22% of Patients Receiving LYNPARZA Remained
Progression-Free After Two Years vs. 10% on Placebo, Following
Platinum-Based Chemotherapy
AstraZeneca and Merck’s LYNPARZA is the Only
PARP Inhibitor to Demonstrate Benefit in This Setting in a Phase 3
Trial
AstraZeneca and Merck (NYSE: MRK), known as MSD outside the
United States and Canada, today announced detailed results from the
Phase 3 POLO trial evaluating LYNPARZA tablets as a first-line
maintenance monotherapy for patients with germline BRCA-mutated
(gBRCAm) metastatic adenocarcinoma of the pancreas (pancreatic
cancer) whose disease had not progressed following platinum-based
chemotherapy. The results of the trial will be featured today in a
press briefing at the 55th Annual Meeting of the American Society
of Clinical Oncology (ASCO) in Chicago and presented as a
late-breaker oral presentation at 1:00 p.m. CDT during the plenary
session (Abstract #LBA4). The results will also be published online
simultaneously in the New England Journal of Medicine (NEJM).
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Kaplan-Meier estimates of PFS by blinded,
independent central review (Graphic: Business Wire)
Results from the trial showed a statistically-significant and
clinically-meaningful improvement in progression-free survival
(PFS) for LYNPARZA compared to placebo, reducing the risk of
disease progression or death by 47% (HR 0.53 [95% CI 0.35-0.82],
p=0.004). The median PFS for patients treated with LYNPARZA was 7.4
months compared to 3.8 months for those on placebo, with more than
twice as many patients remaining progression free at both one year
(34% on LYNPARZA vs. 15% on placebo) and two years (22% vs. 10%)
respectively.
Summary of PFSi,ii
Lynparza (n=92) Placebo
(n=62) Number of patients with event (%)iii 60 (65)
44 (71) Median (in months) 7.4
3.8 Hazard ratio (95% CI) 0.53 (0.35-0.82)
P-value P=0.004
i Blinded, independent central reviewii Median duration of
follow-up for progression was 9.1 months (range, 0 to 39.6) and 3.8
months (range, 0 to 29.8) in the olaparib and placebo arms,
respectivelyiii Analysis of the primary endpoint was performed at
68% data maturity
José Baselga, executive vice president, Oncology R&D,
AstraZeneca said, “These remarkable results raise new hope for a
patient population that has seen little progress over the last 20
years. The POLO trial showed that at six months, more than twice as
many patients taking LYNPARZA were progression free compared to
those on placebo. We are now working with regulatory authorities to
bring LYNPARZA to patients as quickly as possible.”
Dr. Roy Baynes, senior vice president and head of global
clinical development, chief medical officer, Merck Research
Laboratories, said, “We are encouraged by the results of the POLO
trial which showed a considerable reduction in risk of disease
progression or death with LYNPARZA for germline BRCA-mutated
metastatic pancreatic cancer patients who did not progress on
chemotherapy. Currently, less than 3% of metastatic pancreatic
cancer patients survive more than five years after diagnosis. The
results of this trial reinforce Merck and AstraZeneca’s commitment
to develop innovative treatments for cancers with few options.”
Dr. Hedy L. Kindler, MD, Co-Principal Investigator of the POLO
trial and professor of medicine, University of Chicago Medicine,
said, “Despite efforts to identify therapies, targeted or
combination treatments to improve patient outcomes, pancreatic
cancer remains an area of high unmet need. The results of the POLO
trial may open the door to a new era of personalized, biomarker-led
care in metastatic pancreatic cancer and reinforces the importance
of knowing BRCA status at diagnosis.”
The safety and tolerability profile of LYNPARZA in the POLO
trial was in line with that observed in prior clinical trials. 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.
LYNPARZA is not currently approved by the U.S. Food and Drug
Administration (FDA) for gBRCAm pancreatic cancer.
LYNPARZA is currently approved in 64 countries, including those
in the EU, for the maintenance treatment of platinum-sensitive
relapsed ovarian cancer regardless of BRCA status. It is approved
in the U.S. as first-line maintenance treatment in BRCAm advanced
ovarian cancer following response to platinum-based chemotherapy.
It is also approved in 38 countries, including the U.S., countries
in the EU, and Japan, for germline BRCAm HER2-negative metastatic
breast cancer previously treated with chemotherapy; in the EU this
includes locally advanced breast cancer. Regulatory reviews are
underway in other jurisdictions for both ovarian cancer and breast
cancer.
About POLO
POLO is a Phase 3 randomized, double-blinded,
placebo-controlled, multi-center study 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 include overall survival, time to second
disease progression, overall response rate, disease control rate
and health-related quality of life.
About Pancreatic Cancer
Pancreatic cancer is the 12th most common cancer worldwide, with
458,918 new cases in 2018 alone. With the worst survival rate of
all the most common cancers, it is the seventh leading cause of
cancer death, and less than 3% of patients with metastatic disease
survive more than five years after diagnosis. Early diagnosis of
pancreatic cancer is difficult, as often there are no symptoms
until it is too late. Around 80% of patients are diagnosed at the
metastatic stage.
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.
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 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.
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 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 us
on Twitter, Facebook, Instagram, YouTube
and LinkedIn.
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