TIDMAZN
RNS Number : 8046A
AstraZeneca PLC
04 June 2021
3 June 2021 22:00 BST
Lynparza reduced the risk of cancer recurrence by 42% in the
adjuvant treatment of patients with germline BRCA-mutated high-risk
early breast cancer in OlympiA Phase III trial
First medicine targeting BRCA mutations to show clinical benefit
in adjuvant setting
Results from the OlympiA Phase III trial showed AstraZeneca and
MSD's Lynparza (olaparib) demonstrated a statistically significant
and clinically meaningful improvement in invasive disease-free
survival (iDFS) versus placebo in the adjuvant treatment of
patients with germline BRCA-mutated (gBRCAm) high-risk human
epidermal growth factor receptor 2 (HER2)-negative early breast
cancer.
The results will be presented during the plenary session of the
2021 American Society of Clinical Oncology (ASCO) Annual Meeting on
6 June 2021 (abstract LBA#1) and were published today in The New
England Journal of Medicine.
An estimated 2.3 million people were diagnosed with breast
cancer worldwide in 2020 and BRCA mutations are found in
approximately 5% of breast cancer patients.(1,2)
Sue Friedman, Executive Director, Facing Our Risk of Cancer
Empowered (FORCE) and member of the OlympiA trial steering
committee, said: "While there have been great strides in the early
treatment of breast cancer, the fear of cancer returning is still
at the forefront of patients' minds. New targeted treatment
approaches are needed in the adjuvant setting that can help keep
cancer and that fear at bay."
Andrew Tutt, chair of the OlympiA trial steering committee and
professor of Oncology at The Institute of Cancer Research, London
and Kings College London, said: "We are thrilled that our global
academic and industry partnership in OlympiA has been able to help
identify a possible new treatment option for patients with
early-stage breast cancer and who have inherited mutations in their
BRCA1 or BRCA2 genes. Patients with early-stage breast cancer who
have inherited BRCA mutations are typically diagnosed at a younger
age compared to those without such a mutation. Olaparib has the
potential to be used as a follow-on to all the standard initial
breast cancer treatments to reduce the rate of life-threatening
recurrence and cancer spread for many patients identified through
genetic testing to have mutations in these genes."
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, said: "This is the first time that any medicine targeting a
BRCA mutation has demonstrated the potential to change the course
of early-stage breast cancer and offer hope for a cure. By
providing a treatment which significantly reduces the risk of
breast cancer returning in these high-risk patients, we hope
Lynparza will set a new benchmark demonstrating sustained clinical
benefit. We are working with regulatory authorities to bring
Lynparza to these patients as quickly as possible."
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, MSD Research Laboratories,
said: "Results of the OlympiA trial represent a potential step
forward for patients with high-risk early breast cancer. These new
data support the importance of testing at diagnosis for BRCA1/2
mutations, which are actionable biomarkers that can help identify
patients with early breast cancer who may be eligible for adjuvant
treatment with Lynparza. Testing for BRCA mutations in addition to
hormone receptor status and the expression of the HER2 protein will
allow clinicians to better inform potential treatment plans for
their patients."
In the overall trial population of patients who had completed
local treatment and standard neoadjuvant or adjuvant chemotherapy,
results showed Lynparza reduced the risk of invasive breast cancer
recurrences, second cancers or death by 42% (based on a hazard
ratio [HR] of 0.58; 99.5% confidence interval [CI] 0.41-0.82;
p<0.0001). At three years, 85.9% of patients treated with
Lynparza remained alive and free of invasive breast cancer and
second cancers versus 77.1% on placebo.
Lynparza also demonstrated a statistically significant and
clinically meaningful improvement in the key secondary endpoint of
distant disease-free survival (DDFS) in the overall trial
population. Lynparza reduced the risk of distant disease recurrence
or death by 43% (based on an HR of 0.57; 99.5% CI 0.39-0.83;
p<0.0001). At the time of this initial data cut-off, fewer
deaths had occurred in patients receiving Lynparza, but the
difference in overall survival (OS) did not reach statistical
significance. The trial will continue to assess OS as a secondary
endpoint.
In February 2021 , the Independent Data Monitoring Committee
recommended for the OlympiA trial to move to early primary analysis
and reporting. Based on the planned interim analysis, the IDMC
concluded that the trial crossed the superiority boundary for its
primary endpoint of iDFS and demonstrated a sustainable and
clinically relevant treatment effect for Lynparza versus
placebo.
Summary of OlympiA results
Lynparza Placebo
(n=921) (n=915)
iDFS (primary endpoint)
--------------------
HR (99.5% CI) 0.58 (0.41, 0.82)
--------------------
p-value p<0.0001
--------------------
iDFS rates
--------------------
One year 93.3% 88.4%
--------- ---------
Two years 89.2% 81.5%
--------- ---------
Three years 85.9% 77.1%
--------- ---------
DDFS (secondary endpoint)
HR (99.5% CI) 0.57 (0.39, 0.83)
--------------------
p-value p<0.0001
--------------------
DDFS rates
--------------------
One year 94.3% 90.2%
--------- ---------
Two years 90.0% 83.9%
--------- ---------
Three years 87.5% 80.4%
--------- ---------
OS at interim (secondary endpoint) (ii)
HR (99% CI) 0.68 (0.44, 1.05)
--------------------
p-value p=0.024
--------------------
OS rates
--------------------
One year 98.1% 96.9%
--------- ---------
Two years 94.8% 92.3%
--------- ---------
Three years 92.0% 88.3%
--------- ---------
i The data cut-off date for the interim analysis was 27 March
2020.
ii Statistical significance not reached based on the interim
analysis plan for alpha conservation for future survival
analyses.
The safety and tolerability profile of Lynparza in this trial
was in line with that observed in prior clinical trials. The most
common adverse events (AEs) were nausea (57%), fatigue (40%),
anaemia (23%) and vomiting (23%). Grade 3 or higher AEs were
anaemia (9%), neutropenia (5%), leukopenia (3%), fatigue (2%), and
nausea (1%). Approximately 10% of patients treated with Lynparza
discontinued treatment early due to AEs.
OlympiA is a global collaborative Phase III trial coordinated by
the Breast International Group (BIG) worldwide, in partnership with
NRG Oncology, the US National Cancer Institute (NCI), Frontier
Science & Technology Research Foundation (FSTRF), AstraZeneca
and MSD.(3) The trial is sponsored by NRG Oncology in the US and by
AstraZeneca outside the US.
Lynparza is approved in the US, Japan, and a number of other
countries for gBRCAm, HER2-negative, metastatic breast cancer
previously treated with chemotherapy; in the EU, this includes
locally advanced breast cancer.
Early breast cancer
Breast cancer is the most common cancer among women worldwide
and an estimated 70% of all breast cancer is diagnosed at an early
stage.(4,5) Breast cancer is one of the most biologically diverse
tumour types with various factors underlying its development and
progression.(6) The discovery of biomarkers in the development of
breast cancer has greatly impacted scientific understanding of the
disease and treatment of patients who develop the disease.(7)
OlympiA
OlympiA is a Phase III, double-blind, placebo-controlled,
multicentre trial testing the efficacy and safety of Lynparza
tablets versus placebo as adjuvant treatment in patients with
gBRCAm, high-risk, HER2-negative early breast cancer, who have
completed definitive local treatment and neoadjuvant or adjuvant
chemotherapy. The primary endpoint of the trial is iDFS defined as
time from randomisation to date of first loco-regional or distant
recurrence, new cancer or death from any cause. Key secondary
endpoints include OS and DDFS, which is defined as time from
randomisation until documented evidence of first distant recurrence
of breast cancer or death without distant recurrence.(3)
BIG
The Breast International Group (BIG) is an international
not-for-profit organisation for academic breast cancer research
groups from around the world, based in Brussels, Belgium.
Founded by leading European opinion leaders in 1999, the
organisation aims to address fragmentation in breast cancer
research and now represents a network of over 50 like-minded
research groups affiliated with specialised hospitals, research
centres and leading experts across approximately 70 countries on
six continents.
BIG's research is supported in part by its philanthropy unit,
known as BIG against breast cancer, which is used to interact with
the general public and donors, and to raise funds for BIG's purely
academic breast cancer trials and research programmes.
FSTRF
Frontier Science & Technology Research Foundation (FSTRF) is
a non-profit, research organisation which supports research
networks, pharmaceutical companies and investigators to conduct
scientifically meaningful high-quality clinical trials. The OlympiA
trial involved research staff in the US and in the Affiliate office
in Scotland.
FSTRF works with scientists and technicians in more than 800
laboratories, universities and medical centres around the world to
provide a comprehensive range of research services throughout the
clinical trial process including design, analysis and
reporting.
Through its work, FSTRF aims to advance the application of
statistical science and practice and data management techniques in
science, healthcare and education.
NRG Oncology
NRG Oncology is a network group funded by the US National Cancer
Institute (NCI), a part of the National Institutes of Health. NRG
Oncology brings together the National Surgical Adjuvant Breast and
Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG),
and the Gynecologic Oncology Group (GOG), with the mission to
improve the lives of cancer patients by conducting
practice-changing multi-institutional clinical and translational
research. NRG Oncology sponsored OlympiA in the US and collaborated
with the other adult cancer clinical trials research groups funded
by the NCI, Alliance, ECOG/ACRIN and the Southwest Oncology Group.
The NCI and AstraZeneca are collaborating under a Cooperative
Research and Development Agreement between the parties.
BRCA1 and BRCA2
BRCA1 and BRCA2 are human genes that produce proteins
responsible for repairing damaged DNA and play an important role
maintaining the genetic stability of cells. When either of these
genes is mutated or altered such that its protein product either is
not made or does not function correctly, DNA damage may not be
repaired properly, and cells become unstable. As a result, cells
are more likely to develop additional genetic alterations that can
lead to cancer and confer sensitivity to PARP inhibitors including
Lynparza.(8-11)
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 homologous recombination
repair (HRR), such as mutations in BRCA1 and/or BRCA2. 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 being tested in a range of PARP-dependent tumour
types with defects and dependencies in the DDR pathway.
Lynparza is currently approved in a number of countries,
including those in the EU, for the maintenance treatment of
platinum-sensitive relapsed ovarian cancer. It is approved in the
US, the EU, Japan, China, and several other countries as 1st-line
maintenance treatment of BRCA-mutated advanced ovarian cancer
following response to platinum-based chemotherapy. It is also
approved in the US, EU and Japan as a 1st-line maintenance
treatment with bevacizumab for patients with HRD-positive advanced
ovarian cancer (BRCAm and/or genomic instability). Lynparza is
approved in the US, Japan, and a number of other countries for
germline BRCA-mutated, HER2-negative, metastatic breast cancer,
previously treated with chemotherapy; in the EU, this includes
locally advanced breast cancer. It is also approved in the US, the
EU, Japan and several other countries for the treatment of germline
BRCAm metastatic pancreatic cancer. Lynparza is approved in the US
for HRR gene-mutated metastatic castration-resistant prostate
cancer (BRCAm and other HRR gene mutations) and in the EU and Japan
for BRCAm metastatic castration-resistant prostate cancer.
Regulatory reviews are underway in several countries for ovarian,
breast, pancreatic and prostate cancers.
Lynparza , which is being jointly developed and commercialised
by AstraZeneca and MSD, has been used to treat over 40,000 patients
worldwide. Lynparza has the broadest and most advanced clinical
trial development programme of any PARP inhibitor, 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 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 breast cancer
Driven by a growing understanding of breast cancer biology,
AstraZeneca is starting to challenge, and redefine, the current
clinical paradigm for how breast cancer is classified and treated
to deliver even more effective treatments to patients in need -
with the bold ambition to one day eliminate breast cancer as a
cause of death.
AstraZeneca has a comprehensive portfolio of approved and
promising compounds in development that leverage different
mechanisms of action to address the biologically diverse breast
cancer tumour environment. AstraZeneca aims to continue to
transform outcomes for HR-positive breast cancer with foundational
medicines Faslodex (fulvestrant) and Zoladex (goserelin) and the
next-generation SERD and potential new medicine camizestrant. PARP
inhibitor, Lynparza (olaparib) is a targeted treatment option for
metastatic breast cancer patients with an inherited BRCA mutation.
AstraZeneca with MSD continue to research Lynparza in metastatic
breast cancer patients with an inherited BRCA mutation and are
exploring new opportunities to treat these patients earlier in
their disease state.
Building on the first approval of Enhertu (trastuzumab
deruxtecan), a HER2-directed antibody-drug conjugate (ADC), in
previously treated HER2-positive metastatic breast cancer,
AstraZeneca and Daiichi Sankyo are exploring its potential in
earlier lines of treatment and in new breast cancer settings. To
bring much needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is testing immunotherapy Imfinzi (durvalumab) in
combination with other oncology medicines, including Lynparza and
Enhertu, assessing the potential of AKT kinase inhibitor,
capivasertib, in combination with chemotherapy, and collaborating
with Daiichi Sankyo to explore the potential of TROP2-directed ADC,
datopotamab deruxtecan.
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 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. World Health Organization. Estimated number of cases in 2020,
worldwide, both sexes, all ages. Available at:
https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf
. Accessed May 2021.
2. Mitri Z, et al. The HER2 Receptor in Breast Cancer:
Pathophysiology, Clinical Use, and New Advances in Therapy.
Chemother Res Pract. 2012;743193.
3. ClinicalTrials.gov. Olaparib as Adjuvant Treatment in
Patients with Germline BRCA-mutated High Risk HER2 Negative Primary
Breast Cancer (OlympiA). Available at
clinicaltrials.gov/ct2/show/NCT02032823 . Accessed May 2021.
4. Breast Cancer School. Will I survive breast cancer? Available
at:
https://www.breastcancercourse.org/will-i-survive-breast-cancer/ .
Accessed May 2021.
5. Bertozzi S, et al. Biomarkers in Breast Cancer. Intechopen.
2018.
6. Yersal O, and Barutca S. Biological Subtypes of Breast
Cancer: Prognostic and therapeutic implications. World J Clin
Oncol. 2014;5(3):412-424.
7. Rivenbark A, et al. Molecular and Cellular Heterogeneity in
Breast Cancer: Challenges for Personalized Medicine. Am J Pathol.
2013;183(4):1113-1124.
8. Roy R, et al. BRCA1 and BRCA2: Different Roles in a Common
Pathway of Genome Protection. Nat Rev Cancer. 2021;12(1):68-78.
9. Wu J, et al. The Role of BRCA1 in DNA Damage Response.
Protein Cell . 2010;1(2):117-11.
10. Gorodetska I, et al. BRCA Genes: The Role in Genome
Stability, Cancer Stemness and Therapy Resistance. J Cancer.
2019;10(9):2109-2127.
11. Li H, et al. PARP Inhibitor Resistance: The Underlying
Mechanisms and Clinical Implications. Mol Cancer. 2020;19:107.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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