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January 12, 2018 12:45 pm ET

LYNPARZA is the Only PARP Inhibitor Approved for Use Beyond Ovarian Cancer

LYNPARZA Reduced Risk of Disease Progression or Death by 42 Percent Compared to Standard of Care Chemotherapy

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
^®
(olaparib) for use in
patients with deleterious or suspected deleterious germline BRCA-mutated
(gBRCAm), human epidermal growth factor receptor 2
(HER2)-negative metastatic breast cancer who have been previously
treated with chemotherapy in the neoadjuvant, adjuvant or metastatic
setting. Patients with hormone receptor positive (HR+) breast cancer
should have been treated with a prior endocrine therapy or be considered
inappropriate for endocrine therapy. Patients are selected for therapy
based on an FDA-approved companion diagnostic from Myriad Genetics.

Dave Fredrickson, executive vice president, head of the oncology
business unit, AstraZeneca, said, “This new approval for LYNPARZA makes
it the first and only PARP inhibitor approved in metastatic breast
cancer, and the only PARP inhibitor approved outside of ovarian cancer.
This is significant for breast cancer patients, as the
identification of BRCA status, in addition to hormone receptor
and HER2 status, becomes a potentially critical step in the management
of their disease.”

Dr. Roy Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories, said,
“This additional approval for LYNPARZA, based on the compelling data
from the OlympiAD trial, represents an important advance for women with
germline BRCA-mutated HER2-negative metastatic breast cancer,
which is a difficult-to-treat cancer. Moreover, this approval adds
further impetus to our important collaboration with AstraZeneca in
developing cancer therapies.”

The approval was based on data from the randomized, open-label, phase 3
OlympiAD trial, which investigated LYNPARZA (olaparib) versus
physician’s choice of chemotherapy (capecitabine, eribulin or
vinorelbine). In the trial, LYNPARZA significantly prolonged
progression-free survival (PFS) compared with chemotherapy, and reduced
the risk of disease progression or death by 42 percent (HR 0.58; 95% CI
0.43-0.80; P=0.0009 median 7.0 vs 4.2 months). Patients with measurable
disease taking LYNPARZA (n=167) experienced an objective response rate
of 52 percent (95% CI 44-60), double the response rate for those in the
chemotherapy arm (n=66), which was 23 percent (95% CI 13-35).
Additionally, patients experienced a confirmed complete response rate of
7.8 percent for LYNPARZA compared to 1.5 percent for the chemotherapy
arm. The data from the OlympiAD trial can be found in the June 2017
issue of the New England Journal of Medicine.

“Patients diagnosed with BRCA-related metastatic breast cancer
are often younger than other breast cancer patients, and their disease
is often much more aggressive and difficult to treat,” said Dr. Susan M.
Domchek, executive director of the Basser Center for BRCA at the
Abramson Cancer Center of the University of Pennsylvania, and national
leader on the OlympiAD trials. “While there is currently no cure for
metastatic breast cancer, today’s approval offers a new, targeted option
that may help to delay disease progression for these patients.”

Sue Friedman, executive director and founder of the nonprofit
organization, Facing Our Risk of Cancer Empowered (FORCE), said, “We
know there are limited treatment options for patients with metastatic
breast cancer. For the portion of the 155,000 women in the U.S. living
with metastatic breast cancer who have an inherited BRCA mutation,
today’s news is encouraging. By undergoing genetic testing for BRCA
mutations, we can gain critical information that will inform
personalized treatment options specifically for women with this
mutation.”

The most common adverse reactions in the OlympiAD trial of patients who
received LYNPARZA were nausea (58%), anemia (40%), fatigue (including
asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract
infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).
The percentage of patients who discontinued treatment in the LYNPARZA
arm was 5 percent compared to the chemotherapy arm, which was 8 percent. Please
see Important Safety Information below.

This is the third indication approved for LYNPARZA (olaparib) in the
U.S., where it has been used to treat nearly 4,000 advanced
ovarian cancer patients. LYNPARZA has a broad clinical development
program, and AstraZeneca and Merck are working together to deliver
LYNPARZA as quickly as possible to more patients across multiple
settings, including breast, ovarian, prostate and pancreatic cancers.

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. 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. 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 (olaparib) and to not donate sperm during
this time.

Adverse Reactions—Maintenance Setting

Most common adverse reactions (Grades 1-4) in ≥20% of patients in
clinical trials of LYNPARZA in the maintenance setting for SOLO-2:
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%), and decreased
appetite (21%).

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 (including 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%), increase in mean
corpuscular volume (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 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 (olaparib) 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 hepatic impairment (Child-Pugh
classification A). There are no data in patients with moderate or severe
hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary
in patients with mild renal impairment (CLcr=51-80 mL/min). 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).

Dosing and Administration

To avoid substitution errors and overdose, do not substitute LYNPARZA
(olaparib) tablets with LYNPARZA capsules on a
milligram-to-milligram basis due to differences in the dosing and
bioavailability of each formulation. Recommended tablet dose is 300 mg,
taken orally twice daily, with or without food. Continue treatment until
disease progression or unacceptable toxicity. For adverse reactions,
consider dose interruption or dose reduction.

Indications

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

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.

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.

In patients with deleterious or suspected deleterious gBRCAm, human
epidermal growth factor receptor 2 (HER2)-negative metastatic breast
cancer who have previously 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
treatment. Select patients for therapy based on an FDA-approved
companion diagnostic for LYNPARZA.

NOTES TO EDITORS

About OlympiAD

OlympiAD is a randomized, open-label, multicenter phase 3 trial
assessing the efficacy and safety of LYNPARZA tablets (300 mg twice
daily) compared to physician’s choice of chemotherapy in 302 patients
with HER2-negative metastatic breast cancer with gBRCA1 or gBRCA2
mutations, which are confirmed or suspected to be deleterious. The
international trial was conducted in 19 countries across Europe, Asia,
North America and South America.

Patients in the OlympiAD trial had HER2-negative gBRCA1- or gBRCA2-mutated
breast cancer, which was HR+ or triple negative, and received LYNPARZA
(olaparib) for metastatic disease. Approximately half of the patients in
the LYNPARZA and chemotherapy arm of the trial were HR+ (n=152), and
approximately half were triple negative (n=150). Among the 205 patients
treated with LYNPARZA, the median age was 44 years (range: 22 to 76).
Before enrollment, patients had prior treatment with an anthracycline
(unless contraindicated) and a taxane chemotherapy either in the
neoadjuvant, adjuvant or metastatic setting and no more than two prior
lines of chemotherapy for metastatic disease. HR+ patients had received
at least one endocrine medicine or were not eligible for endocrine
medicines. Prior treatments with endocrine medicines were not counted as
prior lines of chemotherapy.

The primary endpoint of the trial was PFS as measured by a Blinded
Independent Central Review. Secondary endpoints included overall
survival, time to second progression or death, objective response rate,
and effect on health-related quality of life.

About Metastatic Breast Cancer

Three main receptors drive tumor growth in breast cancer: Progesterone
Receptors (PR), estrogen receptors (ER) and HER2 receptors. A patient’s
breast cancer will test either negative or positive for these three
receptors. If a tumor tests positive for PR and/or ER, it is considered
HR+. If a tumor tests negative for all three receptors, it is considered
triple negative.

MBC is the most advanced stage of breast cancer (Stage IV), and occurs
when cancer cells have spread beyond the initial tumor site to other
parts of the body outside of the breast.

Despite the increase in treatment options during the past three decades,
there is currently no cure for patients diagnosed with MBC and only 26.9
percent of patients survive five years after diagnosis. Thus, the
primary aim of treatment is to slow progression of the disease for as
long as possible, improving, or at least maintaining, a patient’s
quality of life.

It is estimated that in 2018, there will be approximately 155,000 women
in the U.S. living with MBC, and this number is projected to increase to
approximately 160,000 by the year 2020.

About Germline BRCA Mutations

BRCA1 and BRCA2 are human genes that produce
proteins responsible for repairing damaged DNA and play an important
role 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 the first FDA-approved oral poly ADP-ribose polymerase
(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. Specifically, in vitro
studies have shown that LYNPARZA-induced cytotoxicity may involve
inhibition of PARP enzymatic activity and increased formation of
PARP-DNA complexes, resulting in DNA damage and cancer cell death.

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. The collaboration is based on increasing evidence
that PARP and MEK inhibitors can be combined with PD-L1/PD-1 inhibitors
for a range of tumor types. Working together, the companies will jointly
develop LYNPARZA and selumetinib in combination with other potential new
medicines and as a monotherapy. 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, helping people
fight cancer is our passion and supporting accessibility to our cancer
medicines is our commitment. Our focus is on pursuing research in
immuno-oncology and we are accelerating every step in the journey – from
lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the
potential of immuno-oncology with one of the fastest-growing development
programs in the industry. We are currently executing an expansive
research program evaluating our anti-PD-1 therapy across more than 30
tumor types. We also continue to strengthen our immuno-oncology
portfolio through strategic acquisitions and are prioritizing the
development of several promising immunotherapeutic 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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Please see complete 

Prescribing
Information

for LYNPARZA (olaparib), including Patient
Information (Medication Guide)

Merck
Media:
Pamela Eisele, 267-305-3558
Courtney Ronaldo, 908-442-5695
or
Investors:
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