REG - AstraZeneca PLC - Lynparza approved in EU for early breast cancer

AstraZenecaAnnouncement

04/08/2022 07:15

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RNS Number : 9049U  AstraZeneca PLC  04 August 2022

 

4 August 2022 07:00 BST

 

Lynparza approved in the EU as adjuvant treatment for patients with

germline BRCA-mutated HER2-negative high-risk early breast cancer

 

First and only approved medicine targeting

BRCA mutations in early breast cancer

AstraZeneca and MSD's Lynparza (olaparib) has been approved in the European
Union (EU) as monotherapy or in combination with endocrine therapy for the
adjuvant treatment of adult patients with germline BRCA1/2 mutations (gBRCAm),
who have human epidermal growth factor receptor 2 (HER2)-negative high-risk
early breast cancer previously treated with neoadjuvant or adjuvant
chemotherapy.

 

This approval by the European Commission was based on results from the OlympiA
Phase III trial
(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)
published in The New England Journal of Medicine
(https://www.nejm.org/doi/full/10.1056/NEJMoa2105215) in June 2021 and follows
the recommendation for approval
(https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-recommended-in-eu-for-early-breast-cancer.html)
in the EU by the Committee for Medicinal Products for Human Use of Lynparza in
this setting.(1) In the trial, Lynparza demonstrated a statistically
significant and clinically meaningful improvement in invasive disease-free
survival (iDFS), reducing the risk of invasive breast cancer recurrences, new
cancers, or death by 42% versus placebo (based on a hazard ratio  HR  of 0.58;
99.5% confidence interval  CI  0.41-0.82; p<0.0001).

 

Lynparza also demonstrated a statistically significant and clinically
meaningful improvement in overall survival
(https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/lynparza-reduced-risk-of-death-by-32-percent-in-the-adjuvant-treatment-of-patients-with-germline-brca-mutated-high-risk-early-breast-cancer.html)
(OS), reducing the risk of death by 32% versus placebo (based on a HR of 0.68;
98.5% CI 0.47-0.97; p=0.009). The safety and tolerability profile of Lynparza
in this trial was in line with that observed in prior clinical trials.

 

Breast cancer is the most diagnosed cancer worldwide with an estimated 2.3
million patients diagnosed in 2020.(2) Approximately 90% of all breast cancer
patients worldwide are diagnosed with early breast cancer and BRCA mutations
are found in approximately 10% of HER2-negative patients in Europe.(3-5)

 

Professor Andrew Tutt, Global Chair of the OlympiA Phase III trial and
Professor of Oncology at The Institute of Cancer Research, London and King's
College London, said: "Today's approval marks a new era of care in Europe for
patients with an inherited form of breast cancer. For patients with high-risk
early-stage breast cancer, including those with germline BRCA mutations,
recurrence rates remain unacceptably high, with more than one in four of these
patients seeing their cancer return following surgery and systemic treatment.
Olaparib is the first PARP inhibitor to demonstrate improved overall survival
for high-risk early-stage breast cancer patients with germline BRCA mutations
and I am hopeful it will become a new standard of care."

 

 

 

Dave Fredrickson, Executive Vice President, Oncology Business Unit,
AstraZeneca, said:

"With this approval, Lynparza is now the first and only PARP inhibitor
available for patients with germline BRCA-mutated HER2-negative early breast
cancer in Europe. We can now bring the benefits of Lynparza to this earlier
setting to help reduce the risk of life-threatening recurrence."

 

Dr Eliav Barr, Senior Vice President, Head of Global Clinical Development and
Chief Medical Officer, MSD Research Laboratories, said: "Today's approval
offers patients with germline BRCA-mutated HER2-negative early-stage breast
cancer a new, much-needed treatment option. Lynparza as adjuvant treatment can
significantly reduce the risk of disease recurrence and death, reinforcing the
importance of conducting germline BRCA testing as soon as possible after
diagnosis."

 

In March 2022, Lynparza was approved
(https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-approved-in-the-us-as-adjuvant-treatment-for-patients-with-germline-brca-mutated-her2-negative-high-risk-early-breast-cancer.html)
in the US for the treatment of gBRCAm, HER2-negative high-risk early breast
cancer. Lynparza is also approved in the US, EU, Japan, and many other
countries for the treatment of patients with gBRCAm, 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

 
Financial considerations

Following this approval for Lynparza in the EU, AstraZeneca will receive a
regulatory milestone payment from MSD of $75m, anticipated to be booked as
Collaboration Revenue during the third quarter of 2022.

 

Early breast cancer

Early breast cancer is defined as cancer confined to the breast with or
without regional lymph node involvement, and the absence of distant metastatic
disease.(6,7) In the EU, breast cancer alone accounts for approximately 29% of
all cancers in women with 1 in 7 women developing the disease in their
lifetime. In 2020, breast cancer accounted for an estimated 350,000 new cases
and over 90,000 deaths.(8) Despite advancements in the treatment of early
breast cancer, up to 30% of patients with high-risk clinical and/or pathologic
features recur within the first few years and patients with gBRCA mutations
are more likely to be diagnosed at a younger age than those without these
mutations.(5,9)

 

Breast cancer is one of the most biologically diverse tumour types with
various factors fuelling its development and progression.(10) The discovery of
biomarkers in the development of breast cancer has greatly impacted scientific
understanding of the disease.(11)

 

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 gBRCAm high-risk HER2-negative
early breast cancer, who have completed definitive local treatment and
neoadjuvant or adjuvant chemotherapy.(12)

 

The primary endpoint of the trial was iDFS defined as time from randomisation
to date of first locoregional or distant recurrence or new cancer or death
from any cause.(1)

 

The OlympiA Phase III trial is led by the Breast International Group in
partnership with the Frontier Science & Technology Research Foundation,
NRG Oncology, the US National Cancer Institute, AstraZeneca and MSD. The trial
is sponsored by NRG Oncology in the US and by AstraZeneca outside the US.

 

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.(9) 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 alterations that can lead
to cancer. Cancers with BRCA mutations are more likely to be sensitive to PARP
inhibitors including Lynparza.(13-16)

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 - 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.

 

Lynparza is currently approved in a number of countries across PARP-dependent
tumour types with defects and dependencies in the DDR pathway 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 the EU and US); for gBRCAm metastatic pancreatic
cancer; and 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, 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. The
companies will develop Lynparza and Koselugo in combination with their
respective PD-L1 and PD-1 medicines independently.

 

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 and Zoladex and the
next-generation oral selective oestrogen receptor degrader (SERD) and
potential new medicine camizestrant.

 

The PARP inhibitor, Lynparza, is an approved targeted treatment option for
early and metastatic breast cancer patients with an inherited BRCA mutation.
AstraZeneca with MSD continue to research Lynparza in breast cancer patients
with an inherited BRCA mutation.

 

Building on the initial approvals of Enhertu, 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 in combination with other oncology medicines, including
Lynparza and Enhertu, evaluating 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.   Tutt ANJ, et al. Adjuvant Olaparib for Patients with BRCA1- or
BRCA2-Mutated Breast Cancer. N Engl J Med. 2021;384:2394-2405.

2.   International Agency for Research on Cancer. Globocan 2020 - Breast.
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 August 2022.

3.   Cardoso F, et al. Locally recurrent or metastatic breast cancer: ESMO
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann.
Oncol. 2012;23:vii11-9.

4.   Asselain B, et al. Long-term outcomes for neoadjuvant versus adjuvant
chemotherapy in early breast cancer: meta-analysis of individual patient data
from ten randomised trials. Lancet. Oncol. 2018;19(1):27-39.

5.   O'Shaughnessy J, et al. Prevalence of germline BRCA mutations in
HER2-negative metastatic breast cancer: global results from the real-world,
observational BREAKOUT study. Breast Cancer Research. 2020;22(114).

6.   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 August 2022.

7.   Cancer Research UK. Breast cancer stages, types and grades. Available
at
https://www.cancerresearchuk.org/about-cancer/breast-cancer/stages-types-grades/number-stages/stage-1
(https://www.cancerresearchuk.org/about-cancer/breast-cancer/stages-types-grades/number-stages/stage-1)
. Accessed August 2022.

8.   European Commission. Breast cancer burden in EU-27. Available at
https://ecis.jrc.ec.europa.eu/pdf/Breast_cancer_factsheet-Oct_2020.pdf
(https://ecis.jrc.ec.europa.eu/pdf/Breast_cancer_factsheet-Oct_2020.pdf) .
Accessed August 2022.

9.   Colleoni M, et al. Annual Hazard Rates of Recurrence for Breast Cancer
During 24 Years of Follow-Up: Results From the International Breast Cancer
Study Group Trials I to V. J Clin Oncol. 2016;34(9):927-935.

10.  Yersal O and Barutca S. Biological subtypes of breast cancer: Prognostic
and therapeutic implications. World J Clin Oncol. 2014;5(3):412-424.

11.  Rivenbark AG, et al. Molecular and Cellular Heterogeneity in Breast
Cancer: Challenges for Personalized Medicine. Am J Pathol. 2013;183:1113-1124.

12.  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 August 2022.

13.  Roy R, et al. BRCA1 and BRCA2: different roles in a common pathway of
genome protection. Nat Rev Cancer. 2016;12(1):68-78.

14.  Wu J, et al. The role of BRCA1 in DNA damage response. Protein Cell.
2010;1(2):117-123.

15.  Gorodetska I, et al. BRCA Genes: The Role in Genome Stability, Cancer
Stemness and Therapy Resistance. Journal of Cancer. 2019;10:2109-2127.

16. Li H, et al. PARP inhibitor resistance: the underlying mechanisms and
clinical implications. Molecular Cancer. 2020;19:1-16.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

 

 

 

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