Blueprint
FORM 6-K
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
Report
of Foreign Issuer
Pursuant
to Rule 13a-16 or 15d-16 of
the
Securities Exchange Act of 1934
For the
month of January
2020
Commission
File Number: 001-11960
AstraZeneca PLC
1
Francis Crick Avenue
Cambridge
Biomedical Campus
Cambridge
CB2 0AA
United
Kingdom
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
FDA
grants Lynparza Priority Review for PROfound
20 January 2020 07:00 GMT
Lynparza regulatory submission granted Priority
Review in the US
for HRR-mutated metastatic castration-resistant
prostate cancer
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 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 and
follow the Company on Twitter @AstraZeneca.
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References
1. Bray et al. (2018). Global cancer
statistics 2018: GLOBOCAN estimates of incidence and mortality
worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for
Clinicians, 68(6),
pp.394-424.
2. Cancer.Net. (2019). Treatment of
metastatic castration-resistant prostate
cancer. www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer Last
Accessed: November 2019.
3. Cancer.Net. (2019). Prostate Cancer
- Statistics. Available at: www.cancer.net/cancer-types/prostate-cancer/statistics Last
Accessed: November 2019.
4. Li et al. (2008). Homologous
recombination in DNA repair and DNA damage
tolerance. Cell
Research, 18(1),
pp.99-113.
5. Ledermann et al. (2016). Homologous
recombination deficiency and ovarian
cancer. European Journal of
Cancer, 60,
pp.49-58.
Adrian Kemp
Company Secretary
AstraZeneca PLC
SIGNATURES
Pursuant
to the requirements of the Securities Exchange Act of 1934, the
Registrant has duly caused this report to be signed on its behalf
by the undersigned, thereunto duly authorized.
Date:
20 January
2020
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By: /s/
Adrian Kemp
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Name:
Adrian Kemp
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Title:
Company Secretary
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