a4589
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 May 2020
Commission
File Number: 001-11960
AstraZeneca PLC
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Lynparza approved in the US for HRR
gene-mutated metastatic
castration-resistant prostate cancer
20 May 2020 07:00 BST
Lynparza approved in the US for HRR
gene-mutated
metastatic castration-resistant prostate cancer
Only PARP inhibitor to improve overall survival vs. enzalutamide
or
abiraterone in a biomarker-based subset of prostate cancer
patients
with BRCA1/2 or ATM mutations
Approximately 20-30% of men with metastatic
castration-resistant
prostate cancer have an HRR gene mutation
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
patients with homologous recombination repair (HRR) gene-mutated
metastatic castration-resistant prostate cancer
(mCRPC).
The approval by the US Food and Drug Administration (FDA) was based
on results from the Phase III PROfound
trial, which were published
in The
New England Journal of Medicine.
Prostate cancer is the second-most common cancer in men and despite
an increase in the number of available therapies for men with
mCRPC, five-year survival remains low. HRR gene mutations occur in
approximately 20-30% of patients with mCRPC.
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: "Prostate cancer
has lagged behind other solid tumours in the era of precision
medicine. I am thrilled by the approval of Lynparza which now brings a molecularly targeted
treatment to men with HRR gene-mutated metastatic
castration-resistant prostate cancer in the US. The PROfound trial
was an international effort and I want to thank the patients, their
families, the investigators and their teams involved in making it
possible."
Dave Fredrickson, Executive Vice President, Oncology Business Unit,
said: "Today marks the first approval for Lynparza in prostate cancer. In the PROfound
trial, Lynparza more than doubled the median radiographic
progression-free survival and is the only PARP inhibitor to improve
overall survival, versus enzalutamide or abiraterone for men with
BRCA or ATM mutations. These results further establish that genomic
testing for HRR mutations should be a critical step for the
diagnosis and determination of treatment options for men with
advanced prostate cancer."
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, MSD Research
Laboratories, said, "Lynparza is the only PARP inhibitor approved with
Phase III data for men with HRR gene-mutated metastatic
castration-resistant prostate cancer. This approval highlights the
importance of genomic testing to help identify treatment options
for men in this patient population. We are proud to work in
collaboration with AstraZeneca toward our overall goal of improving
outcomes for patients."
The primary endpoint of the trial was radiographic progression-free
survival (rPFS) in men with BRCA1/2 or ATM gene mutations, a
subpopulation of HRR gene mutations. Results
showed Lynparza reduced the risk of disease progression or
death by 66% (equal to a hazard ratio of 0.34; p-value <0.0001)
and improved rPFS to a median of 7.4 months versus 3.6 months with
enzalutamide or abiraterone.
Lynparza also showed an
rPFS benefit in the overall HRR gene-mutated trial population, a
key secondary endpoint, and reduced the risk of disease progression
or death by 51% (equal to a hazard ratio of 0.49; p-value
<0.0001) and improved rPFS to a median of 5.8 months versus 3.5
months with enzalutamide or abiraterone.
Additional results from the PROfound trial announced
on 24 April
2020 demonstrated a
statistically significant and clinically meaningful improvement in
the key secondary endpoint of overall survival (OS)
with Lynparza versus enzalutamide or abiraterone in
men with mCRPC and BRCA1/2 or ATM gene mutations. Results
showed Lynparza reduced the risk of death by 31% (equal
to a hazard ratio of 0.69; p-value=0.0175) and improved OS to a
median of 19.0 months versus 14.6 months with enzalutamide or
abiraterone.
The full indication is for the treatment of adult patients with
deleterious or suspected deleterious germline or somatic HRR
gene-mutated mCRPC who have progressed following prior treatment
with enzalutamide or abiraterone. Patients are to be selected for
treatment based on an FDA-approved companion diagnostic test
for Lynparza.
Lynparza is currently
under regulatory review in the EU and other jurisdictions as a
treatment for men with HRR gene-mutated mCRPC.
AstraZeneca and MSD are testing Lynparza in additional trials in metastatic prostate
cancer including the ongoing Phase III PROpel trial as a 1st-line
treatment in combination with abiraterone acetate for patients with
mCRPC versus abiraterone acetate alone.
Financial considerations
Following this approval for Lynparza in the US, AstraZeneca will receive a
regulatory milestone payment from MSD of $35m, anticipated to be
booked as Collaboration Revenue by the Company during the second
quarter of 2020.
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
HRR gene mutations
HRR gene mutations occur in approximately 20-30% of patients with
mCRPC.4, HRR
genes allow for accurate repair of damaged DNA in normal
cells.5,6 HRR
deficiency (HRD) interferes with normal cell DNA repair mechanisms
and can result in normal cell death.6 This
is different in cancer cells, where a mutation in HRR pathways
leads to abnormal cell growth and therefore
cancer.6 The
inability to properly repair DNA damage leads to genomic
instability and contributes to cancer aetiology.6 HRD
is a well-documented target for PARP inhibitors, such
as Lynparza. PARP inhibitors block a rescue DNA damage repair
mechanism by trapping 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.6
PROfound
PROfound
is a prospective, multicentre, randomised, open-label, Phase III
trial testing the efficacy and safety of Lynparza versus enzalutamide or
abiraterone in patients with mCRPC who have progressed on prior
treatment with enzalutamide or abiraterone and have a qualifying
tumour mutation in BRCA1/2, ATM or one of 12 other genes involved
in the HRR pathway.
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).
In the
US, patients are selected for treatment with Lynparza based on the following
FDA-approved companion diagnostics:
●
FoundationOne CDX: to identify patients
with HRR-gene alterations in prostate tumour tissue. FoundationOne
is a registered trademark of Foundation Medicine, Inc.
●
BRACAnalysis CDX: a germline test to
identify patients with BRCA1 and BRCA2 gene mutations. Myriad
Genetics, Inc. owns and commercialises BRACAnalysis
CDX.
Lynparza
Lynparza 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, a kinase 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 of
new 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 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 & Metabolism, and Respiratory
& 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 and
follow the Company on Twitter @AstraZeneca.
Contacts
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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 [Accessed:
November 2019].
3.
Kirby, M., 2011. Characterising the
castration-resistant prostate cancer population: a systematic
review. International Journal of
Clinical Practice, 65(11), pp.1180-1192.
4.
Mateo, J, et al (2015). DNA-repair defects and
olaparib in metastatic prostate cancer. New England Journal of Medicine,
373(18), pp.1697 - 1708.
5.
Li et al. (2008). Homologous recombination in DNA repair and DNA
damage tolerance. Cell
Research, 18(1), pp.99-113.
6.
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 May 2020
|
By: /s/
Adrian Kemp
|
|
Name:
Adrian Kemp
|
|
Title:
Company Secretary
|