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

AstraZenecaAnnouncement

27/06/2022 07:00

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RNS Number : 2099Q  AstraZeneca PLC  27 June 2022

 

27 June 2022 07:00 BST

 

Lynparza recommended for approval in the EU by CHMP as adjuvant treatment for
patients with germline BRCA-mutated HER2-negative high-risk early breast
cancer

 

First PARP inhibitor to improve overall survival in early-stage breast cancer

AstraZeneca and MSD's Lynparza (olaparib) has been recommended for marketing
authorisation 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 HER2-negative high-risk early breast
cancer previously treated with neoadjuvant or adjuvant chemotherapy.

 

The Committee for Medicinal Products for Human Use (CHMP) of the European
Medicines Agency based its positive opinion 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.(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 are diagnosed with early breast cancer.(4,5) In Europe, BRCA
mutations are found in up to 10% of patients.(6)

 

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: "For patients with high-risk, early-stage breast cancer,
the risk of recurrence remains unacceptably high and cancer will return for
more than one in four of these patients. Today's recommendation is hopeful
news for patients in Europe, as we move closer to setting a potential new
standard of care that improves overall survival in patients suitable for
treatment with olaparib."

 

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca,
said: "If approved, Lynparza will become a new targeted treatment option for
patients with germline BRCA-mutated HER2-negative early breast cancer in
Europe. By treating patients with curative-intent as early as possible in
their disease, we hope to avoid life-threatening recurrence and give people
more time with their loved ones."

 

Dr. Eliav Barr, Head of Global Clinical Development and Chief Medical Officer,
MSD Research Laboratories, said: "Patients with germline BRCA-mutated
HER2-negative early breast cancer will often develop breast cancer at an
earlier age than those without BRCA mutations, impacting people in their
prime. Today's announcement brings us closer to our goal of offering a
much-needed new treatment option to these patients."

 

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

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.(7,8) In the US, 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).(6) 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 gBRCAm are more likely to be
diagnosed at a younger age than those without these mutations.(6,9)

 

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.(10) 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.(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 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 (US only); 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. The Company has 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 June 2022.

3.   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 June 2022.

4.   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.

5.   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.

6.   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).

7.   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 June 2022.

8.   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 June 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 June 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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