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2020-05-11

AstraZeneca: Lynparza approved in the US as 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovari...

Patients treated with Lynparza and bevacizumab lived without disease
progression for 37.2 months vs. 17.7 months median for bevacizumab
alone

One in two women with advanced ovarian cancer has an HRD-positive
tumour

AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck &
Co., Inc. inside the US and Canada) today announced that Lynparza
(olaparib) in combination with bevacizumab has been approved in the
US for the maintenance treatment of adult patients with advanced
epithelial ovarian, fallopian tube or primary peritoneal cancer who
are in complete or partial response to 1st-line platinum-based
chemotherapy and whose cancer is associated with homologous
recombination deficiency (HRD) positive status defined by either a
deleterious or suspected deleterious BRCA mutation, and/or genomic
instability. Patients will be selected for therapy based on an
FDA-approved companion diagnostic test.

The approval by the US Food and Drug Administration (FDA) was based on
a biomarker subgroup analysis of the Phase III PAOLA-1 trial
(https://www.astrazeneca.com/media-centre/press-releases/2019/lynparza-im...)
which showed that Lynparza in combination with bevacizumab
maintenance treatment reduced the risk of disease progression or
death by 67% (equal to a hazard ratio of 0.33). The addition of
Lynparza improved progression-free survival (PFS) to a median of 37.2
months versus 17.7 months with bevacizumab alone in patients with
HRD-positive advanced ovarian cancer.

Approximately one in two women with advanced ovarian cancer has an
HRD-positive tumour. For patients with advanced ovarian cancer, the
primary aim of 1st-line treatment is to delay disease progression for
as long as possible with the intent to achieve long-term remission.

Isabelle Ray-Coquard, principal investigator of the PAOLA-1 trial and
medical oncologist, Centre Léon Bérard and President of the GINECO
group, said: "Ovarian cancer is a devastating disease. The magnitude
of benefit in HRD-positive patients in the PAOLA-1 trial is
impactful. The combination of Lynparza and bevacizumab now provides
women with HRD-positive advanced ovarian cancer with a new standard
of care and I look forward to seeing this translate into clinical
practice."

Dave Fredrickson, Executive Vice President, Oncology Business Unit,
said: "This approval represents another milestone for Lynparza in
patients with ovarian cancer. The median progression-free survival of
more than three years offers new hope for more women to delay relapse
in this difficult-to-treat disease. These results further establish
that HRD-positive is a distinct subset of ovarian cancer, and HRD
testing is now a critical component for the diagnosis and tailoring
of treatment for women with advanced ovarian cancer."

Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, MSD Research Laboratories, said:
"Advances in understanding the role of biomarkers and PARP inhibition
have fundamentally changed how physicians treat this aggressive type
of cancer. Today's approval based on the PAOLA-1 trial highlights the
importance of HRD testing at diagnosis to identify those who may
benefit from Lynparza in combination with bevacizumab as a 1st-line
maintenance treatment."

The full results from the Phase III PAOLA-1 trial were published in
The New England Journal of Medicine
(https://www.nejm.org/doi/full/10.1056/NEJMoa1911361).

Regulatory reviews are currently underway in the EU, Japan and other
countries for Lynparza based on results from the PAOLA-1 trial. As
part of a broad development programme, Lynparza is being tested as a
monotherapy and in combination across multiple tumour types including
as a potential adjuvant treatment of patients with germline
BRCA-mutated high-risk HER2-negative primary breast cancer in the
Phase III OlympiA trial.

Financial considerations

Following this approval for Lynparza in the US, AstraZeneca will
receive from MSD $100m in Collaboration Revenue, anticipated to be
booked by the Company during the second quarter of 2020.

Ovarian cancer

Ovarian cancer is the eighth most common cause of death from cancer in
women worldwide.[1] In 2018, there were nearly 300,000 new cases
diagnosed and around 185,000 deaths.[2] Most women are diagnosed with
advanced (Stage III or IV) ovarian cancer and have a five-year
survival rate of approximately 30%.[3] Approximately 50% of ovarian
cancers are HRD-positive including BRCA1/2 mutation.[ 4,5][ ]Some 22%
of ovarian cancers have a BRCA1/2 mutation.[5][ ]

For patients with advanced ovarian cancer, the primary aim of 1st-line
treatment is to delay progression of the disease for as long as
possible and maintain the patient's quality of life with the intent
of achieving complete remission.[6,7,8,9]

In the US, bevacizumab was approved for use in combination with
chemotherapy for the 1st-line treatment of advanced ovarian cancer in
2018. Within two years nearly half of all patients with advanced
ovarian cancer are receiving this combination treatment.[10]

PAOLA-1

PAOLA-1 is a double-blind Phase III trial testing the efficacy and
safety of Lynparza in combination with bevacizumab vs. bevacizumab
alone, as a 1st-line maintenance treatment for newly diagnosed
advanced FIGO Stage III-IV high-grade serous or endometroid ovarian,
fallopian tube, or peritoneal cancer patients who had a complete or
partial response to 1st-line treatment with platinum-based
chemotherapy and bevacizumab. AstraZeneca and MSD announced in August
2019
(https://www.astrazeneca.com/media-centre/press-releases/2019/lynparza-ph...)
that the trial met its primary endpoint of PFS.

Simultaneously, the Myriad Genetics myChoice CDx test has been
approved in the US as a companion diagnostic for Lynparza in this new
indication.

Homologous recombination deficiency

HRD, which defines a sub-group of ovarian cancer, encompasses a wide
range of genetic abnormalities, including BRCA mutations and beyond.
As with BRCA gene mutations, HRD interferes with normal cell DNA
repair mechanisms and confers sensitivity to PARP inhibitors
including Lynparza.[5]

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, 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 a number of countries, including
those in the EU, for the maintenance treatment of platinum-sensitive
relapsed ovarian cancer. 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 the US, Japan,
and a number of other countries for germline BRCA-mutated,
HER2-negative, metastatic breast cancer, previously treated with
chemotherapy; in the EU, this includes locally advanced breast
cancer. Lynparza is approved in the US and several other countries
for the treatment of germline BRCA-mutated metastatic pancreatic
cancer. Regulatory reviews are underway in several jurisdictions for
ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by
AstraZeneca and MSD, has been used to treat over 30,000 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

The AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US,
known as MSD outside the US and Canada, announced a global strategic
oncology collaboration to co-develop and co-commercialise Lynparza,
the world's first PARP inhibitor, and Koselugo (selumetinib), a MEK
inhibitor, for multiple cancer types. Working together, the companies
will develop Lynparza and Koselugo in combination with other
potential new medicines and as monotherapies. Independently, the
companies will develop Lynparza and Koselugo in combination with
their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a
quickly growing portfolio ofnew medicines that has the potential to
transform patients' lives and the Company's future. With six new
medicines launched between 2014 and 2020, and a broad pipelineof
small molecules and biologics in development, the Company is
committed to advance oncology as a key growth driver for AstraZeneca
focused on lung, ovarian, breast and blood cancers. In addition to
AstraZeneca's main capabilities, the Company is actively pursuing
innovative partnerships and investment that accelerate the delivery
of our strategy, as illustrated by the investment in Acerta Pharma in
haematology.

By harnessing the power of four scientific platforms -
Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response
and Antibody Drug Conjugates - and by championing the development of
personalised combinations, AstraZeneca has the vision to redefine
cancer treatment and, one day, eliminate cancer as a cause of death.

AstraZeneca

AstraZeneca (LSE/STO/NYSE: AZN) is a global, science-led
biopharmaceutical company that focuses on the discovery, development
and commercialisation of prescription medicines, primarily for the
treatment of diseases in three therapy areas - Oncology,
Cardiovascular, Renal and Metabolism, and Respiratory and Immunology.
Based in Cambridge, UK, AstraZeneca operates in over 100 countries
and its innovative medicines are used by millions of patients
worldwide. Please visit astrazeneca.com (http://www.astrazeneca.com/)
...

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