Market Overview

LYNPARZA® (olaparib) Approved by US FDA in Germline BRCA-Mutated Metastatic Breast Cancer

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LYNPARZA is the first and only PARP inhibitor approved for use
beyond ovarian cancer

LYNPARZA reduced the risk of disease progression or death by 42%
compared to standard of care chemotherapy

AstraZeneca and Merck (Merck: known as MSD outside the US and Canada)
today announced that the US 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.1

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 beyond 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."

Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, Merck Research Laboratories, said:
"This additional approval for LYNPARZA represents an important advance
for women with HER2-negative metastatic breast cancer with a germline BRCA
mutation, 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
III OlympiAD trial
, which investigated LYNPARZA 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% (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% (95% CI 44-60), double the
response rate for those in the chemotherapy arm (n=66) which was 23%
(95% CI 13-35). Additionally, patients experienced a confirmed complete
response rate of 7.8% for LYNPARZA compared to 1.5% 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
.1,2

Dr. Susan M. Domchek, Executive Director of the Basser Center for BRCA
at the Abramson Cancer Center of the University of Pennsylvania, and a
national leader on the OlympiAD trials said: "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. 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 US 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 (≥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 5% compared to the chemotherapy arm which was 8%. Please
see Important Safety Information below.

This is the third indication approved for LYNPARZA in the US, where it
has been used to treat nearly 4,000 advanced ovarian cancer patients.1,3
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.4-7

Sustainable and Ongoing Externalization Revenue

Under the oncology collaboration with Merck, announced in July 2017,
AstraZeneca is potentially eligible for more than $6 billion of future
Sustainable and Ongoing Externalization Revenue in the form of
sales-related and approval-related payments in addition to option
payments until 2019. Following this new approval for LYNPARZA,
AstraZeneca will receive $70 million in Sustainable and Ongoing
Externalization Revenue.

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).

– ENDS –

NOTES TO EDITORS

About OlympiAD
OlympiAD is a randomized, open-label,
multicenter Phase III 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 germline BRCA1 or BRCA2 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.2,8

Patients in the OlympiAD trial had HER2-negative gBRCA1- or gBRCA2-mutated
breast cancer, which was HR+ or triple negative, and received LYNPARZA
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.2,8

The primary endpoint of the trial was PFS as measured by a Blinded
Independent Central Review.2,8 Secondary endpoints included
overall survival, time to second progression or death, objective
response rate, and effect on health-related quality of life.2,8

About Metastatic Breast Cancer (MBC)
Three main receptors
drive tumor growth in breast cancer: Progesterone receptors (PR),
estrogen receptors (ER) and HER2 receptors.9,10 A patient's
breast cancer will test either negative or positive for these three
receptors.9,10 If a tumor tests positive for PR and/or ER, it
is considered HR+.9 If a tumor tests negative for all three
receptors, it is considered triple negative.9

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.11,12

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 five years after diagnosis.13-15
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.16

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 2020.17

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.18

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.19-21
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.1

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.19-21

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 PDL-1/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.

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 New Oncology as one of
AstraZeneca's five 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, DNA Damage Response 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 &
Metabolic Diseases 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.

Media Inquiries

Michele Meixell +1 302 885 2677
Stephanie Wiswall +1 302 885 2677

References

  1. LYNPARZA (olaparib) Tablets Prescribing Information. AstraZeneca
    Pharmaceuticals LP, Wilmington, DE.
  2. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast
    cancer in patients with a germline BRCA mutation. N Engl J Med.
    2017; DOI: 10.1056/NEJMoa1706450
  3. Data on File, US-16345, AstraZeneca Pharmaceuticals LP.
  4. US National Institutes of Health. Olaparib as Adjuvant Treatment in
    Patients With Germline BRCA Mutated High Risk HER2 Negative Primary
    Breast Cancer (OlympiA). Available
    Online
    . Accessed January 2018.
  5. National Institutes of Health. Olaparib Maintenance Monotherapy in
    Patients with BRCA Mutated Ovarian Cancer Following First Line
    Platinum Based Chemotherapy. (SOLO-1) Available
    Online.
    Accessed January 2018.
  6. US National Institutes of Health. Olaparib in gBRCA Mutated Pancreatic
    Cancer Whose Disease Has Not Progressed on First Line Platinum-Based
    Chemotherapy (POLO). Available
    Online
    . Accessed January 2018.
  7. US National Institutes of Health. Study of Olaparib (Lynparza™) Versus
    Enzalutamide or Abiraterone Acetate in Men With Metastatic
    Castration-Resistant Prostate Cancer (PROfound Study). Available
    Online
    . Accessed January 2018.
  8. US National Institutes of Health. Assessment of the Efficacy and
    Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy
    in the Treatment of Metastatic Breast Cancer Patients With Germline
    BRCA1/2 Mutations (OlympiAD). Available
    Online
    . Accessed January 2018.
  9. American Cancer Society. Breast Cancer Hormone Receptor Status. Available
    Online
    . Accessed January 2018.
  10. American Cancer Society. Breast Cancer HER2 Status. Available
    Online
    . Accessed January 2018.
  11. Cleveland Clinic. Diseases and Conditions: Breast Cancer. Available
    Online
    . Last Updated September 5, 2013. Accessed January 2018.
  12. Mayo Clinic. Breast Cancer Diagnosis. Available
    Online
    . Last Updated August 16, 2016. Accessed January 2018.
  13. American Cancer Society. Breast Cancer Facts & Figures 2017-2018. Available
    Online
    . Accessed January 2018.
  14. American Cancer Society. Managing Cancer as a Chronic Illness. Available
    Online
    . Accessed January 2018
  15. National Cancer Institute. SEER Cancer Fact Sheet: Female Breast
    Cancer. Available
    Online
    . Accessed January 2018.
  16. O'Shaughnessy J. Extending survival with chemotherapy in metastatic
    breast cancer. The Oncologist. 2005;10(3):20–29.
  17. CancerMPact.Khapps.com: ONC-Prevalence of Metastatic Breast Cancer in
    Women 2014-2020. Accessed January 2018.
  18. National Cancer Institute. BRCA1 and BRCA2: Cancer Risk and Genetic
    Testing. Available
    Online
    . Accessed January 2018.
  19. US Food and Drug Administration. FDA approves Lynparza to treat
    advanced ovarian cancer. Accessed January 2018.
  20. O'Connor M. Targeting the DNA damage response in cancer. Mol Cell.
    2015; 60:547-560. Accessed January 2018.
  21. Tutt ANJ, Lord CJ, McCabe N. Exploiting the DNA repair defect in BRCA
    mutant cells in the design of new therapeutic strategies for cancer. Cold
    Spring Harb Symp Quant Biol. 
    2005; 70:139-148.

US-14448 Last Updated 1/18

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