REG - AstraZeneca PLC - Lynparza granted FDA Priority Review for OlympiA

AstraZenecaAnnouncement

30/11/2021 07:00

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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
(https://www.astrazeneca.com/media-centre/press-releases/2021/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.html#:~:text=Phase%20III%20trial-,Lynparza%20reduced%20the%20risk%20of%20cancer%20recurrence%20by%2042%25%20in,in%20OlympiA%20Phase%20III%20trial)
during the 2021 American Society of Clinical Oncology Annual Meeting and
simultaneously published in The New England Journal of Medicine
(https://www.nejm.org/doi/full/10.1056/NEJMoa2105215) .

 

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
(https://www.astrazeneca.com/media-centre/press-releases/2018/lynparza-approved-by-us-fda-in-germline-brca-mutated-metastatic-breast-cancer-12012018.html)
, EU, Japan
(https://www.astrazeneca.com/media-centre/press-releases/2018/lynparza-approved-in-japan-for-brca-mutated-metastatic-breast-cancer-02072018.html)
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 (http://www.astrazeneca.com/) and follow the
Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca) .

 

Contacts

For details on how to contact the Investor Relations Team, please click here
(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html)
.

 

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
(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
(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
(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
(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
(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
(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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