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

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April 15, 2018 3:50 pm ET

AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States
and Canada, today presented data from the Phase 3 OlympiAD trial showing
the final overall survival (OS) results for LYNPARZA in
metastatic breast cancer at the American Association for Cancer Research
(AACR) Annual Meeting in Chicago from April 14-18.

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 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 cutoff (64% maturity), 13 percent 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
3 trial to demonstrate disease control with a PARP inhibitor in gBRCA-mutated,
HER2-negative metastatic breast cancer. While the trial was not powered
to show overall survival compared to chemotherapy, the results are
another encouraging factor in the use of LYNPARZA for this
patient population.”

Dr. 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.”

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*
        LYNPARZA      

Physician’s choice

of chemotherapy

                       
Prior chemotherapy for metastatic breast cancer                                        
No (1L)       22.6       14.7       0.51       0.29-0.90       0.02
Yes (2L/3L)       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                                        
Oestrogen receptor positive (ER+) and/or progesterone 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
percent of patients who received LYNPARZA vs 49.5% of patients in the
chemotherapy arm. AEs leading to drug discontinuation were 4.9 percent
for LYNPARZA vs 7.7 percent for chemotherapy. AEs leading to dose
reductions were 25.4 percent for LYNPARZA vs 30.8 percent for
chemotherapy. AEs leading to dose interruptions were 36.1 percent for
LYNPARZA vs 28.6 percent for chemotherapy. Please see Important
Safety Information below.

These results build on previously reported primary and secondary
endpoints, 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 U.S. Food and Drug
Administration (FDA) for use in the treatment of g BRCA-mutated
metastatic breast cancer based on the OlympiAD data. A Type 2 Variation
application was recently validated by the European Medicines Agency for
LYNPARZA in BRCA-mutated, HER2-negative metastatic breast
cancer.

A Phase 3 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 around 60 countries for advanced ovarian cancer
and has treated more than 20,000 patients globally. It has the broadest
clinical development program of any PARP inhibitor, and AstraZeneca and
Merck are working together to bring LYNPARZA to more patients across
multiple cancers.

Important Safety Information for LYNPARZA

®


(olaparib)

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
(olaparib) 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 (olaparib) 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 (olaparib). 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 for LYNPARZA

®

(olaparib) in the
U.S.

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


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

NOTES TO EDITORS

About OlympiAD

OlympiAD is 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 chemotherapy (physician’s choice of
capecitabine, eribulin or vinorelbine). 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 breast cancer and received LYNPARZA for treatment
in the metastatic setting. Prior to enrollment, 71 percent of patients
had received no more than two previous chemotherapy treatments for
metastasized breast cancer and 28 percent of patients had received prior
platinum-based chemotherapy. Also enrolled were patients with hormone
receptor (HR)-positive 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, overall response rate, health-related
quality of life, and safety and tolerability.

About Metastatic Breast Cancer

Progesterone receptors (PR), estrogen receptors (ER) 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 HR-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 4), 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
percent 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.

Breast cancer is the most common cancer in women, with an estimated 1.67
million new cases diagnosed worldwide in 2012 alone – one in four of all
cancer cases. Approximately 30 percent of women who are diagnosed with
early breast cancer will go on to develop advanced disease.

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, which has the broadest clinical development program of any
PARP inhibitor, is being investigated in a range of DDR-deficient tumor
types.

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 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
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 evaluating oncology medicines in more than 30
tumor types. We also continue to strengthen our oncology portfolio
through strategic acquisitions and are prioritizing the development of
several promising 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
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