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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 (5

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