a2279g
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 November 2022
Commission
File Number: 001-11960
AstraZeneca PLC
1
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Cambridge
Biomedical Campus
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United
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Lynparza combo recommended in the EU for mCRPC
14
November 2022 07:00 GMT
Lynparza in combination with
abiraterone recommended for approval
in the EU by CHMP as 1st-line treatment for
patients
with metastatic castration-resistant prostate cancer
First PARP inhibitor to demonstrate clinical benefit in combination
with a new hormonal agent in this setting
AstraZeneca
and MSD's Lynparza (olaparib) in
combination with abiraterone and prednisone or
prednisolone has been recommended for marketing
authorisation in the European Union (EU) for the treatment of adult
patients with metastatic
castration-resistant prostate cancer (mCRPC) for whom chemotherapy
is not clinically indicated.
The
Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Agency based its positive opinion on results
from the PROpel Phase III
trial which were published in NEJM
Evidence in June 2022.
In the trial, Lynparza in combination with abiraterone and
prednisone or prednisolone, reduced the risk of disease progression
or death by 34% versus abiraterone alone (based on a hazard ratio
[HR] of 0.66; 95% confidence interval [CI] 0.54-0.81; p<0.0001).
Median radiographic progression-free survival (rPFS) was 24.8
months for Lynparza plus abiraterone versus 16.6 months for
abiraterone alone. Results also showed
that Lynparza in
combination with abiraterone extended median rPFS by almost one
year, with a median rPFS of 27.6 months versus 16.4 with
abiraterone alone, as assessed by blinded independent central
review (BICR).
Updated results also showed a favourable trend in improved overall
survival with Lynparza plus abiraterone versus abiraterone alone,
however the difference did not reach statistical significance at
the time of this data cut-off (analysis at 40% data
maturity).
Prostate cancer is the most common cancer in men in Europe, with an
estimated 473,000 patients diagnosed and 108,000 deaths in
2020.1-2 Overall
survival for patients with mCRPC is approximately three years in
clinical trial settings, and even shorter in real-world
settings.3 Approximately
half of patients with mCRPC may receive only one line of active
treatment, with diminishing benefit of subsequent
therapies.4-9
Noel
Clarke, Urological Surgeon and Professor of Urological Oncology at
Manchester's Christie/Salford Royal Hospitals and Manchester
University, the PROpel trial joint senior investigator, said:
"Patients with metastatic castration-resistant prostate cancer in
the European Union have limited treatment options. This form of
advanced prostate cancer has a poor prognosis and treatment
decisions after initial diagnosis are critical. If approved in the
European Union for prostate cancer of this type, olaparib in
combination with abiraterone will provide a much-needed new
treatment option for the many men with this
condition."
Susan
Galbraith, Executive Vice President, Oncology R&D, AstraZeneca,
said: "With the incidence and mortality of prostate cancer set to
double in the coming decades, it is more important than ever that
we bring new treatment options to suitable patients at the earliest
possible moment in their care. If approved, Lynparza in combination with
abiraterone and prednisone or prednisolone will represent the first
combination of a PARP inhibitor and new hormonal agent available to
patients in the European Union."
Eliav
Barr, Senior Vice President, Head of Global Clinical Development
and Chief Medical Officer, MSD Research Laboratories,
said: "While
prostate cancer has seen many advances in care in recent decades,
for those with mCRPC, new treatment options are urgently needed. We
are fully committed to bringing Lynparza in combination with
abiraterone and prednisone or prednisolone to suitable patients in
the European Union as quickly as possible."
Lynparza in combination with abiraterone and prednisone or
prednisolone is undergoing Priority Review in the US for the
treatment of mCRPC in adult patients based on results from the
PROpel Phase III trial, with a decision expected in Q4
2022.
Lynparza is approved in the US based on results from
the PROfound Phase III
trial as monotherapy for patients with homologous
recombination repair (HRR) gene-mutated mCRPC (BRCA-mutated and
other HRR gene mutations) who have progressed following prior treatment with
enzalutamide or abiraterone; and in the EU, Japan, and China for
patients with BRCA-mutated mCRPC who have progressed following
prior therapy that included a new hormonal
agent.
Notes
Metastatic castration-resistant prostate cancer
Metastatic
prostate cancer is associated with a significant mortality
rate.10 Development of
prostate cancer is often driven by male sex hormones called
androgens, including testosterone.11
In
patients with mCRPC, their 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.5 Approximately
10-20% of men with advanced prostate cancer will develop
castration-resistant prostate cancer (CRPC) within five years, and
at least 84% of these men will have metastases at the time of CRPC
diagnosis.5 Of patients with no
metastases at CRPC diagnosis, 33% are likely to develop metastases
within two years.5
Despite
the advances in mCRPC treatment in the past decade with taxane and
new hormonal agent (NHA) treatment, there is high unmet need in
this population.5,7,8,12
PROpel
PROpel
is a randomised, double-blind, multi-centre Phase
III trial testing the efficacy, safety, and tolerability
of Lynparza versus placebo when given
in addition to abiraterone in men with mCRPC who had not received
prior chemotherapy or NHAs in the mCRPC setting.
Men in
both treatment groups also receive either prednisone or
prednisolone twice daily. The primary endpoint is rPFS and
secondary endpoints include overall survival, time to secondary
progression or death, and time to first subsequent
therapy.
In the
PROpel Phase III trial, Lynparza is combined with
abiraterone, an NHA which targets the androgen receptor (AR)
pathway.
AR
signalling engages a transcriptional programme that is critical for
tumour cell growth and survival in prostate cancer.13,14 Preclinical
models have identified interactions between PARP signalling and the
AR pathway which support the observation of a combined anti-tumour
effect of Lynparza and NHAs, like
abiraterone, in both HRR deficient and HRR proficient prostate
cancer.15-17
The
PARP1 protein has been reported to be required for the
transcriptional activity of androgen receptors; therefore,
inhibiting PARP with Lynparza may impair the expression
of androgen receptor target genes and enhance the activity of
NHAs.13,16,18 Additionally,
it is thought that abiraterone may alter/inhibit the transcription
of some HRR genes which may induce HRR deficiency and increase
sensitivity to PARP inhibition.15,17,19,20
For
more information about the trial please visit ClinicalTrials.gov.
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 HRR, such as those with mutations in BRCA1 and/or
BRCA2, or those where deficiency is induced by other agents (such
as NHAs).
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 currently approved in a number of
countries across multiple tumour types including maintenance
treatment of platinum-sensitive relapsed ovarian cancer and as both
monotherapy and in combination with bevacizumab for the 1st-line
maintenance treatment of BRCA-mutated (BRCAm) and homologous
recombination repair deficient (HRD)-positive advanced ovarian
cancer, respectively; for gBRCAm, HER2-negative metastatic breast
cancer (in the EU and Japan this includes locally advanced breast
cancer); for gBRCAm, HER2-negative high-risk early breast cancer
(in Japan this includes all BRCAm HER2-negative high-risk early
breast cancer); for gBRCAm metastatic pancreatic cancer; and HRR
gene-mutated metastatic castration-resistant prostate cancer (BRCAm
only in the EU and Japan). In
China, Lynparza is approved for the
treatment of BRCA-mutated metastatic castration-resistant prostate
cancer as well as a 1st-line maintenance therapy in BRCA-mutated
advanced ovarian cancer.
Lynparza, which is being jointly
developed and commercialised by AstraZeneca and MSD, has been used
to treat over 75,000 patients worldwide. Lynparza has a broad clinical
trial development programme, 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 mitogen-activated protein kinase (MEK) inhibitor, for
multiple cancer types.
Working together, the companies will
develop Lynparza and Koselugo and
other potential new medicines as monotherapies and as combinations.
The companies will also develop Lynparza and Koselugo in
combination with their respective PD-L1 and PD-1 medicines
independently.
AstraZeneca in oncology
AstraZeneca
is leading a revolution in oncology with the ambition to provide
cures for cancer in every form, following the science to understand
cancer and all its complexities to discover, develop and deliver
life-changing medicines to patients.
The
Company's focus is on some of the most challenging cancers. It is
through persistent innovation that AstraZeneca has built one of the
most diverse portfolios and pipelines in the industry, with the
potential to catalyse changes in the practice of medicine and
transform the patient experience.
AstraZeneca
has the vision to redefine cancer care and, one day, eliminate
cancer as a cause of death.
AstraZeneca
AstraZeneca
(LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical
company that focuses on the discovery, development, and
commercialisation of prescription medicines in Oncology, Rare
Diseases, and BioPharmaceuticals, including 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
For
details on how to contact the Investor Relations Team, please
click here. For Media
contacts, click here.
References
1.
Rawla, P. The Epidemiology of Prostate
Cancer. World J Oncol.
2019;10(2):63-89.
2. IARC Globocan. Estimated number of
incident cases and deaths Europe, both sexes, all ages (excl.
NMSC). Available at https://gco.iarc.fr/today/online-analysis-multi-bars?v=2020&mode=cancer&mode_population=countries&population=900&populations=908&key=total&sex=0&cancer=39&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&nb_items=10&group_cancer=1&include_nmsc=0&include_nmsc_other=1&type_multiple=%257B%2522inc%2522%253Atrue%252C%2522mort%2522%253Atrue%252C%2522prev%2522%253Afalse%257D&orientation=horizontal&type_sort=0&type_nb_items=%257B%2522top%2522%253Atrue%252C%2522bottom%2522%253Afalse%257D#collapse-group-0-4.
Accessed November 2022
3.
Ng K, et al.
Metastatic Hormone-Sensitive Prostate Cancer (mHSPC): Advances and
Treatment Strategies in the First-Line Setting. Oncol Ther.
2020;8:209-230.
4.
de Wit R, et
al. Real-world evidence of patients with metastatic
castration-resistant prostate cancer treated with cabazitaxel:
comparison with the randomized clinical study
CARD. Prostate Cancer
Prostatic. 2022;2660.
5. Kirby M, et al. Characterising the castration-resistant
prostate cancer population: systematic
review. International Journal of
Clinical Practice.
2021;65(11):1180-1192.
6.
Smith MR, et al.
Natural history of rising serum prostate-specific antigen in men
with castrate nonmetastatic prostate cancer. J Clin Oncol.
2005;23(13):2918-25.
7. UroToday. What is Changing in
Advanced Prostate Cancer? Available at https://www.urotoday.com/journal/everyday-urology-oncology-insights/articles/122176-what-is-changing-in-advanced-prostate-cancer.html.
Accessed November 2022.
8. Liu
J, et al. Second-line
Hormonal Therapy for the Management of Metastatic
Castration-resistant Prostate Cancer: a Real-World Data Study Using
a Claims Database. Scientific
Report. 2020;10(4240):2020.
9.
Mateo J, et al.
DNA-Repair Defects and Olaparib in Metastatic Prostate
Cancer. N Engl J
Med. 2015; 373:1697-1708.
10.
Chowdhury S, et al.
Real-world outcomes in first-line treatment of metastatic
castration-resistant prostate cancer: the prostate cancer
registry. Target
Oncol. 2020;15(3):301-315.
11. Cancer.Net. Prostate Cancer: Types of
Treatment. Available at https://www.cancer.net/cancer-types/prostate-cancer/types-treatment#:~:text=Chemotherapy%20may%20help%20those%20with,a%20set%20period%20of%20time.
Accessed November 2022.
12. UroToday. Beyond First-line Treatment of
Metastatic Castrate-resistant Prostate Cancer. Available
at https://www.urotoday.com/library-resources/mcrpc-treatment/114592-beyond-first-line-treatment-of-metastatic-castrate-resistant-prostate-cancer.html.
Accessed November 2022.
13.
Schiewer MJ, et
al. Dual roles of PARP-1 promote cancer growth and
progression. Cancer
Discov. 2012;2(12):1134-1149.
14.
Schiewer MJ & Knudsen KE. AMPed up to treat prostate cancer:
novel AMPK activators emerge for cancer therapy. EMBO Mol Med.
2014;6(4):439-441.
15. Li
L, et
al. Androgen receptor inhibitor-induced "BRCAness" and
PARP inhibition are synthetically lethal for castration-resistant
prostate cancer. Sci
Signal. 2017; 10(480):eaam7479.
16.
Polkinghorn WR, et
al. Androgen receptor signaling regulates DNA repair in
prostate cancers. Cancer
Discov. 2013;3(11):1245-1253.
17.
Asim M, et al.
Synthetic lethality between androgen receptor signalling and the
PARP pathway in prostate cancer. Nat Commun. 2017;374(8).
18. Ju
B-G, et al. A
topoisomerase IIbeta-mediated dsDNA break required for regulated
transcription. Science.
2006;312(5781):1798-1802.
19.
Goodwin JF, et al. A
hormone-DNA repair circuit governs the response to genotoxic
insult. Cancer Discov.
2013;3(11):1254-1271.
20. Tarish FL, et al. Castration radiosensitizes prostate cancer
tissue by impairing DNA double-strand break
repair. Sci Transl
Med. 2015; 7(312):312re11.
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:
14 November 2022
|
By: /s/
Adrian Kemp
|
|
Name:
Adrian Kemp
|
|
Title:
Company Secretary
|