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February 26, 2019 6:55 am ET

Phase 3 POLO Trial Met Its Primary Endpoint of Progression-Free Survival

AstraZeneca and Merck’s LYNPARZA Is the First PARP Inhibitor to Demonstrate Benefit in gBRCAm Metastatic Pancreatic Cancer in a Phase 3 Trial

KENILWORTH, N.J.–(BUSINESS WIRE)–AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States
and Canada, today announced positive results from the Phase 3 POLO trial.

Results from the trial showed a statistically-significant and
clinically-meaningful improvement in progression-free survival (PFS)
with LYNPARZA versus placebo. The safety and tolerability profile of
LYNPARZA was consistent with previous trials.

POLO is a randomized, double-blinded, placebo-controlled trial exploring
the efficacy of LYNPARZA tablets as first-line maintenance monotherapy
in patients with germline BRCA-mutated (gBRCAm) metastatic
adenocarcinoma of the pancreas (pancreatic cancer) whose disease has not
progressed on platinum-based chemotherapy.

José Baselga, executive vice president, research and development,
oncology, AstraZeneca, said, “This is the first positive Phase 3 trial
of any PARP inhibitor in germline BRCA-mutated metastatic
pancreatic cancer, a devastating disease with critical unmet need. Most
patients are diagnosed late, leaving them with a poor prognosis and very
limited treatment options. Based on POLO, LYNPARZA becomes the first
PARP inhibitor to demonstrate positive Phase 3 results beyond ovarian
cancer and breast cancer.”

Dr. Roy Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories, said,
“Trials like POLO demonstrate the shared commitment of Merck and
AstraZeneca to assess treatments for difficult-to-treat cancers. The
clinically-meaningful results of this trial potentially support the
value of testing for germline BRCA mutations in patients with
metastatic pancreatic cancer. We will discuss these results with global
health authorities as soon as possible.”

AstraZeneca and Merck plan to present the full data from the trial at a
forthcoming medical meeting.

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 see 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 versus placebo. The trial randomized 154
patients with gBRCAm metastatic pancreatic cancer whose disease
has 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 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. LYNPARZA is
being tested in a range of DDR-deficient tumor types.

About Pancreatic Cancer

Pancreatic cancer is the 12th most common cancer worldwide. Germline BRCA-mutated
pancreatic cancer accounts for five to seven percent of all cases
globally. With the worst survival rate of the most common cancers,
pancreatic cancer is the fourth leading cause of cancer death, and less
than seven percent of patients survive more than five years after
diagnosis. Early diagnosis of pancreatic cancer is difficult, as often
there are no symptoms until the disease has advanced. Around 80 percent
of patients are diagnosed at the metastatic stage.

In the U.S. this year, approximately 56,700 people will be diagnosed and
more than 45,000 will die from pancreatic cancer, which accounts for
about seven percent of all U.S. cancer deaths. The five-year survival
rate in the U.S. for all stages is just nine percent and for the 52
percent of people who are diagnosed after the cancer has spread to a
distant part of the body, the five-year survival rate is just three
percent.

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 us on Twitter,
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Instagram,
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LinkedIn.

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