Blueprint
FORM 6-K
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
Report
of Foreign Issuer
Pursuant
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the
Securities Exchange Act of 1934
For the
month of September
2019
Commission
File Number: 001-11960
AstraZeneca PLC
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Lynparza more than doubled
the time without radiographic disease progression in patients with
BRCA1/2- or ATM-mutated metastatic castration-resistant prostate
cancer
30 September 2019 15:30 BST
Lynparza more than doubled the time without
radiographic disease progression in patients with BRCA1/2- or
ATM-mutated metastatic castration-resistant prostate
cancer
AstraZeneca and MSD's Lynparza reduced the risk of disease
progression or
death by 51% in men with homologous recombination repair (HRR) gene
mutations
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 presented detailed results
from the Phase III PROfound trial in 387 men with metastatic
castration-resistant prostate cancer (mCRPC) who have a mutation in
their homologous recombination repair (HRRm) genes and whose
disease had progressed on prior treatment with new hormonal agent
(NHA) treatments (e.g. abiraterone or enzalutamide).
The
trial was designed to analyse men with HRRm genes in two cohorts:
the primary endpoint was in those with mutations in BRCA1/2 or ATM
genes and then, if Lynparza (olaparib) showed
clinical benefit, a formal analysis was performed of the overall
trial population of men 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 men with BRCA1/2- or ATM-mutated mCRPC
lived without disease progression or death to a median of 7.4
months vs. 3.6 months for those treated with abiraterone or
enzalutamide. Lynparza reduced the risk of
disease progression or death by 66% (equal to a hazard ratio of
0.34) for these men.
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% (equal to a hazard ratio of
0.49) and improved rPFS to a median of 5.8 months vs. 3.5 months
for abiraterone or enzalutamide.
The
results were presented during the Presidential Symposium at the
2019 European Society of Medical Oncology (ESMO) congress in
Barcelona, Spain (Abstract #LBA12_PR).
Results
also showed a trend at this interim analysis time point for
improvement in overall survival (OS), another key secondary
endpoint, in the two groups. Lynparza extended OS to 18.5
months vs.15.1 months for abiraterone or enzalutamide in men with
BRCA1/2- or ATM-mutated tumours, despite that at this interim
analysis 81% of patients on NHA crossed over to Lynparza at progression. A similar
trend in OS was observed at this interim analysis in the overall
HRRm population with a median of 17.5 months' OS for men treated
with Lynparza vs.
14.3 months for abiraterone or enzalutamide (analysis at 41% data
maturity).
José
Baselga, Executive Vice President, Oncology R&D, said: "Results
from PROfound demonstrate that, in addition to providing
substantial benefit as a precision medicine for men with metastatic
castration-resistant prostate cancer with BRCA-mutated
tumours, Lynparza is effective beyond just
BRCA in tumours with mutations in other genes associated with
homologous recombination repair. PROfound validates the concept of
PARP sensitivity across multiple genes associated with homologous
recombination repair in this disease and marks the first positive
Phase III trial using a molecular biomarker to identify men for
targeted treatment for metastatic castration-resistant prostate
cancer. We are working with global health authorities to
bring Lynparza to
these patients as quickly as possible."
Roy
Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, MSD Research Laboratories,
said: "The results from the Phase III PROfound trial are a
testament to MSD and AstraZeneca's lasting commitment to patients
with cancer. The trial met the primary endpoint in men with
metastatic castration-resistant prostate cancer that progressed on
prior hormonal therapy, a notoriously difficult-to-treat disease.
The benefit seen in patients beyond just those with BRCA mutations
underscores the potential value of genomic testing in prostate
cancer."
Maha
Hussain, one of the principal investigators of the PROfound trial
and Deputy Director of the Robert H. Lurie Comprehensive Cancer
Center of Northwestern University, said: "We have seen advances in
the treatment over the last 15 years for men with metastatic
castration-resistant prostate cancer. However, to date treatments
for this state of disease continue to use 'one size fits all'
approaches overlooking the genomic make-up of the tumour and how it
could inform treatment decisions to better personalise care and
impact outcomes. I am thrilled by the PROfound results
and Lynparza's clinically meaningful benefit
which offers the potential of a molecularly targeted treatment for
this patient population with advanced disease. I am confident we
are now entering a new era of personalised care and precision
medicine for metastatic castration-resistant prostate
cancer."
Summary of resultsi
|
Cohort A
(BRCA1/2 or ATM)
|
Cohort A+B ii
(Overall HRRm)
|
|
Lynparza
n=162
|
pcNHA
n=83
|
Lynparza
n=256
|
pcNHA
n=131
|
rPFS
|
Median,
months
|
7.4
|
3.6
|
5.8
|
3.5
|
%
progression-free at 6 months
|
59.8
|
22.6
|
49.7
|
23.7
|
%
progression-free at 12 months
|
28.1
|
9.4
|
22.1
|
13.5
|
Hazard
ratio (95% CI)
|
0.34
(0.25-0.47)
|
0.49
(0.38-0.63)
|
p-value
|
<0.0001
|
<0.0001
|
Confirmed ORR
|
Patients
with response (%)
|
33.3
|
2.3
|
21.7
|
4.5
|
Odds
ratio (95% CI)
|
20.86
(4.18-379.18)
|
5.93
(2.01-25.40)
|
p-value
|
<0.0001
|
0.0006
(nominal)
|
Time to pain progression iii
|
Median,
months
|
NR
|
9.92
|
|
|
Hazard
ratio (95% CI)
|
0.44
(0.22-0.91)
|
|
p-value
|
0.0192
|
|
OS (interim) iv
|
Median,
months
|
18.5
|
15.1
|
17.5
|
14.3
|
Hazard
ratio (95% CI)
|
0.64
(0.43-0.97)
|
0.67
(0.49-0.93)
|
p-value
|
0.0173
|
0.0063
(nominal)
|
NR, not reached; ORR, objective response rate; pc, physician's
choice
i Assessed by blinded
independent central review (BICR)
ii Cohort B included
patients with any 1 of 12 other HRR mutations
iii Time to pain
progression in Cohort A was a secondary endpoint included in the
formal testing hierarchy
iv Interim analysis was
done at 38% (Cohort A) and 41% (Cohort A+B) data maturity; Alpha
spend at interim was 0.01; statistical significance not
reached
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%). Grade 3 or above AEs were anaemia (22%), pulmonary
embolism (4%), fatigue/asthenia (3%), vomiting (2%), dyspnoea (2%),
urinary tract infection (2%), decreased appetite (1%), diarrhoea
(1%) and backpain (1%). 16% of patients on Lynparza discontinued treatment
due to AEs.
AstraZeneca
and MSD are also exploring additional trials in prostate cancer,
including the ongoing Phase III PROpel trial,
testing Lynparza as a 1st-line therapy in
mCRPC, in combination with abiraterone.
About 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.
About 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.1Development
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.3Of
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
About 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
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 64 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 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 43 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,
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.
About 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, we
are committed to advance Oncology as one of AstraZeneca's four
Growth Platforms focused on lung, ovarian, breast and blood
cancers. In addition to our core capabilities, we actively pursue
innovative partnerships and investments that accelerate the
delivery of our strategy, as illustrated by our 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.
About AstraZeneca
AstraZeneca 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 (CVRM), 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 us on Twitter @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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Hägerstrand
|
Sweden
|
+46 8 552 53 106
|
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Meixell
|
US
|
+1 302
885 2677
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Investor
Relations
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Thomas
Kudsk Larsen
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+44 203
749 5712
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Wheeler
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+44 203
749 5797
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Gruvris
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(CV, metabolism)
|
+44 203
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+44 203
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+44 203
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Corporate
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References
1. Bray, F., Ferlay, 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.
https://www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer [Accessed
September 2019].
3. Cancer.Net. (2019). Prostate Cancer - Statistics. Available
at: www.cancer.net/cancer-types/prostate-cancer/statistics [Accessed
September 2019].
4. Li, X. and Heyer, W. (2008). Homologous recombination in DNA
repair and DNA damage tolerance. Cell
Research, 18(1),
pp.99-113.
5. Ledermann, J., Drew, Y. and Kristeleit, R. (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:
30 September
2019
|
By: /s/
Adrian Kemp
|
|
Name:
Adrian Kemp
|
|
Title:
Company Secretary
|