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2019-12-17

AstraZeneca: Lynparza recommended by FDA advisory committee for 1st-line maintenance treatment of germline BRCA-mutated met...

ODAC voted that Lynparza demonstrated a clinically meaningful and
favourable risk-benefit profile for patients based on Phase III POLO
trial results

AstraZeneca and MSD Inc., Kenilworth, NJ, US (MSD: known as Merck &
Co., Inc. inside the US and Canada) today announced that the US Food
and Drug Administration (FDA) Oncologic Drugs Advisory Committee
(ODAC) voted 7 to 5 to recommend Lynparza (olaparib) as a 1st-line
maintenance monotherapy for patients with germline BRCA-mutated
(gBRCAm) metastatic adenocarcinoma of the pancreas (pancreatic
cancer), whose disease has not progressed following 1st-line
platinum-based chemotherapy.

In August 2019, the FDA accepted the supplemental New Drug Application
(sNDA) for Lynparza for this indication with Priority Review and set
a Prescription Drug User Fee Act (PDUFA) date for the fourth quarter
of 2019.

José Baselga, Executive Vice President, Oncology R&D, said: "We are
pleased with the ODAC's recommendation for Lynparza and the potential
to bring a personalised, biomarker-targeted medicine to patients with
germline BRCA-mutated metastatic pancreatic cancer. Patients with
advanced pancreatic cancer historically have faced poor outcomes due
to the aggressive nature of the disease and limited treatment
advances over the last few decades. We look forward to working with
the FDA as it completes the review of our application."

Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, MSD Research Laboratories, said:
"We are encouraged by the ODAC's favourable vote for Lynparza as a
1st-line maintenance therapy in germline BRCA-mutated metastatic
pancreatic cancer. This recommendation is a significant step towards
reaching our goal to help patients with this deadly disease."

The sNDA submission was based on the positive results from the Phase
III POLO trial published in The New England Journal of Medicine
(https://www.nejm.org/doi/full/10.1056/NEJMoa1903387) and presented
at the 2019 American Society of Clinical Oncology Annual Meeting. The
results showed a statistically significant and clinically meaningful
improvement in progression-free survival and reduced the risk of
disease progression or death by 47% based on a hazard ratio of 0.53
(p=0.0038). Lynparza nearly doubled the time patients with gBRCAm
metastatic pancreatic cancer lived without disease progression or
death to a median of 7.4 months vs. 3.8 months on placebo.

The benefit of maintenance with Lynparza was seen consistently across
a range of clinically meaningful endpoints. At each time point, from
six months onwards, more than twice as many patients treated with
Lynparza showed no disease progression vs. those on placebo. In
patients with measurable disease at baseline, 23% responded to
Lynparza vs.12% on placebo and had a median duration of treatment in
excess of two years (24.9 months) vs 3.7 months on placebo. Overall
survival (OS), a secondary endpoint, at interim analysis was 18.9
months for Lynparza vs. 18.1 months for placebo but did not reach
statistical significance (HR=0.90; p=0.68). The safety and
tolerability profile of Lynparza in the Phase III POLO trial was in
line with that observed in prior clinical trials.

The ODAC provides the FDA with independent, expert advice and
recommendations on marketed and potential new medicines for use in
the treatment of cancer. The FDA will consider the vote as it reviews
the submission and is not bound by the Committee's recommendation.

In addition to the US, Lynparza is currently under regulatory review
in the EU, Canada and other jurisdictions as a 1st-line maintenance
treatment for patients with gBRCAm metastatic pancreatic cancer.

Pancreatic cancer is a rare, life-threatening disease that accounts
for about 3% of all cancers in the US. The FDA granted Lynparza
Orphan Drug Designation in October 2018
(https://www.astrazeneca.com/media-centre/press-releases/2018/us-fda-gran...!),
which is for medicines intended to treat, diagnose or prevent rare
diseases or disorders that affect fewer than 200,000 people in the
US.

Lynparza was the first PARP inhibitor to be approved and has been used
in over 25,000 patients worldwide. Lynparza is currently approved in
65 countries including the US for the maintenance treatment of
platinum-sensitive relapsed ovarian cancer, regardless of BRCA
status. It is approved in the US, the EU, Japan and several other
countries as 1st-line maintenance treatment of BRCA-mutated advanced
ovarian cancer following response to platinum-based chemotherapy. It
is also approved in 44 countries, including the US and Japan, for
germline BRCA-mutated, HER2-negative, metastatic breast cancer,
previously treated with chemotherapy; in the EU, this includes
locally advanced breast cancer.

About pancreatic cancer

Pancreatic cancer is a deadly cancer with a high unmet medical need.
It is the 12th most commonly occurring cancer[2 ]and the 7th leading
cause of cancer death globally.[3] The disease has the lowest
survival rate of the most common cancers[4,5] and is the only major
cancer with a single-digit five-year survival rate (2-9%) in nearly
every country.[5] There were approximately 460,000 new cases
worldwide in 20186. As there are often no symptoms, or symptoms may
be non-specific in the early stages[7], it is most commonly diagnosed
at an incurable stage.[8 ]Around 80% of pancreatic cancer patients
are diagnosed when the disease has metastasised and for these the
average survival is less than a year.[9] Despite advances in
treatment1[0], few improvements have been made in diagnosis and
treatment over the decades.1[1,12] Current treatment is surgery (for
which approximately only 10-20% of patients are eligible),

chemotherapy and radiotherapy, highlighting a critical unmet medical
need for more effective treatment options.1[3]

About POLO

POLO is a Phase III randomised, double-blinded, placebo-controlled,
multi-centre trial of Lynparza tablets (300mg twice daily) as
maintenance monotherapy vs. placebo. The trial randomised 154
patients with gBRCAm metastatic pancreatic cancer whose disease had
not progressed on 1st-line platinum-based chemotherapy. Patients were
randomised (3:2) to receive Lynparza or placebo until disease
progression. The primary endpoint was PFS and key secondary endpoints
included overall survival, time to second disease progression,
overall response rate and health-related quality of life.1

The results showed a statistically significant and clinically
meaningful improvement in progression-free survival, where Lynparza
nearly doubled the time patients with gBRCAm metastatic pancreatic
cancer lived without disease progression or death to a median of 7.4
months vs. 3.8 months on placebo and reduced the risk of disease
progression or death by 47% (HR 0.53 [95% CI, 0.35-0.82], p=0.004).
The benefit of maintenance with Lynparza was seen consistently across
a range of clinically meaningful endpoints. From six months onwards,
more than twice as many patients receiving Lynparza showed no disease
progression vs. those receiving placebo. In patients with measurable
disease at baseline, 23% responded to Lynparza vs.12% on placebo
(odds ratio, 2.30; 95% CI, 0.89 to 6.76) and had a median duration of
treatment in excess of two years (24.9 months; 95% CI, 14.8 to could
not be calculated) vs 3.7 months on placebo (95% CI, 2.1 to could not
be calculated). Overall survival (OS), a secondary endpoint, at
interim analysis was 18.9 months for Lynparza vs. 18.1 months for
placebo but did not reach statistical significance (HR=0.90; p=0.68).

The safety and tolerability profile of Lynparza in the POLO trial was
in line with that observed in prior clinical trials. The most common
adverse events (AEs) ?20% were fatigue/asthenia (60%), nausea (45%),
abdominal pain (29%), diarrhoea (29%), anaemia (28%), decreased
appetite (25%) and constipation (23%). The most common ? grade 3 AEs
were anaemia (11%), fatigue/asthenia (5%), decreased appetite (3%),
abdominal pain (2%), vomiting (1%) and arthralgia (1%). AEs led to
dose reduction in 16% of patients on Lynparza while 5% of patients
discontinued treatment.

There are currently no precision medicine treatment options for gBRCAm
pancreatic cancer patients. However, based on the results of POLO,
the National Comprehensive Cancer Network (NCCN) guidelines were
updated in July 2019 to recommend Lynparza as maintenance treatment
for gBRCAm pancreatic cancer.[14]

About BRCA mutations

BRCA1 and BRCA2 (breast cancer susceptibility genes 1/2) 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 Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first
targeted treatment to block DNA damage response (DDR) in
cells/tumours harbouring a deficiency in homologous recombination
repair (HRR), such as mutations in BRCA1 and/or BRCA2. 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 PARP-dependent tumour types
with defects and dependencies in the DDR pathway.

Lynparza is currently approved in 65 countries, including those in the
EU, for the maintenance treatment of platinum-sensitive relapsed
ovarian cancer, regardless of BRCA status. It is approved in the US,
the EU, Japan, China and several other countries as 1st-line
maintenance treatment of BRCA-mutated advanced ovarian cancer
following response to platinum-based chemotherapy. It is also
approved in 44 countries, including the US and Japan, for germline
BRCA-mutated, HER2-negative, metastatic breast cancer, previously
treated with chemotherapy; in the EU, this includes locally advanced
breast cancer. Regulatory reviews are underway in other jurisdictions
for ovarian, breast, prostate and pancreatic cancers.

...

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