LYNPARZA® (olaparib) Approved in EU for the Treatment of Germline BRCA-Mutated HER2-Negative Advanced Breast Cancer

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April 10, 2019 5:45 am ET

AstraZeneca and Merck’s LYNPARZA Reduced the Risk of Disease Progression or Death by 42 Percent Versus Chemotherapy in Phase 3 OlympiAD Trial

First PARP Inhibitor Approved in the EU for This Indication and Third EU Approval for LYNPARZA

KENILWORTH, N.J.–(BUSINESS WIRE)–AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United
States and Canada, today announced the European Commission has approved
LYNPARZA as a monotherapy for the treatment of adult patients with
germline BRCA1/2-mutations (gBRCAm), and who have human
epidermal growth factor receptor 2 (HER2)-negative locally advanced or
metastatic breast cancer.

Under the licensed indication, patients should have previously been
treated with an anthracycline and a taxane in the (neo)adjuvant or
metastatic setting unless they were unsuitable for these treatments.
Patients with hormone receptor (HR)-positive breast cancer should also
have progressed on or after prior endocrine therapy or be considered
unsuitable for endocrine therapy.

Dave Fredrickson, executive vice president, oncology, AstraZeneca, said,
“With this approval, LYNPARZA provides patients throughout the EU with a
targeted and oral chemotherapy-free treatment option for a
difficult-to-treat cancer. It also reinforces the importance of testing
for biomarkers, including BRCA, hormone receptor and HER2
expression, helping physicians to make the most informed treatment
decisions for patients.”

Dr. Roy Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories, said,
“In the OlympiAD trial, which supported this approval, LYNPARZA
demonstrated a meaningful improvement in progression-free survival
compared to chemotherapy in patients with germline BRCA-mutated
metastatic breast cancer. We look forward to making this new option
available across the EU, where we hope it will improve outcomes for many
patients.”

The approval was based on data from the randomized, open-label, Phase 3
OlympiAD trial which investigated LYNPARZA versus physician’s choice of
chemotherapy (capecitabine, eribulin or vinorelbine). In the trial,
LYNPARZA provided patients with a statistically significant median
progression-free survival improvement of 2.8 months (7.0 months for
LYNPARZA vs 4.2 months for chemotherapy). Patients taking LYNPARZA
experienced an objective response rate (ORR) of 52 percent, which was
double the ORR for those in the chemotherapy arm (23%).

The most common adverse reactions (≥20%) 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 five percent versus eight percent in the
chemotherapy arm.

This is the third indication for LYNPARZA in the EU, and AstraZeneca and
Merck are working together to deliver LYNPARZA as quickly as possible to
more patients across multiple settings. LYNPARZA has a broad clinical
development program, including the ongoing Phase 3 trial OlympiA which
is evaluating LYNPARZA as an adjuvant treatment in patients with gBRCAm
HER2-negative 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%).

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 OlympiAD

OlympiAD was a global, randomized, open-label, multi-center Phase 3
trial of 302 patients, assessing the efficacy and safety of LYNPARZA tablets
(300 mg twice daily) compared to the physician’s choice of chemotherapy
(capecitabine, eribulin or vinorelbine). Two-hundred and five patients
were randomized to receive LYNPARZA and 97
patients were randomized to receive chemotherapy. Patients in the
OlympiAD trial had germline BRCA1 and/or BRCA2-mutated,
HER2-negative (hormone receptor-positive [HR+] or triple-negative)
breast cancer and received LYNPARZA for treatment in
the metastatic setting.

Prior to enrollment, all patients were treated with an anthracycline
(unless it was contraindicated) and a taxane chemotherapy in the
neoadjuvant, adjuvant or metastatic setting. Patients with metastatic
breast cancer (71% of patients) had received no more than two previous
chemotherapy treatments for metastatic disease. Patients with
HR-positive breast cancer had received at least one endocrine (hormonal)
therapy (in the adjuvant or metastatic setting) and had disease
progression during therapy, unless they had disease for which endocrine
therapy was considered inappropriate. Previous treatment with platinum
chemotherapy in the neoadjuvant, adjuvant or metastatic setting was
allowed (28% of patients).

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 Advanced Breast Cancer

Advanced/metastatic breast cancer refers to Stage III tumors that cannot
be fully excised by surgery and Stage IV breast cancer. Stage III
disease may also be referred to as locally-advanced breast cancer, while
metastatic disease is the most-advanced stage of breast cancer (Stage
IV) and occurs when cancer cells have spread beyond the initial tumor
site to other organs of the body outside the breast. Since there is no
cure for the disease, the goal of current treatment is to delay disease
worsening or death.

In 2018, there were an estimated 2.1 million new cases of breast cancer
worldwide – one in four cancer cases among women (24.2%). In Europe the
estimated five-year prevalence of breast cancer in 2018 was 2,054,887
cases. Approximately 30 percent of women who are diagnosed with early
breast cancer will go on to develop advanced disease.

About BRCA Mutations

Breast cancer susceptibility gene 1/2 (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, Facebook, Instagram,
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and LinkedIn.

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