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 2023
Commission
File Number: 001-11960
AstraZeneca PLC
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Cambridge
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AstraZeneca PLC
INDEX
TO EXHIBITS
1. ODAC vote on Lynparza combo in prostate cancer
2 May 2023
Update on FDA Advisory Committee vote
on Lynparza plus
abiraterone for metastatic castration-resistant prostate
cancer
The Food and Drug Administration's (FDA) Oncologic Drugs Advisory
Committee (ODAC) has recognised a favourable benefit risk profile
for AstraZeneca and MSD's Lynparza (olaparib) plus
abiraterone and prednisone or prednisolone for the treatment of
adult patients with BRCA-mutated (BRCAm) metastatic
castration-resistant prostate cancer (mCRPC) based on the PROpel
Phase III trial. The Committee voted 11 to 1, with 1 abstaining,
that the indication should be limited to patients whose tumours
have a BRCA mutation.
In August 2022, the FDA accepted the supplemental New Drug
Application (sNDA) for Lynparza based on positive results from the pivotal
PROpel trial, also published in NEJM
Evidence. The ODAC provides the
FDA with independent, expert advice and recommendations on marketed
and investigational medicines for use in the treatment of cancer.
The FDA is not bound by the Committee's guidance but takes its
advice into consideration. AstraZeneca and MSD will continue to
work with the FDA as it completes its review of the
application.
Neal Shore, Chief
Medical Officer of Urology and Surgical Oncology for Genesis Care,
US and PROpel trial investigator, said: "Today's recommendation by the ODAC is
disappointing news for clinicians and prostate cancer patients
alike. Preventing or delaying radiographic progression is an
important clinical endpoint in assessing oncologic treatment and is
very relevant to patients, their caregivers and their families. It
is essential that physicians and patients have an opportunity to
choose treatment with the goal of optimising cancer care
outcomes."
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca said: "Novel treatment options are urgently needed for
patients with metastatic castration-resistant prostate cancer.
While we are pleased with the recognition of the benefit
of Lynparza plus abiraterone for patients with
BRCA-mutated metastatic castration-resistant prostate cancer, we
are disappointed with the outcome of today's ODAC meeting. We
strongly believe in the results of the PROpel trial, which
demonstrated the clinically meaningful benefit for this combination
in a broad population of patients regardless of biomarker
status."
Eliav Barr, Senior Vice President, Head of Global Clinical
Development and Chief Medical Officer, MSD Research Laboratories,
said "With
the incidence and mortality of prostate cancer set to double in the
coming decades, it is critical that we bring new treatment options
with the potential to reduce the risk of disease progression or
death to patients at the earliest possible moment in their
care. While
we are pleased that the ODAC recommended Lynparza for patients with metastatic
castration-resistant prostate cancer who have BRCA mutations,
we believe
in the potential of Lynparza plus abiraterone for a broad range of
patients with metastatic castration-resistant prostate cancer,
based on the results of PROpel. We look forward to the outcome of
the FDA's review of the application."
Results from the PROpel trial showed
a statistically significant and clinically meaningful 34% reduction
in the risk of radiographic disease progression or death
with Lynparza plus abiraterone with prednisone or
prednisolone, versus abiraterone alone in patients with mCRPC
(hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.54-0.81;
p<0.001). Median radiographic progression-free survival (rPFS)
was 24.8 months and 16.6 months, respectively.1
Further results from the final prespecified overall survival (OS)
analysis presented at ASCO Genitourinary
Cancers Symposium 2023 showed Lynparza plus abiraterone and prednisone or
prednisolone demonstrated median OS of 42.1 months versus 34.7
months for abiraterone plus placebo. This result represents a
7.4-month absolute difference in median OS versus a standard of
care (47.9% maturity, HR of 0.81, 95% CI 0.67-1.00; p=0.0544).
While this numerical increase in median OS did not achieve
statistical significance, it builds on the meaningful survival
gains achieved for patients in this setting treated with
abiraterone alone, a current standard of care.
In exploratory analyses of the BRCAm
subgroup, Lynparza plus abiraterone demonstrated improvements
in both rPFS (HR of 0.23, 95% CI, 0.12-0.43) and OS (HR of 0.29,
95% CI, 0.14-0.56). In the non-BRCAm
subgroup, Lynparza plus abiraterone also showed improvements in
rPFS (HR of 0.76, 95% CI, 0.61-0.94), and a modest trend for OS (HR
of 0.91, 95% CI, 0.73-1.13).
The safety and tolerability of Lynparza plus abiraterone in PROpel was in line with
that observed in prior clinical trials and the known profiles of
the individual medicines.
Lynparza in
combination with abiraterone and prednisone or prednisolone is
approved in the EU and several other countries for the treatment of
adult patients with mCRPC based on the PROpel
trial.
Notes
Prostate cancer
Prostate cancer is the second most commonly diagnosed cancer in men
and the fifth leading cause of cancer death in men globally, with
an incidence of 1.4 million and 375,000 deaths in
2020.2-4 In
the United States, it is estimated that there will be 288,300 new
cases and 34,700 deaths in 2023.5 Overall
survival for patients with mCRPC is approximately three years in
clinical trial settings, and even shorter in the
real-world.6 Approximately
half of patients with mCRPC may receive only one line of active
treatment, and those that go on to receive further treatment often
have diminishing benefit of subsequent
therapies.7-12
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.15 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.16 Of
patients with no metastases at CRPC diagnosis, 33% are likely to
develop metastases within two years.16
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.15-18
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 combination
with 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 OS,
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.18,19 In
addition, the AR also plays a role in repairing DNA damage in
prostate cancer cells, including damage not normally repaired by
homologous recombination repair (HRR). Preclinical models have
suggested a number of potential mechanisms that could account for
increased combination efficacy in both HRR deficient and HRR
proficient prostate cancer.1,19-25 Recent
data provide evidence that PARP facilitates AR-DNA binding in the
presence of DNA damage (AZ internal data on file) and that combined
inhibition of PARP with Lynparza and AR activity with an NHA results in
enhanced DNA damage and anti-tumour activity in non-HRRm prostate
cancer models.1,21,24,26,27
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; in combination with abiraterone for the
treatment of metastatic castration-resistant prostate cancer in
whom chemotherapy is not clinically indicated (EU) and as
monotherapy in HRR gene-mutated metastatic castration-resistant
prostate cancer in patients who have progressed on prior NHA
treatment (BRCAm only in the EU and Japan). In
China, Lynparza is approved for the treatment of
BRCA-mutated metastatic castration-resistant prostate cancer, as a
1st-line maintenance therapy in BRCA-mutated advanced ovarian
cancer as well as 1st-line maintenance treatment with bevacizumab
for HRD-positive 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. Clarke N, et al. Abiraterone and Olaparib for Metastatic
Castration-Resistant Prostate Cancer. NEJM Evid. 2022;1(9).
2. Clarke N, et al. Final Overall Survival (OS) in PROpel:
Abiraterone (abi) and Olaparib (ola) Versus Abiraterone and Placebo
(pbo) as First-Line (1L) Therapy For Metastatic
Castration-Resistant Prostate Cancer (mCRPC). Presented at ASCO
Genitourinary Cancers Symposium. California, USA. 16 January
2023.
3. Cancer.Net.
Prostate Cancer: Statistics. Available at https://www.cancer.net/cancer-types/prostate-cancer/statistics.
Accessed March 2023.
4. Rawla
P. Epidemiology of Prostate Cancer. World J
Oncol. 2019;
10(2):63-89.
5. Sung
H, et
al. Global Cancer Statistics
2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for
36 Cancers in 185 Countries. CA Cancer J
Clin. 2021;
71(3):209-249.
6. Cancer.Org.
Key Statistics For Prostate Cancer. Available
at https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html. Accessed
March 2023.
7. 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.
8. 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.
9. 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
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. Cancer.Net. Treatment
of Metastatic Castration-Resistant Prostate
Cancer. Available
at https://www.cancer.net/cancer-types/prostate-cancer/types-treatment. Accessed
March 2023.
16. Kirby M, et al. Characterising the Castration-Resistant
Prostate Cancer Population: Systematic
Review. Int J of Clin
Pract.
2021;65(11):1180-1192.
17. 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 March 2023.
18. 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.
19. 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-resistan%20t-prostate-cancer.html.
Accessed March 2023.
20. Schiewer
MJ, et
al. Dual
roles of PARP-1 Promote Cancer Growth and
Progression. Cancer
Discov. 2012;2(12):1134-1149.
21. Asim M, et al. Synthetic Lethality Between Androgen
Receptor Signalling and the PARP Pathway in Prostate
Cancer. Nature. 2017;8:374.
22. 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.
23. Polkinghorn WR, et. Androgen Receptor Signalling Regulates DNA
Repair in Prostate Cancers. Cancer
Discov. 2013;
3(11):1245-1253.
24. Clarke N, et al. Olaparib Combined with Abiraterone in Patients
with Metastatic Castration-Resistant Prostate Cancer: A Randomised,
Double-Blind, Placebo-Controlled, Phase 2
Trial. Lancet
Oncol.
2018;19(7):975-986.
25. Pommier Y, et al. Laying a Trap to Kill Cancer Cells: PARP
Inhibitors and Their Mechanisms of Action. Sci Transl
Med. 2016;8(362):362ps17.
26. 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.
27. Gui
B, et
al. Selective
Targeting of PARP-2 Inhibits Androgen Receptor Signaling and
Prostate Cancer Growth Through Disruption of FOXA1
Function. Proc Natl
Acad Sci U S A. 2019 Jul 16; 116(29):
14573-14582.
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:
02 May 2023
|
|
By: /s/
Adrian Kemp
|
|
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Name:
Adrian Kemp
|
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Title:
Company Secretary
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