a6586b
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 February
2022
Commission
File Number: 001-11960
AstraZeneca PLC
1
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Lynparza combo delays progression risk in prostate
15 February 2022 07:00 GMT
Lynparza plus
abiraterone reduced risk of disease progression by 34% vs.
standard-of-care in 1st-line metastatic castration-resistant
prostate cancer
Combination was well tolerated and allowed patients to maintain
their quality of life vs. patients treated with abiraterone
alone
PROpel Phase III trial results show clinically meaningful benefit
in patients irrespective of homologous recombination repair gene
mutations
Positive results from the PROpel Phase III trial showed AstraZeneca
and MSD's Lynparza (olaparib) in combination with abiraterone
demonstrated a statistically significant and clinically meaningful
improvement in radiographic progression-free survival (rPFS) versus
current standard-of-care abiraterone as a 1st-line treatment for
patients with metastatic castration-resistant prostate cancer
(mCRPC) with or without homologous recombination repair (HRR) gene
mutations.
These results will be presented on 17 February at the
2022 American Society of Clinical Oncology (ASCO)
Genitourinary Cancers Symposium.
Prostate cancer is the second most common cancer in male patients,
causing approximately 375,000 deaths in
2020.1 Patients with
advanced prostate cancer have a particularly poor prognosis and the
five-year survival rate remains low.1,2,3 Approximately
half of patients with mCRPC receive only one line of active
treatment, with diminishing benefit of subsequent
therapies.4,5,6,7 HRR
gene mutations occur in approximately 20-30% of patients with
mCRPC.8
Fred Saad, Professor and Chairman of Urology and Director of
Genitourinary Oncology at the University of Montreal Hospital
Center and principal investigator in the trial, said: "It is clear
to me that the prognosis for metastatic castration resistant
prostate cancer (mCRPC) is extremely poor, and many patients are
only able to receive one line of effective
therapy. The results of
the PROpel trial, which showed that olaparib in combination with
abiraterone significantly delayed disease progression versus
abiraterone by more than eight months, demonstrate the potential
for this combination to become a new standard of care option in
mCRPC if approved."
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: "This Lynparza combination has the potential to afford
first-line patients more time without disease progression while
also maintaining their quality of life. The PROpel results are
impressive because active comparator trials set a high bar and, in
this trial, Lynparza plus abiraterone showed a significant
clinical improvement when compared to an active standard of care in
patients with metastatic castration-resistant prostate cancer,
regardless of whether they have an HRR gene
mutation."
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, MSD Research Laboratories,
said: "Results from the PROpel trial showed
that Lynparza in combination with abiraterone plus
prednisone reduced the risk of disease progression or death by a
third compared to abiraterone plus prednisone in the first-line
setting for patients with metastatic castration-resistant prostate
cancer, regardless of their biomarker status. We look forward to
discussing these important results with global health authorities
as quickly as possible. We thank the patients, caregivers and
health care providers for participating in this
study."
In a predefined interim analysis, 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 rPFS was
24.8 months for Lynparza plus abiraterone versus 16.6 for abiraterone
alone.
Results also showed a favourable trend towards improved overall
survival (OS) 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 29% data maturity). The
trial will continue to assess OS as a key secondary
endpoint.
Additional data from efficacy endpoints such as time to first
subsequent therapy (TFST), second progression-free survival (PFS2),
objective response rate (ORR), as well as prostate-specific antigen
levels and circulating-tumour-cell counts
further support the treatment benefit of Lynparza and abiraterone compared to abiraterone
alone in the overall trial population.
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. 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 (FACT-P (Functional Assessment of
Cancer Therapy-Prostate) questionnaire).
Summary of PROpel results
|
Lynparza +
abiraterone
(n=399)
|
Placebo + abiraterone
(n=397)
|
rPFS by Investigator 1
|
|
Number
of patients with events (%)
|
168
(42)
|
226
(57)
|
Median
PFS (in months)
|
24.8
|
16.6
|
HR (95%
CI)
p-value
|
0.66
(0.54, 0.81)
<0.0001
|
rPFS by BICR2
|
Number
of patients with events (%)
|
157
(39)
|
218
(55)
|
Median
PFS (in months)
|
27.6
|
16.4
|
HR (95%
CI)
p-value5
|
0.61
(0.49, 0.74)
<0.0001
|
OS3
|
Number
of patients with events (%)
|
107
(27)
|
121
(30)
|
Median
OS (in months)
|
NC4
|
NC
|
HR (95%
CI)
p-value
|
0.86
(0.66, 1.12)
0.2923
|
PFS2
|
Number
of patients with events (%)
|
70
(18)
|
94
(24)
|
Median
(in months)
|
NC
|
NC
|
HR (95%
CI)
p-value5
|
0.69
(0.51, 0.94)
0.0184
|
TFST
|
Number
of patients with events (%)
|
183
(46)
|
221
(56)
|
Median
(95% CI) (in months)
|
25.0
(22.2, NC)
|
19.9
(17.1, 22.0)
|
HR (95%
CI)
p-value5
|
0.74
(0.61, 0.90)
0.0040
|
Objective Response Rate
|
Number
of evaluable patients6
|
161
|
160
|
Number
of patients with responses (%)
|
94
(58)
|
77
(48)
|
Odds
ratio (95% CI)
|
1.60
(1.02, 2.53)
|
p-value5
|
0.0409
|
rPFS by HRR gene mutation status7
|
HRRm
|
Number
of patients randomized
|
111
|
115
|
Number
of patients with events (%)
|
43
(39)
|
73
(63)
|
Median
(in months)
|
NC
|
13.9
|
HR (95%
CI)
|
0.50
(0.34, 0.73)
|
Non-HRRm
|
Number
of patients randomized
|
279
|
273
|
Number
of patients with events (%)
|
119
(43)
|
149
(55)
|
Median
(95% CI) (in months)
|
24.1
(19.6, 27.6)
|
19.0 (14.3,
21.9)
|
HR (95%
CI)
|
0.76
(0.60, 0.97)
|
1.
Investigator-assessed
PFS data; Interim analysis with 50% maturity (394 events in 796
patients)
2.
Assessed
by blinded independent central review (BICR)
3.
OS
analysis was done at 29% maturity (228 events in 796 patients) and
boundary for significance 0.001 (2-sided); statistical significance
not reached. Survival follow up continues and further analyses were
planned.
6.
Patients
with measurable disease at baseline as per RECIST 1.1 criteria,
investigator assessment.
7.
Exploratory
subgroup analysis by HRR status. The HRRm status of patients in
PROpel was determined retrospectively using results from tumour
tissue and plasma ctDNA HRRm tests. Patients were classified as
HRRm if (one or more) HRR gene mutation was detected by either
test; patients were classified as non-HRRm if no HRR gene mutation
was detected by either test; 18 patients did not have a valid HRR
testing result from either a tumour tissue or ctDNA test and were
excluded from this subgroup analysis. The analysis was performed
using a Cox proportional hazards model including terms for
treatment group, the subgroup factor, and a treatment by subgroup
interaction.
The most common adverse events (AEs) (greater than or equal to 20%
of patients) were anaemia (45%), nausea (28%) and fatigue (28%).
Grade 3 or higher AEs were anaemia (15%), hypertension (4%),
urinary tract infection (2%), fatigue (1%), decreased appetite
(1%), vomiting (1%), asthenia (1%), back pain (1%), diarrhoea (1%).
Approximately 86% of patients treated with Lynparza in
combination with abiraterone who experienced AEs remained on
treatment at the time of data cut-off.
In September
2021 at a planned interim
analysis, the Independent Data Monitoring Committee concluded
that the PROpel trial met the primary endpoint of
rPFS.
Lynparza is approved in
the US for patients with HRR gene-mutated mCRPC (BRCA-mutated and
other HRR gene mutations); and in the EU, Japan and China for
patients with BRCA-mutated mCRPC.
Notes
Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant
mortality rate.3 Development
of prostate cancer is often driven by male sex hormones called
androgens, including testosterone.9
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.10 Approximately
10-20% of patients with advanced prostate cancer will develop
castration-resistant prostate cancer (CRPC) within five years, and
at least 84% of these patients will have metastases at the time of
CRPC diagnosis.10
Of patients with no metastases at CRPC diagnosis, 33% are likely to
develop metastases within two years.11 Despite
the advances in mCRPC treatment in the past decade with taxane
and new hormonal agent (NHA) treatment, once patients failed
first line therapy, the treatment effect of second line anti-cancer
therapy diminished significantly hence there is high unmet medical
need in this population.10,12,13,14
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 1st-line setting.
Men in both treatment groups will also receive either prednisone or
prednisolone twice daily. The primary endpoint is rPFS and
secondary endpoints include OS, PFS2, and TFST.
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 proteins 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.15,16 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.17,18,19
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.15,18,20 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.17,19,21,22
Lynparza is currently
approved in a number of countries across PARP-dependent tumour
types with defects and dependencies in the DDR pathway. It is
approved for the maintenance treatment of platinum-sensitive
relapsed ovarian cancer as a monotherapy and in combination with
bevacizumab for the 1st-line maintenance treatment of BRCA-mutated
(BRCAm) and homologous recombination deficiency (HRD) positive
advanced ovarian cancer, respectively.
Lynparza is also approved
for BRCAm, HER2-negative metastatic breast cancer (in the EU this
includes locally advanced breast cancer); for germline BRCAm
metastatic pancreatic cancer, and for 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 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
(olaparib), 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 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 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 astrazenca.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.
IARC. Cancer Today - Estimated
number of new cases in 2020, worldwide, both sexes, all ages.
Available at https://gco.iarc.fr/today/home.
Accessed January 2022.
2.
Moreira D, et al. Predicting Time From Metastasis to Overall
Survival in Castration-Resistant Prostate Cancer: Results From
SEARCH. Clin Genitourin
Cancer.
2017;15(1):60-66.e2.
3.
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.
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(4):284-294.
5.
de Bono JS, et al. Subsequent Chemotherapy and Treatment
Patterns After Abiraterone Acetate in Patients with Metastatic
Castration-resistant Prostate Cancer: Post Hoc Analysis of
COU-AA-302. Eur Urol. 2017;71(4):656-664.
6.
Ryan CJ, 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;16(2):152-160.
7.
Beer TM, et
al. Enzalutamide
in Men with Chemotherapy-naïve Metastatic Castration-resistant
Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL
Study. Eur
Urol.
2017;71(2):151-154
8.
Mateo, J, et al (2015). DNA-repair defects and
olaparib in metastatic prostate cancer. The New England Journal of
Medicine, 373(18), pp.1697 -
1708.
9.
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
January 2022.
10.
Kirby, M, et al. Characterising the castration-resistant prostate
cancer population: a systematic review. International Journal of
Clinical Practice,
2021;65(11):1180-1192.
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Smith MR, et al. Natural history of rising serum
prostate-specific antigen in men with castrate nonmetastatic
prostate cancer. J Clin
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2005;23(13):2918-25.
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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
January 2022.
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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
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2020;10(4240):2020.
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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 January 2022.
15.
Schiewer MJ, et al. Dual roles of PARP-1 promote cancer growth
and progression. Cancer
Discov. 2012;2(12):1134-1149.
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Schiewer MJ & Knudsen KE. AMPed up to treat
prostate cancer: novel AMPK activators emerge for cancer
therapy. EMBO Mol
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Li L, et
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inhibitor-induced "BRCAness" and PARP inhibition are synthetically
lethal for castration-resistant prostate
cancer. Sci
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Polkinghorn WR, et al. Androgen receptor signaling regulates DNA
repair in prostate cancers. Cancer
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19.
Asim M, et al. Synthetic lethality between androgen receptor
signalling and the PARP pathway in prostate
cancer. Nat Commun. 2017;374(8).
20.
Ju B-G, et al. A topoisomerase IIbeta-mediated dsDNA break
required for regulated transcription. Science. 2006;312(5781):1798-1802.
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Goodwin JF, et al. A hormone-DNA repair circuit governs the
response to genotoxic insult. 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:
15 February
2022
|
By: /s/
Adrian Kemp
|
|
Name:
Adrian Kemp
|
|
Title:
Company Secretary
|