TIDMAZN
RNS Number : 0051U
AstraZeneca PLC
30 November 2021
30 November 2021 07:00 GMT
Lynparza granted Priority Review in the US for
BRCA-mutated HER2-negative high-risk early breast cancer
First medicine targeting BRCA mutations to show clinical benefit
in adjuvant setting
AstraZeneca's supplemental New Drug Application (sNDA) for
Lynparza (olaparib) has been accepted and granted Priority Review
in the US for the adjuvant treatment of patients with BRCA-mutated
(BRCAm) HER2-negative high-risk early breast cancer who have
already been treated with chemotherapy either before or after
surgery.
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 during the first quarter of 2022.
Breast cancer is now the most diagnosed cancer worldwide with an
estimated 2.3 million patients diagnosed in 2020.(2) Nearly 91% of
all breast cancer patients are diagnosed at an early stage of
disease and BRCA mutations are found in approximately 5% of
patients.(3,4,5)
The sNDA was based on results from the OlympiA Phase III trial
presented during the 2021 American Society of Clinical Oncology
Annual Meeting and simultaneously published in The New England
Journal of Medicine .
These results showed Lynparza demonstrated a statistically
significant and clinically meaningful improvement in invasive
disease-free survival (iDFS), reducing the risk of invasive breast
cancer recurrence, second cancers or death by 42% versus placebo
(based on a hazard ratio of 0.58; 99.5% confidence interval
0.41-0.82; p<0.0001). The safety and tolerability profile of
Lynparza in this trial was in line with that observed in prior
clinical trials.
Lynparza is approved in the US , EU, Japan and several other
countries for the treatment of patients with germline BRCAm,
HER2-negative, metastatic breast cancer previously treated with
chemotherapy based on results from the OlympiAD Phase III trial. In
the EU, this indication also includes patients with locally
advanced breast cancer.
Notes
Early breast cancer
Early breast cancer is defined as disease confined to the breast
with or without regional lymph node involvement, and the absence of
distant metastatic disease.(6) The 5-year survival rate is 99% for
localised breast cancer (only found in the breast area) and 86% for
regional breast cancer (cancer that has spread outside the breast
to nearby structures or lymph nodes).(3) Despite advancements in
the treatment of early breast cancer, up to 30% of patients with
high-risk clinical and/or pathologic features, such as BRCA
mutations, recur within the first few years.(7,8)
Breast cancer is one of the most biologically diverse tumour
types with various factors fuelling its development and
progression.(9) The discovery of biomarkers in the development of
breast cancer has greatly impacted scientific understanding of the
disease.(10)
OlympiA
OlympiA is a Phase III, double-blind, parallel group,
placebo-controlled, multicentre trial testing the efficacy and
safety of Lynparza tablets versus placebo as adjuvant treatment in
patients with germline BRCAm high-risk HER2-negative early breast
cancer, who have completed definitive local treatment and
neoadjuvant or adjuvant chemotherapy.(11)
The primary endpoint of the trial is iDFS defined as time from
randomisation to date of first loco-regional or distant recurrence
or new cancer or death from any cause.(11)
The OlympiA Phase III trial is led by the Breast International
Group (BIG) in partnership with the Frontier Science &
Technology Research Foundation (FSTRF), NRG Oncology, AstraZeneca
and MSD. (11)
BRCA
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.(11)
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.(1) (2-15)
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 those with mutations in BRCA1 and/or BRCA2,
or those where deficiency is induced by other agents (such as new
hormonal agents).
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
selective estrogen receptor degraders (SERD) and potential new
medicine camizestrant (formerly known as AZD9833).
Lynparza is a targeted treatment option for metastatic breast
cancer patients with an inherited BRCA mutation. AstraZeneca with
MSD continue to research Lynparza in early and metastatic breast
cancer patients with a BRCA mutation.
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.
Results from the DESTINY-Breast03 Phase III trial showed that
Enhertu significantly improved progression-free survival in
patients with HER2-positive metastatic breast cancer.
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, 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 November 2021.
2. GLOBOCAN. Breast Cancer. Available at
https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf
. Accessed November 2021.
3. Cancer.org. Survival rates for breast cancer. Available at
https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html
. Accessed November 2021.
4. De Talhouet S, et al. Clinical outcome of breast cancer in
carriers of BRCA1 and BRCA2 mutations according to molecular
subtypes. Scientific Reports. 2020;10:7073.
5. Cancer.gov. Early-stage breast cancer. Available at
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/early-stage-breast-cancer
. Accessed November 2021.
6. WHO. Early stage breast cancer. Available at
https://www.who.int/selection_medicines/committees/expert/20/applications/EarlyStageBreast.pdf?ua=1
. Accessed November 2021.
7. Johnston S, et al. Abemaciclib Combined With Endocrine
Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive,
High-Risk, Early Breast Cancer (monarchE). J Clin Oncol.
2020;38(34):3987-3998.
8. Smith KL, Isaacs C. BRCA mutation testing in determining
breast cancer therapy. Cancer J. 2011;17(6):492-499.
doi:10.1097/PPO.0b013e318238f579
9. Yersal O, and Barutca S. Biological Subtypes of Breast
Cancer: Prognostic and therapeutic implications. World J Clin
Oncol. 2014;5(3):412-424.
10. Rivenbark A, et al. Molecular and Cellular Heterogeneity in
Breast Cancer: Challenges for Personalized Medicine. Am J Pathol.
2013;183(4):1113-1124.
11. ClinicalTrials.gov. Olaparib as Adjuvant Treatment in
Patients with Germline BRCA Mutated High Risk HER2 Negative Primary
Breast Cancer (OlympiA). Available at
https://clinicaltrials.gov/ct2/show/NCT02032823 . Accessed November
2021.
12. Roy R, et al. BRCA1 and BRCA2: Different Roles in a Common
Pathway of Genome Protection. Nat Rev Cancer. 12(1):68-78.
13. Wu J, et al. The Role of BRCA1 in DNA Damage Response.
Protein Cell. 2010;1(2):117-123.
14. Gorodetska I, et al. BRCA Genes: The Role in Genome
Stability, Cancer Stemness and Therapy Resistance. J Cancer.
2019;10(9):2109-2127.
15. 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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