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 August 2022
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.
Lynparza granted FDA priority review for PROpel
16 August 2022 07:00 BST
Lynparza in
combination with abiraterone granted Priority Review
in
the US for patients with metastatic castration-resistant prostate
cancer
First PARP inhibitor to demonstrate clinical benefit in combination
with a new hormonal agent irrespective of homologous recombination
repair (HRR) gene mutations
AstraZeneca's supplemental New Drug Application (sNDA)
for Lynparza (olaparib) in combination with abiraterone
and prednisone or prednisolone has been accepted and granted
Priority Review in the US for the treatment of adult patients with
metastatic castration-resistant prostate cancer
(mCRPC).
Lynparza is
being jointly developed and commercialised by AstraZeneca and
MSD.
The Food and Drug Administration (FDA) grants Priority Review to
applications for medicines that offer significant advantages over
available options by demonstrating safety or efficacy improvements,
preventing serious conditions, or enhancing patient
compliance.1 The
Prescription Drug User Fee Act date, the FDA action date for their
regulatory decision, is anticipated during the fourth quarter of
2022.
In the US, prostate cancer is the second most common cancer in male
patients and is projected to cause approximately 35,000 deaths in
2022.2 Overall
survival for patients with mCRPC is approximately three years in
clinical trial settings, and even shorter in the real
world.3-6 Approximately
half of patients with mCRPC may receive only one line of active
treatment, with diminishing benefit of subsequent
therapies.6-11
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: "There remains a critical unmet need among
patients diagnosed with metastatic
castration-resistant prostate cancer, where the prognosis remains
poor and treatment options are limited. Today's news is another
step towards bringing forward a
new, much-needed treatment option in this setting. If
approved, Lynparza with abiraterone will become the first
combination of a PARP inhibitor and a new hormonal agent for
patients with this disease."
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. We
look forward to working with the FDA towards the goal of bringing a
new option to patients with mCRPC with or without HRR gene
mutations."
The sNDA was based on results from the PROpel Phase III
trial presented at
the 2022 American Society of Clinical Oncology (ASCO) Genitourinary
Cancers Symposium and later published in NEJM
Evidence.
These results showed Lynparza in combination with abiraterone 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 for abiraterone
alone. The safety and tolerability of Lynparza in combination with abiraterone was in line
with that observed in prior clinical trials and the known profiles
of the individual medicines.12
Lynparza is
approved in the US for patients with 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 (NHA). These approvals were based on
the data from the PROfound Phase III trial.
Notes
Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant
mortality rate.13 Development
of prostate cancer is often driven by male sex hormones called
androgens, including testosterone.14
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.7 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.7 Of
patients with no metastases at CRPC diagnosis, 33% are likely to
develop metastases within two years.6
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.7,9,10,15
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 in men with mCRPC who had not received prior
chemotherapy or NHAs in the mCRPC setting.
Men in both treatment groups will 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.
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. In the PROpel Phase III trial, Lynparza is
combined with abiraterone, an NHA which targets the androgen
receptor (AR) pathway.
Androgen receptor 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 deficiency and increase
sensitivity to PARP inhibition.18,20,22,23
Lynparza is
currently approved in a number of countries across PARP-dependent
tumour types with defects and dependencies in the DDR pathway
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 germline
BRCAm (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; for gBRCAm
metastatic pancreatic cancer; and HRR gene-mutated metastatic
castration-resistant prostate cancer (BRCAm only in the EU and
Japan).
Lynparza, which is being
jointly developed and commercialised by AstraZeneca and MSD, is the
foundation of AstraZeneca's industry-leading portfolio of potential
new medicines.
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. 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. US Food and Drug Administration.
Priority Review. Available at: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review.
Accessed August 2022.
2. Cancer.org.
Key Statistics for Prostate Cancer. Available at
https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html.
Accessed August 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. Shore N, et al. Real-World Treatment Patterns and Overall
Survival of Patients with Metastatic Castration-Resistant Prostate
Cancer in the US Prior to PARP Inhibitors. Adv Ther. 2021;38:4520-4540.
5. Wallis C, et al. Real-World Use of Androgen-Deprivation Therapy:
Intensification Among Older Canadian Men With de Novo Metastatic
Prostate Cancer. JNCI Cancer
Spectrum. 2021;5(6):pkab082.
6. George D, 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. Clinical Genitourinary
Cancer. 2020
Aug;18(4):284-294.
7. Kirby, M, et al. Characterising the castration-resistant prostate
cancer population: a systematic review. International Journal of
Clinical Practice,
2021;65(11):1180-1192.
8. 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.
9. 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 August 2022.
10. 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.
11. Mateo J, et al. DNA-Repair Defects and
Olaparib in Metastatic Prostate Cancer. N Engl J
Med. 2015;
373:1697-1708.
12. Clarke N, et al. Abiraterone and Olaparib for Metastatic
Castration-Resistant Prostate Cancer. NEJM. 2022;1(7)
13. 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):301-15.
14. 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 August 2022.
15. 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 August 2022.
16. Schiewer MJ, et al. Dual roles of PARP-1 promote cancer growth
and progression. Cancer
Discov. 2012;2(12):1134-1149.
17. 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.
18. 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
Discov. 2013;3(11):1245-1253.
20. Asim M, et al. Synthetic lethality between androgen receptor
signalling and the PARP pathway in prostate
cancer. Nat Commun. 2017;374(8).
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
Discov.
2013;3(11):1254-1271.
23. 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:
16 August 2022
|
By: /s/
Adrian Kemp
|
|
Name:
Adrian Kemp
|
|
Title:
Company Secretary
|
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