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 December 2022
Commission File
Number: 001-11960
AstraZeneca
PLC
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Biomedical Campus
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United
Kingdom
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AstraZeneca
PLC
INDEX
TO EXHIBITS
1. Lynparza approved in EU for prostate cancer
21
December 2022 07:05 GMT
Lynparza in
combination with abiraterone approved in the EU as 1st-line
treatment for
patients with metastatic castration-resistant prostate
cancer
First approved PARP inhibitor to demonstrate clinically meaningful
benefits in combination with
a new hormonal agent
Lynparza in combination with abiraterone extended median
radiographic progression free
survival benefit beyond two years in this setting
AstraZeneca and MSD's Lynparza (olaparib) in combination with abiraterone
and prednisone or prednisolone has been approved in the European
Union for the treatment of metastatic castration-resistant
prostate cancer (mCRPC) in adult men for whom chemotherapy is
not clinically indicated.
This approval by the European Commission was based
on results from the PROpel
Phase III trial and follows
the positive recommendation in
the EU by the Committee for Medicinal Products for Human Use in
November 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 and prednisone or prednisolone
(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. Furthermore, a planned rPFS analysis by blinded
independent central review (BICR) showed Lynparza plus abiraterone had a median rPFS of 27.6
months compared to 16.4 months with abiraterone alone, extending
median rPFS by almost one year.
Updated results from a second planned analysis
presented at ESMO 2022 showed a favourable trend towards improved
overall survival with Lynparza plus abiraterone versus abiraterone alone
(based on HR of 0.83; 95% CI 0.66-1.03; p=0.11), 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 the
real-world.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, a senior investigator of the PROpel trial, said: "The
results of the PROpel Phase III trial of olaparib in combination
with abiraterone as a first-line treatment show that this
therapeutic combination can provide significant clinical benefit to
patients with metastatic castration-resistant prostate
cancer. Patients with this condition in the EU will now, for
the first time, have the opportunity to benefit from this new
treatment combination."
Dave Fredrickson, Executive Vice President,
Oncology Business Unit, AstraZeneca, said: "Many patients with
metastatic castration-resistant prostate cancer are only able to
receive one line of active therapy, as the disease can progress
quickly. Lynparza in combination with abiraterone has been
shown to reduce the risk of disease progression by 34% versus the
standard of care treatment in the PROpel trial. Moreover, the
combination of Lynparza with abiraterone as a first-line treatment
expands the use of Lynparza to a broader group of metastatic
castration-resistant prostate cancer patients than those treated
with Lynparza alone in the second-line setting in the
PROfound trial. Today's approval marks a significant advance toward
addressing the unmet need of patients with metastatic
castration-resistant prostate cancer in the
EU."
Dr. Eliav Barr, Senior Vice President, Head of
Global Clinical Development and Chief Medical Officer, MSD Research
Laboratories, said: "MSD
is committed to developing new treatment options for patients
with metastatic
castration-resistant prostate cancer, a complex disease that
urgently needs more therapies. This approval by the European
Commission marks another step towards delivering on that commitment
and we look forward to extending the benefits
of Lynparza to more patients with metastatic
castration-resistant prostate cancer in
the EU."
The safety and tolerability
of Lynparza in combination with abiraterone in PROpel
was in line with that observed in prior clinical trials and the
known profiles of the individual medicines. There was no increase
in the rate of discontinuation of abiraterone in patients treated
with Lynparza in combination with abiraterone and no
detrimental effect on health-related quality of life versus those
treated with abiraterone alone (Functional Assessment of Cancer
Therapy-Prostate questionnaire).
In August, supplemental
New Drug Application (sNDA) for Lynparza in
combination with abiraterone and prednisone or prednisolone was
accepted and granted Priority Review in the US for the treatment of
adult patients with mCRPC. The Prescription Drug User Fee Act
(PDUFA) date is anticipated during
the first quarter of 2023.
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 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.
Financial considerations
Following this approval
for Lynparza in the EU, AstraZeneca will receive a
regulatory milestone payment from MSD of $105m, anticipated to be
booked as Collaboration Revenue by the Company during the fourth
quarter of 2022.
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.12 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.12 Of
patients with no metastases at CRPC diagnosis, 33% are likely to
develop metastases within two years.12
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.12,13,14,15
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, as well as prednisone or prednisolone, in men with
mCRPC who had not received prior chemotherapy or NHAs in the mCRPC
setting.
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
& survival in prostate cancer.16,17 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.18-20
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.16,19,21 Additionally,
it is thought that abiraterone may alter/inhibit the transcription
of some HRR genes which may induce HRR deficient phenotype, which
may increase sensitivity to PARP inhibition.18,20,22,23
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
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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. Prostate Cancer
Factsheet. 2020. Available at https://gco.iarc.fr/today/data/factsheets/cancers/27-Prostate-fact-sheet.pdf.
Accessed December 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.
George DJ, et al. Treatment Patterns and Outcomes in Patients with
Metastatic Castration-Resistant Prostate Cancer in a Real-World
Clinical Practice Setting in the United
States. Clin Genitourin
Cancer.
2020;18:284-294.
5.
de Bono J, et al. Antitumour Activity and Safety of Enzalutamide
in Patients with Metastatic Castration-Resistant Prostate Cancer
Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24
weeks in Europe. Eur Urol. 2018;74(1):37-45
6.
Hussein M, et al. Prostate-Specific Antigen Progression Predicts
Overall Survival in Patients with Metastatic Prostate Cancer: Data
from Southwest Oncology Group Trials 9346 (Intergroup Study 0162)
and 9916. J Clin
Oncol.
2009;27(15):2450.
7.
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
Dis.
2022;2660.
8.
Ryan C, et al. Abiraterone Acetate Plus Prednisone Versus
Placebo Plus Prednisone in Chemotherapy-Naive Men with Metastatic
Castration-Resistant Prostate Cancer (COU-AA-302): Final Overall
Survival Analysis of a Randomised, Double-Blind, Placebo-Controlled
Phase 3 Study. Lancet
Oncol. 2015
Feb;16(2):152-60.
9.
Miller K, et al. The Phase 3 COU-AA-302 Study of Abiraterone
Acetate Plus Prednisone in Men with Chemotherapy-Naïve Metastatic
Castration-Resistant Prostate Cancer: Stratified Analysis Based on
Pain, Prostate-Specific Antigen, and Gleason
Score. Eur Urol. 2018;74(1):17-23.
10.
Chowdhury S, et al. Real-World Outcomes in First-Line Treatment of
Metastatic Castration-Resistant Prostate Cancer: The Prostate
Cancer Registry. Target
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2020;15(3):301-315.
11.
Cancer.Net. Treatment of
metastatic castration-resistant prostate cancer. Available
at www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer. Accessed:
December 2022.
12.
Kirby M, et al. Characterising the Castration-Resistant
Prostate Cancer Population: Systematic
Review. Int J of Clin
Pract.
2021;65(11):1180-1192.
13.
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 December 2022.
14.
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. Sci Rep. 2020;10(1):4240.
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UroToday. Beyond First-line
Treatment of Metastatic Castrate-resistant Prostate Cancer.
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Accessed December 2022
16.
Schiewer MJ, et al. Dual roles of PARP-1 promote cancer growth
and progression. Cancer
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Schiewer MJ & Knudsen KE. AMPed Up To Treat
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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.
19.
Polkinghorn WR, et al. Androgen Receptor Signaling Regulates DNA
Repair in Prostate Cancers. Cancer
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20.
Asim M, et al. Synthetic Lethality Between Androgen Receptor
Signalling and the PARP Pathway in Prostate
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21.
Ju B-G, et al. A Topoisomerase IIbeta-Mediated dsDNA Break
Required for Regulated Transcription. Science. 2006;312(5781):1798-1802.
22.
Goodwin JF, et al. A Hormone-DNA Repair Circuit Governs the
Response to Genotoxic Insult. Cancer
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Tarish FL, et al. Castration Radiosensitizes Prostate Cancer
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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:
21 December 2022
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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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