Oncologic Drugs Advisory Committee Voted
That LYNPARZA Demonstrated a Favorable Benefit-Risk Profile for
Patients Based on Phase 3 POLO Trial Results
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) Oncologic Drugs Advisory Committee (ODAC)
voted 7-5 to recommend LYNPARZA as a first-line maintenance
monotherapy for patients with germline BRCA-mutated (gBRCAm)
metastatic adenocarcinoma of the pancreas (pancreatic cancer),
whose disease has not progressed on at least 16 weeks of first-line
platinum-based chemotherapy.
In August 2019, the FDA accepted the supplemental New Drug
Application (sNDA) for LYNPARZA for this indication with Priority
Review and set a Prescription Drug User Fee Act (PDUFA) date for
the fourth quarter of 2019.
Dr. José Baselga, executive vice president, oncology R&D,
AstraZeneca, said, “We are pleased with the ODAC’s recommendation
for LYNPARZA and the potential to bring a personalized,
biomarker-targeted medicine to patients with germline BRCA-mutated
metastatic pancreatic cancer. 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. We look forward to working with the FDA as it
completes the review of our application.”
Dr. Roy Baynes, senior vice president and head of global
clinical development, chief medical officer, Merck Research
Laboratories, said, “We are encouraged by the ODAC’s favorable vote
for LYNPARZA as a first-line maintenance therapy in germline
BRCA-mutated metastatic pancreatic cancer. This recommendation is a
significant step towards reaching our goal to help patients with
this deadly disease.”
The sNDA submission was based on the positive results from the
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. The results showed a statistically
significant and clinically meaningful improvement in
progression-free survival (PFS) and reduced the risk of disease
progression or death by 47% (HR 0.53 [95% CI, 0.35-0.82], p=0.004).
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.
The most common adverse events
(AEs) ≥20% were fatigue/asthenia (60%), nausea (45%), abdominal
pain (29%), diarrhea (29%), anemia (28%), decreased appetite (25%)
and constipation (23%). The most common ≥ grade 3 AEs were anemia
(11%), fatigue/asthenia (5%), decreased appetite (3%), abdominal
pain (2%), vomiting (1%) and arthralgia (1%). Around 84% of
patients on LYNPARZA remained on the recommended starting dose,
while 16% had a dose reduction vs. 97% who remained on the
recommended dose with placebo, while 3% had a dose reduction.
Additionally, 95% of patients on LYNPARZA continued treatment
without an AE-related discontinuation, while 5% had an AE-related
discontinuation vs. 98% who continued treatment without an
AE-related discontinuation and 2% that had an AE-related
discontinuation with placebo.
The ODAC provides the FDA with independent, expert advice and
recommendations on marketed and investigational medicines for use
in the treatment of cancer. The FDA is not bound by the committee’s
guidance but takes its advice into consideration when deciding
whether or not to approve the application.
In addition to the U.S., LYNPARZA is currently under regulatory
review in the European Union (EU), Canada and other jurisdictions
as a first-line maintenance treatment for patients with gBRCAm
metastatic pancreatic cancer.
Germline BRCAm pancreatic cancer accounts for 5-7% of all cases
globally. The FDA granted LYNPARZA orphan drug designation on
October 18, 2018 for gBRCAm metastatic pancreatic cancer. Orphan
drug designation is for medicines intended to treat, diagnose or
prevent rare diseases or disorders that affect fewer than 200,000
people in the U.S.
LYNPARZA is currently approved in 65 countries, including the
U.S., for the maintenance treatment of platinum-sensitive relapsed
ovarian cancer, regardless of BRCA status. It is approved in the
U.S., 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.
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.
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, 0.35-0.82],
p=0.004).
The safety and tolerability profile of LYNPARZA in the POLO
trial was in line with that observed in prior clinical trials.
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%).
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 adjustment to the starting dose is
necessary in patients with mild renal impairment (CLcr=51-80
mL/min) but patients should be monitored closely for toxicity. In
patients with moderate renal impairment (CLcr=31-50 mL/min), reduce
the dose 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 with gBRCAm
advanced epithelial ovarian, fallopian tube or primary peritoneal
cancer 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.
Please click here for complete Prescribing Information,
including Patient Information (Medication Guide).
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
Pancreatic cancer is a deadly cancer with a high unmet medical
need. It is the 12th most commonly occurring cancer and the seventh
leading cause of cancer death globally. The disease has the lowest
survival rate of the most common cancers and is the only major
cancer with a single-digit five-year survival rate (2-9%) in nearly
every country. There were approximately 460,000 new cases in 2018
and this number is expected to rise to over 800,000 by the year
2040. As there are often no symptoms, or symptoms may be
non-specific in the early stages, it is most commonly diagnosed at
an incurable stage. Around 80% of pancreatic cancer patients are
diagnosed when the disease is metastatic, and for these the average
survival is less than a year. Despite advances in therapy, few
improvements have been made in diagnosis and treatment over the
decades. Current treatment is surgery (for which approximately only
10-20% of patients are eligible), chemotherapy and radiotherapy,
highlighting a critical unmet medical need for more effective
treatment options. 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 & Co., Inc., Kenilworth,
NJ, US, 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 us on Twitter, Facebook,
Instagram, YouTube and LinkedIn.
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Kenilworth, N.J., USA
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