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2019-12-30

AstraZeneca: Lynparza approved in the US as a 1st-line maintenance treatment of germline BRCA-mutated metastatic pancreatic...

Lynparza reduced the risk of disease progression or death by 47% in
patients whose disease had not progressed on at least 16 weeks of a
1st-line platinum-based chemotherapy regimen

Only PARP inhibitor approved in germline BRCA-mutated metastatic
pancreatic cancer

AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck &
Co., Inc. inside the US and Canada) today announced that Lynparza
(olaparib) has been approved in the US for the maintenance treatment
of adult patients with deleterious or suspected deleterious germline
BRCA-mutated (gBRCAm) metastatic pancreatic adenocarcinoma
(pancreatic cancer) whose disease has not progressed on at least 16
weeks of a 1st-line platinum-based chemotherapy regimen. Patients
will be selected for therapy based on an FDA-approved companion
diagnostic for Lynparza.

The approval follows the recommendation
(https://www.astrazeneca.com/media-centre/press-releases/2019/lynparza-re...)
from the US FDA Oncologic Drugs Advisory Committee (ODAC) on 17
December for Lynparza in this indication, and was based on results
from the pivotal Phase III POLO trial
(https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2...)
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.

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. The safety and tolerability profile of
Lynparza in the POLO trial was in line with that observed in prior
clinical trials.

Dave Fredrickson, Executive Vice President, Oncology Business Unit,
said: "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. Lynparza is now
the only approved targeted medicine in biomarker-selected patients
with advanced pancreatic cancer."

Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, MSD Research Laboratories, said:
"Lynparza embodies MSD's and AstraZeneca's commitment to advance the
treatment of challenging types of cancer, including metastatic
pancreatic cancer. The expanded approval of Lynparza represents a
significant milestone for patients and supports the value of germline
BRCA testing in patients with this disease."

Hedy L. Kindler, Co-Principal Investigator of the POLO trial and
Professor of Medicine, University of Chicago Medicine, said: "Today's
approval of olaparib based on the POLO results gives clinicians an
important 1st-line maintenance treatment option which nearly doubled
the progression-free survival benefit in patients with germline
BRCA-mutated metastatic pancreatic cancer."

Julie Fleshman, President and CEO, Pancreatic Cancer Action Network,
said: "Metastatic pancreatic cancer patients have been waiting a long
time for new therapy options for their devastating disease. Today's
approval of Lynparza provides an exciting new treatment option for
patients with germline BRCA-mutated metastatic pancreatic cancer."

The Pancreatic Cancer Action Network (https://www.pancan.org/)
(PanCAN) is a US-based organisation that supports and advocates on
behalf of the patients, caregivers and communities affected by
pancreatic 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 2018[6.] 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
treatment[10], few improvements have been made in diagnosis and
treatment over the decades.[11,12] 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.[13]

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, 0.35-0.81], p=0.0035).
The benefit of maintenance with Lynparza was seen consistently across
a range of clinically meaningful endpoints. 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 reactions (ARs) ?10% were fatigue (60%), nausea (45%),
abdominal pain (34%), diarrhoea (29%), anaemia (27%), decreased
appetite (25%), constipation (23%), vomiting (20%), back pain (19%),
arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnoea (13%),
nasopharyngitis (12%), neutropenia (12%), dysgeusia (11%) and
stomatitis (10%). Grade 3 or above ARs were anaemia (11%), fatigue
(5%), neutropenia (4%), decreased appetite (3%), thrombocytopenia
(3%), abdominal pain (2%), vomiting (1%) and arthralgia (1%). ARs led
to dose reduction in 23% of patients on Lynparza while 6% of patients
discontinued treatment.

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]

In the US, eligible metastatic pancreatic cancer patients will be
selected for therapy based on the FDA-approved companion diagnostic,
BRACAnalysis CDx, a genetic test that detects the presence of a BRCA1
or BRCA2 gene mutation. BRACAnalysis CDx is owned and commercialised
by Myriad Genetics, Inc.

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 and pancreatic cancers.

Lynparza, which is being jointly developed and commercialised by
AstraZeneca and MSD, is approved for advanced ovarian cancer and
metastatic breast cancer and has been used in over 25,000 patients
worldwide. Lynparza has the broadest and most advanced clinical trial
development programme of any PARP inhibitor, and AstraZeneca and MSD
are working together to understand how it may affect multiple
PARP-dependent tumours as a monotherapy and in combination across
multiple cancer types. Lynparza is the foundation of AstraZeneca's
industry-leading portfolio of potential new medicines targeting DDR
mechanisms in cancer cells.

About the AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US,
known as MSD outside the United States and Canada,...

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