnormality occurs, interrupt LYNPARZA
treatment and initiate prompt investigation. Discontinue LYNPARZA
if pneumonitis is confirmed and treat patient appropriately.
Embryo-Fetal Toxicity: Based on its mechanism of action
and findings in animals, LYNPARZA can cause fetal harm. A pregnancy
test is recommended for females of reproductive potential prior to
initiating treatment.
Females Advise females of reproductive potential of the
potential risk to a fetus and to use effective contraception during
treatment and for 6 months following the last dose.
Males Advise male patients with female partners of reproductive
potential or who are pregnant to use effective contraception during
treatment and for 3 months following the last dose of LYNPARZA and
to not donate sperm during this time.
ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced
Ovarian Cancer Most common adverse reactions (Grades 1-4) in
≥10% of patients in clinical trials of LYNPARZA in the
first-line maintenance setting for SOLO-1 were:
nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%),
anemia (38%), diarrhea (37%), constipation (28%), upper respiratory
tract infection/influenza/ nasopharyngitis/bronchitis (28%),
dysgeusia (26%), decreased appetite (20%), dizziness (20%),
neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia
(13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA in the first-line
maintenance setting for SOLO-1 were: decrease in hemoglobin
(87%), increase in mean corpuscular volume (87%), decrease in
leukocytes (70%), decrease in lymphocytes (67%), decrease in
absolute neutrophil count (51%), decrease in platelets (35%), and
increase in serum creatinine (34%).
ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients in
clinical trials of LYNPARZA in the maintenance setting for
SOLO-2 were: nausea (76%), fatigue (including asthenia)
(66%), anemia (44%), vomiting (37%), nasopharyngitis/upper
respiratory tract infection (URI)/influenza (36%), diarrhea (33%),
arthralgia/myalgia (30%), dysgeusia (27%), headache (26%),
decreased appetite (22%), and stomatitis (20%).
Study 19: nausea (71%), fatigue (including asthenia)
(63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory
tract infection (22%), constipation (22%), headache (21%),
decreased appetite (21%), and dyspepsia (20%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA in the maintenance
setting (SOLO-2/Study 19) were: increase in mean corpuscular
volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in
leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease
in absolute neutrophil count (51%/47%), increase in serum
creatinine (44%/45%), and decrease in platelets (42%/36%).
ADVERSE REACTIONS—Advanced gBRCAm ovarian cancer Most
common adverse reactions (Grades 1-4) in ≥20% of patients in
clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer
after 3 or more lines of chemotherapy (pooled from 6 studies)
were: fatigue/asthenia (66%), nausea (64%), vomiting (43%), anemia
(34%), diarrhea (31%), nasopharyngitis/upper respiratory tract
infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased
appetite (22%), and arthralgia/musculoskeletal pain (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA for advanced gBRCAm
ovarian cancer (pooled from 6 studies) were: decrease in
hemoglobin (90%), mean corpuscular volume elevation (57%), decrease
in lymphocytes (56%), increase in serum creatinine (30%), decrease
in platelets (30%), and decrease in absolute neutrophil count
(25%).
ADVERSE REACTIONS—gBRCAm, HER2-negative metastatic breast
cancer Most common adverse reactions (Grades 1-4) in ≥20% of
patients in OlympiAD were: nausea (58%), anemia (40%),
fatigue (including asthenia) (37%), vomiting (30%), neutropenia
(27%), respiratory tract infection (27%), leukopenia (25%),
diarrhea (21%), and headache (20%).
Most common laboratory abnormalities (Grades 1-4) in
>25% of patients in OlympiAD
were: decrease in hemoglobin (82%), decrease in lymphocytes (73%),
decrease in leukocytes (71%), increase in mean corpuscular volume
(71%), decrease in absolute neutrophil count (46%), and decrease in
platelets (33%).
ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic
Pancreatic Adenocarcinoma Most common adverse reactions (Grades
1-4) in ≥10% of patients in clinical trials of LYNPARZA in the
first-line maintenance setting for POLO were: fatigue
(60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia
(27%), decreased appetite (25%), constipation (23%), vomiting
(20%), back pain (19%), arthralgia (15%), rash (15%),
thrombocytopenia (14%), dyspnea (13%), neutropenia (12%),
nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA in the first-line
maintenance setting for POLO were: increase in serum creatinine
(99%), decrease in hemoglobin (86%), increase in mean corpuscular
volume (71%), decrease in lymphocytes (61%), decrease in platelets
(56%), decrease in leukocytes (50%), and decrease in absolute
neutrophil count (25%).
DRUG INTERACTIONS Anticancer Agents: Clinical studies of
LYNPARZA in combination with other myelosuppressive anticancer
agents, including DNA-damaging agents, indicate a potentiation and
prolongation of myelosuppressive toxicity.
CYP3A Inhibitors: Avoid concomitant use of strong or
moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor
must be co-administered, reduce the dose of LYNPARZA. Advise
patients to avoid grapefruit, grapefruit juice, Seville oranges,
and Seville orange juice during LYNPARZA treatment.
CYP3A Inducers: Avoid concomitant use of strong or
moderate CYP3A inducers when using LYNPARZA. If a moderate inducer
cannot be avoided, there is a potential for decreased efficacy of
LYNPARZA.
USE IN SPECIFIC POPULATIONS Lactation: No data are
available regarding the presence of olaparib in human milk, its
effects on the breastfed infant or on milk production. Because of
the potential for serious adverse reactions in the breastfed
infant, advise a lactating woman not to breastfeed during treatment
with LYNPARZA and for 1 month after receiving the final dose.
Pediatric Use: The safety and efficacy of LYNPARZA have
not been established in pediatric patients.
Hepatic Impairment: No adjustment to the starting dose is
required in patients with mild or moderate hepatic impairment
(Child-Pugh classification A and B). There are no data in patients
with severe hepatic impairment (Child-Pugh classification C).
Renal Impairment: No dosage modification is recommended
in patients with mild renal impairment (CLcr 51-80 mL/min estimated
by Cockcroft-Gault). In patients with moderate renal impairment
(CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice
daily. There are no data in patients with severe renal impairment
or end-stage renal disease (CLcr ≤30 mL/min).
INDICATIONS LYNPARZA is a poly (ADP-ribose) polymerase
(PARP) inhibitor indicated:
First-Line Maintenance BRCAm Advanced Ovarian Cancer For
the maintenance treatment of adult patients with deleterious or
suspected deleterious germline or somatic BRCA-mutated (gBRCAm or
sBRCAm) advanced epithelial ovarian, fallopian tube or primary
peritoneal cancer who are in complete or partial response to
first-line platinum-based chemotherapy. Select patients for therapy
based on an FDA-approved companion diagnostic for LYNPARZA.
Maintenance Recurrent Ovarian Cancer For the maintenance
treatment of adult patients with recurrent epithelial ovarian,
fallopian tube, or primary peritoneal cancer, who are in complete
or partial response to platinum-based chemotherapy.
Advanced gBRCAm ovarian cancer For the treatment of adult
patients with deleterious or suspected deleterious germline
BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated
with 3 or more prior lines of chemotherapy. Select patients for
therapy based on an FDA-approved companion diagnostic for
LYNPARZA.
gBRCAm, HER2-negative metastatic breast cancer In
patients with deleterious or suspected deleterious gBRCAm, human
epidermal growth factor receptor 2 (HER2)-negative metastatic
breast cancer who have been treated with chemotherapy in the
neoadjuvant, adjuvant or metastatic setting. Patients with hormone
receptor (HR)-positive breast cancer should have been treated with
a prior endocrine therapy or be considered inappropriate for
endocrine therapy. Select patients for therapy based on an
FDA-approved companion diagnostic for LYNPARZA.
First-Line Maintenance gBRCAm Metastatic Pancreatic
Cancer For the maintenance treatment of adult patients with
deleterious or suspected deleterious gBRCAm metastatic pancreatic
adenocarcinoma whose disease has not progressed on at least 16
weeks of a first-line platinum-based chemotherapy regimen. Select
patients for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.
Please click here for complete Prescribing Information,
including Patient Information (Medication Guide).
About POLO POLO is a Phase 3 randomized, double-blinded,
placebo-controlled, multi-center trial of LYNPARZA tablets (300 mg
twice daily) as maintenance monotherapy vs. placebo. The trial
randomized 154 patients with gBRCAm metastatic pancreatic cancer
whose disease had not progressed on first-line platinum-based
chemotherapy. Patients were randomized (3:2) to receive LYNPARZA or
placebo until disease progression. The primary endpoint was PFS and
key secondary endpoints included OS, time to second disease
progression, overall response rate and health-related quality of
life. Phase 3 POLO results were published in The New England
Journal of Medicine and presented at the 2019 American Society of
Clinical Oncology Annual Meeting.
Results showed a statistically significant and clinically
meaningful improvement in PFS, where LYNPARZA nearly doubled the
time patients with gBRCAm metastatic pancreatic cancer lived
without disease progression or death to a median of 7.4 months vs.
3.8 months on placebo. LYNPARZA reduced the risk of disease
progression or death by 47% (HR 0.53 [95% CI, 0.35-0.81],
p=0.0035).
The safety and tolerability profile of LYNPARZA in the POLO
trial was in line with that observed in prior clinical trials.
Based on the results of POLO, the National Comprehensive Cancer
Network (NCCN) guidelines have been updated in July 2019 to
recommend LYNPARZA as maintenance treatment for gBRCAm pancreatic
cancer.
About LYNPARZA® (olaparib) LYNPARZA is a first-in-class
PARP inhibitor and the first targeted treatment to potentially
exploit DNA damage response (DDR) pathway deficiencies, such as
BRCA mutations, to preferentially kill cancer cells. Inhibition of
PARP with LYNPARZA leads to the trapping of PARP bound to DNA
single-strand breaks, stalling of replication forks, their collapse
and the generation of DNA double-strand breaks and cancer cell
death. LYNPARZA is being tested in a range of tumor types with
defects and dependencies in the DDR.
LYNPARZA, which is being jointly developed and commercialized by
AstraZeneca and Merck, has a broad and advanced clinical trial
development program, and AstraZeneca and Merck are working together
to understand how it may affect multiple PARP-dependent tumors as a
monotherapy and in combination across multiple cancer types.
About Pancreatic Cancer In the U.S. this year, it is
expected that more than 55,000 people will be diagnosed with
pancreatic cancer and over 45,750 people will die of this disease.
Early diagnosis of pancreatic cancer is difficult, as often there
are no symptoms.
There are two types of pancreatic cancer. Exocrine tumors, of
which the most common type is pancreatic ductal adenocarcinoma
(PDAC), start in the exocrine cells, where enzymes help to digest
food. Neuroendocrine tumors start in neuroendocrine cells, which
produce hormones, such as insulin, that control different functions
of the body. Germline BRCA-mutated pancreatic cancer accounts for
5-7% of all cases globally.
About BRCA Mutations BRCA1 and BRCA2 are human genes that
produce proteins responsible for repairing damaged DNA and play an
important role in maintaining the genetic stability of cells. When
either of these genes is mutated, or altered, such that its protein
product either is not made or does not function correctly, DNA
damage may not be repaired properly, and cells become unstable. As
a result, cells are more likely to develop additional genetic
alterations that can lead to cancer.
About the AstraZeneca and Merck Strategic Oncology
Collaboration In July 2017, AstraZeneca and Merck, known as MSD
outside the United States and Canada, announced a global strategic
oncology collaboration to co-develop and co-commercialize LYNPARZA,
the world’s first PARP inhibitor, and potential new medicine
selumetinib, a MEK inhibitor, for multiple cancer types. Working
together, the companies will develop LYNPARZA and selumetinib in
combination with other potential new medicines and as
monotherapies. Independently, the companies will develop LYNPARZA
and selumetinib in combination with their respective PD-L1 and PD-1
medicines.
Merck’s Focus on Cancer Our goal is to translate
breakthrough science into innovative oncology medicines to help
people with cancer worldwide. At Merck, the potential to bring new
hope to people with cancer drives our purpose and supporting
accessibility to our cancer medicines is our commitment. As part of
our focus on cancer, Merck is committed to exploring the potential
of immuno-oncology with one of the largest development programs in
the industry across more than 30 tumor types. We also continue to
strengthen our portfolio through strategic acquisitions and are
prioritizing the development of several promising oncology
candidates with the potential to improve the treatment of advanced
cancers. For more information about our oncology clinical trials,
visit www.merck.com/clinicaltrials.
About Merck For more than a century, Merck, a leading
global biopharmaceutical company known as MSD outside of the United
States and Canada, has been inventing for life, bringing forward
medicines and vaccines for many of the world’s most challenging
diseases. Through our prescription medicines, vaccines, biologic
therapies and animal health products, we work with customers and
operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access
to health care through far-reaching policies, programs and
partnerships. Today, Merck continues to be at the forefront of
research to advance the prevention and treatment of diseases that
threaten people and communities around the world - including
cancer, cardio-metabolic diseases, emerging animal diseases,
Alzheimer’s disease and infectious diseases including HIV and
Ebola. For more information, visit www.merck.com and connect with
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