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2020-01-20

AstraZeneca: Lynparza regulatory submission granted Priority Review in the US for HRR-mutated metastatic castration-resista...

Submission based on PROfound, the first positive Phase III trial
testing a targeted treatment in biomarker-selected prostate cancer
patients

AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck &
Co., Inc. inside the US and Canada) today announced that a
supplemental New Drug Application for Lynparza (olaparib) has been
accepted and granted Priority Review in the US for patients with
metastatic castration-resistant prostate cancer (mCRPC) and
deleterious or suspected deleterious germline or somatic homologous
recombination repair (HRR) gene mutations, who have progressed
following prior treatment with a new hormonal agent.

A Prescription Drug User Fee Act (PDUFA) date is set for the second
quarter of 2020.

The Priority Review by the US Food and Drug Administration (FDA) is
based on results from the Phase III PROfound trial, which were
presented
(https://www.astrazeneca.com/media-centre/press-releases/2019/lynparza-mo...)
during the Presidential Symposium at the 2019 European Society of
Medical Oncology congress.

Results of the PROfound trial showed Lynparza significantly reduced
the risk of disease progression or death by 66% based on a hazard
ratio of 0.34 (p<0.0001) vs. abiraterone or enzalutamide in patients
with BRCA1/2 or ATM-mutated mCRPC, the primary endpoint of the trial.

The trial also showed that Lynparza reduced the risk of disease
progression or death by 51% based on a hazard ratio of 0.49
(p<0.0001) vs. abiraterone or enzalutamide in the overall trial
population of patients with HRR-mutated (HRRm) mCRPC (those with
mutations in the genes for BRCA1/2, ATM, CDK12 or 11 other HRRm
genes; key secondary endpoint). The safety and tolerability profile
of Lynparza in the PROfound trial was in line with that observed in
previous clinical trials.

Metastatic castration-resistant prostate cancer

Prostate cancer is the second-most common cancer in men, with an
estimated 1.3 million new cases diagnosed worldwide in 2018 and is
associated with a significant mortality rate.[1 ]Development of
prostate cancer is often driven by male sex hormones called
androgens, including testosterone.[2] mCRPC occurs when prostate
cancer grows and spreads to other parts of the body despite the use
of androgen-deprivation therapy to block the action of male sex
hormones.[2] Approximately 10-20% of men with advanced prostate
cancer will develop CRPC within five years, and at least 84% of these
will have metastases at the time of CRPC diagnosis.[3] Of men with no
metastases at CRPC diagnosis, 33% are likely to develop metastases
within two years.[3] Despite an increase in the number of available
therapies for men with mCRPC, five-year survival remains low.[3]

PROfound

PROfound is a prospective, multicentre, randomised, open-label, Phase
III trial testing the efficacy and safety of Lynparza versus new
hormonal agents (e.g. abiraterone or enzalutamide) in patients with
mCRPC who have progressed on prior treatment with new hormonal
anticancer treatments and have a qualifying tumour mutation in one of
15 genes involved in the HRR pathway, including among them BRCA1/2,
ATM and CDK12.

The trial was designed to analyse patients with HRRm genes in two
cohorts: the primary endpoint was in those with mutations in BRCA1/2
or ATM genes and then, if Lynparza showed clinical benefit, a formal
analysis was performed of the overall trial population of patients
with HRRm genes (BRCA1/2, ATM, CDK12 and 11 other HRRm genes; key
secondary endpoint).

Results showed a statistically significant and clinically meaningful
improvement with Lynparza in the primary endpoint of radiographic
progression-free survival (rPFS), improving the time patients with
BRCA1/2- or ATM-mutated mCRPC lived without disease progression to a
median of 7.4 months vs. 3.6 months for those treated with
abiraterone or enzalutamide and reduced the risk of disease
progression or death by 66% (HR 0.34 [95% CI, 0.25-0.47], p<0.0001).
The trial also met the key secondary endpoint of rPFS in the overall
HRRm population, where Lynparza reduced the risk of disease
progression or death by 51% and improved rPFS to a median of 5.8
months vs. 3.5 months for those receiving abiraterone or enzalutamide
(HR 0.49 [95% CI, 0.38-0.63], p<0.0001). PROfound is the first
positive Phase III trial testing a targeted treatment in
biomarker-selected prostate cancer patients.

The safety and tolerability profile of Lynparza in the PROfound trial
was in line with that observed in prior clinical trials. The most
common adverse events (AEs) ?20% were anaemia (47%), nausea (41%),
fatigue/asthenia (41%), decreased appetite (30%) and diarrhoea (21%).
The most common Grade 3 or above AEs ?1% were anaemia (22%),
fatigue/asthenia (3%), vomiting (2%), dyspnoea (2%), urinary tract
infection (2%), pulmonary embolism (2%), decreased appetite (1%),
diarrhoea (1%), backpain (1%) and nausea (%). 16% of patients on
Lynparza discontinued treatment due to AEs.

HRR gene mutations

HRR is a DNA repair process that allows for high-fidelity, error-free
repair of damaged DNA, in the form of double-strand breaks and
inter-strand crosslinks (amongst others).[4,5] The inability to
properly repair DNA damage leads to genomic instability and
contributes to cancer aetiology.[5] Deficiency in HRR leads to a
compromised ability to repair damaged DNA, and is a feature of cancer
cells that is a target for PARP inhibitors, such as Lynparza. PARP
inhibitors block DNA damage repair by trapping of PARP bound to DNA
single-strand breaks which leads to replication fork stalling causing
their collapse and the generation of DNA double-strand breaks which
in turn lead to cancer cell death.[4]

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 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. It is approved in the US as a 1st-line maintenance
treatment for germline BRCA-mutated metastatic pancreatic cancer.
Regulatory reviews are underway in other jurisdictions for ovarian,
breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by
AstraZeneca and MSD, is approved for the treatment of advanced
ovarian cancer, metastatic breast cancer and metastatic pancreatic
cancer and has been used to treat more than 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 potential new medicine
selumetinib, a MEK inhibitor, for multiple cancer types. Working
together, the companies will develop Lynparza and selumetinib in
combination with other potential new medicines and as monotherapies.
Independently, the companies will develop Lynparza and selumetinib 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 of new medicines that has the potential to
transform patients' lives and the Company's future. With at least six
new medicines to be launched between 2014 and 2020, and a broad
pipeline of 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. 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/) and follow the Company on Twitter
@AstraZeneca (https://twitter.com/AstraZeneca).

Media Relations
Gonzalo Viña +44 203 749 5916
Rob Skelding Oncology +44 203 749 5821
Rebecca Einhorn Oncology +1 301 518 4122
Matt Kent BioPharmaceuticals +44 203 749 5906
Jennifer Hursit Other +44 203 749 5762

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