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Updated Overall Survival Data for LYNPARZA® (olaparib) in gBRCA-Mutated HER2-Negative Metastatic Breast Cancer Presented at AACR

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AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US (Merck: known as
MSD outside the US and Canada) today presented data from the Phase III
OlympiAD trial, showing the final overall survival (OS) results for
LYNPARZA® (olaparib) in metastatic breast cancer at
the American Association for Cancer Research (AACR) Annual Meeting in
Chicago, April 14-18, 2018.

The trial compared LYNPARZA with chemotherapy (physician's choice
of capecitabine, eribulin or vinorelbine) for patients with germline BRCA-mutated
(gBRCAm) HER2-negative metastatic breast cancer (MBC) and met its
primary endpoint of progression-free survival (PFS).

Results at AACR include updated findings from the secondary endpoint of
overall survival (OS). While the trial was not powered to demonstrate a
statistically-significant difference, the median OS was 19.3 months in
patients treated with LYNPARZA and 17.1 months for patients
treated with chemotherapy (HR 0.90; 95% CI 0.66-1.23; p=0.513). At the
final OS data cut-off (64% maturity), nearly 13% of patients remained on
LYNPARZA and no patients remained on chemotherapy.

Sean Bohen, Executive Vice President, Global Medicines Development and
Chief Medical Officer at AstraZeneca, said: "OlympiAD is the first Phase
III trial to demonstrate disease control with a PARP inhibitor in BRCA-mutated
HER2-negative metastatic breast cancer. While the trial was not powered
to show overall survival compared to chemotherapy, the results are
another encouraging marker in the use of LYNPARZA for this patient
population."

Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, Merck Research Laboratories, said:
"For patients and physicians, these results are meaningful in that they
support the progression-free survival endpoint – which showed that
patients treated with LYNPARZA gained seven months chemotherapy-free
time – and reinforce the importance of identifying BRCA status to
optimize metastatic breast cancer management."

LYNPARZA is indicated in patients with gBRCAm HER2-negative MBC
previously treated with chemotherapy. Hormone receptor (HR)-positive
breast cancer should have been treated with prior endocrine therapy or
be considered inappropriate for endocrine treatment. An FDA-approved
companion diagnostic is required for this indication.

When analyzing the predefined subgroups, the results were consistent
with the overall analysis, which did not show a
statistically-significant difference between arms. The greatest
difference was seen in patients who had not received chemotherapy in the
metastatic setting with a median difference in OS of 7.9 months with
LYNPARZA (HR 0.51; 95% CI 0.29-0.90; nominal p=0.02; median 22.6
vs 14.7 months).

 

Table 1: Predefined subgroups for OS analysis

Subgroup   Median OS

(months)

  HR       95% CI   Nominal p Value
    LYNPARZA  

Physician's
choice of
chemotherapy

               
Prior chemotherapy for metastatic breast cancer                        
No (1st line)   22.6   14.7   0.51       0.29-0.90   0.02
Yes (2nd line / 3rd line)   18.8   17.2   1.13       0.79-1.64   0.52
Prior platinum-based chemotherapy for breast cancer                        
No   20.3   19.6   0.91       0.64-1.33   0.63
Yes   17.2   13.3   0.83       0.49-1.45   0.49
Receptor status                        
Estrogen receptor positive (ER+) and/or hormone-receptor positive
(HR+)
  21.8   21.3   0.86       0.55-1.36   0.51
Triple-negative breast cancer (TNBC)   17.4   14.9   0.93       0.62-1.43   0.75
             

The safety profile of LYNPARZA remained consistent with the primary
analysis. Serious adverse events (AEs) (Grade ≥3) were reported in 38%
of patients who received LYNPARZA vs 49.5% of patients in the
chemotherapy arm. AEs leading to drug discontinuation were 4.9% for
LYNPARZA vs 7.7% for chemotherapy. AEs leading to dose reductions were
25.4% for LYNPARZA vs 30.8% for chemotherapy. AEs leading to dose
interruptions were 36.1% for LYNPARZA vs 28.6% for chemotherapy. Please
see Important Safety Information below.

These results build on previously reported findings, which demonstrated
LYNPARZA significantly improved PFS (HR 0.58; 95% CI 0.43-0.80; p=0.0009
median 7.0 vs 4.2 months) and showed data beyond initial disease
progression, prolonging time to second progression or death (PFS2) by
3.9 months (HR 0.57; 95% CI 0.40-0.83; p=0.003 median 13.2 months vs 9.3
months). Previously reported findings also showed LYNPARZA doubled
objective response rates (52% [95% CI 44-60] vs 23% [95% CI 13-35]). The
data from the OlympiAD trial can be found in the August 10, 2017 issue
of the New
England Journal of Medicine
.

In January 2018, LYNPARZA was approved by the US FDA in the
treatment of gBRCAm metastatic breast cancer based on the
OlympiAD data.

A Phase III trial (n=1800), OlympiA, is evaluating LYNPARZA as an
adjuvant treatment in patients with gBRCA HER2-negative breast
cancer, with results expected in 2020. The trial is powered to assess
potential benefit in OS.

LYNPARZA is approved in the US for advanced ovarian cancer and has
treated more than 4,000 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.

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—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 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
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.

Please see complete Prescribing
Information
, including Patient Information (Medication Guide).

NOTES TO EDITORS

About OlympiAD

OlympiAD is a global, randomized, open-label, multi-center Phase III
trial of 302 patients, assessing the efficacy and safety of LYNPARZA tablets
(300 mg twice daily) compared to chemotherapy (physician's choice of
capecitabine, eribulin or vinorelbine). A total of 205 patients were
randomized to receive LYNPARZA and 97 patients were
randomized to receive chemotherapy.

Patients in the OlympiAD trial had germline BRCA-mutated,
HER2-negative (hormone receptor-positive or triple negative) breast
cancer and received LYNPARZA for treatment in the metastatic
setting. Prior to enrollment, 71% of patients had received no more than
two previous chemotherapy treatments for metastasized breast cancer and
28% of patients had received prior platinum-based chemotherapy. Also
enrolled were patients with HR+ breast cancer who had received at least
one endocrine therapy (adjuvant therapy or therapy for metastatic
disease) and had disease progression during therapy, unless they had
disease for which the endocrine therapy was considered inappropriate.

The primary endpoint was PFS. Secondary endpoints included OS, time to
second progression or death, objective response rate, health-related
quality of life and safety and tolerability.

About Metastatic Breast Cancer (MBC)

PRs, ERs and HER2 receptors may be expressed on breast cancer cells. 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 hormone-receptor positive. If a tumor tests negative for all
three receptors, it is considered triple negative. These receptors
indicate which hormones or other proteins may be promoting growth of the
cancer.

Metastatic Breast Cancer (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 and
nearby lymph nodes.

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% of patients survive for 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 US living with MBC, and this number is projected to increase to
approximately 160,000 by the year 2020.

About 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 was the 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. 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.

LYNPARZA is being investigated in a range of DDR-deficient tumor types,
and is the foundation of AstraZeneca's industry-leading portfolio of
compounds targeting DDR mechanisms in cancer cells.

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. 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 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.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly
growing portfolio of new medicines that has the potential to transform
patients' lives and the Company's future. With at least six new
medicines to be launched between 2014 and 2020 and a broad pipeline of
small molecules and biologics in development, we are committed to
advance Oncology as one of AstraZeneca's Four Growth Platforms focused
on lung, ovarian, breast and blood cancers. In addition to our core
capabilities, we actively pursue innovative partnerships and investments
that accelerate the delivery of our strategy as illustrated by our
investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms – Immuno-Oncology,
Tumor Drivers and Resistance, DDR and Antibody Drug Conjugates – and by
championing the development of personalized combinations, AstraZeneca
has the vision to redefine cancer treatment and one day eliminate cancer
as a cause of death.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that
focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of diseases in three
therapy areas - Oncology, Cardiovascular, Renal & Metabolism and
Respiratory. The Company also is selectively active in the areas of
autoimmunity, neuroscience and infection. AstraZeneca operates in over
100 countries and its innovative medicines are used by millions of
patients worldwide. For more information, please visit www.astrazeneca-us.com
and follow us on Twitter @AstraZenecaUS.

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