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

AstraZenecaAnnouncement

25/08/2022 07:00

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RNS Number : 1543X  AstraZeneca PLC  25 August 2022

 

25 August 2022 07:00 BST

 

Lynparza approved in Japan as adjuvant treatment for patients

with 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 Japan for the
adjuvant treatment of patients with BRCA-mutated (BRCAm), HER2-negative early
breast cancer at high risk of recurrence.

 

This approval by the Japanese Ministry of Health, Labour, and Welfare 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.(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)
, reducing the risk of death by 32% versus placebo (based on an 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) In Japan, an estimated 95,000 people
will be diagnosed with breast cancer in 2022, and over 15,000 will die from
the disease.(3,4) Out of the approximately 80% of patients with HER2-negative
breast cancer, about 11% have BRCA mutations.(5,6)

 

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: "Today's approval marks a new era of care for patients
in Japan. 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. Today's approval offers eligible
patients in Japan an effective and targeted treatment that improves survival
and helps to prevent cancer recurrence."

 

Dave Fredrickson, Executive Vice President, Oncology Business Unit,
AstraZeneca, said:  "Today's approval marks a significant leap forward for
breast cancer patients in Japan, where it is the most commonly diagnosed
cancer among women. Patients with BRCA mutations have high rates of disease
recurrence and lower survival, and Lynparza has been shown to significantly
reduce both the risk of recurrence and death. We hope this approval sets a
new, much-needed standard of care for these early breast cancer patients in
Japan."

 

Dr Eliav Barr, Senior Vice President, Head of Global Clinical Development and
Chief Medical Officer, MSD Research Laboratories, said: "With this approval,
Lynparza becomes the first and only PARP inhibitor available for patients with
BRCA-mutated HER2-negative early breast cancer in Japan. This further
reinforces the critical need to conduct BRCA testing at the point of diagnosis
so that all eligible patients can be identified."

 

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 germline BRCAm (gBRCAm), HER2-negative
high-risk early breast cancer, followed by approval
(https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-approved-in-eu-for-early-breast-cancer.html)
in the EU in August 2022 based on the results of the OlympiA Phase III trial.
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 Japan, breast cancer is both the most commonly diagnosed
cancer overall and the most prevalent cancer among women.(9) Over 90% of
breast cancer patients in Japan are diagnosed with early disease.(10) In 2020,
breast cancer accounted for an estimated 2.3 million new cases and
approximately 700,000 deaths worldwide.(2) 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.(11,12)

 

Breast cancer is one of the most biologically diverse tumour types with
various factors fuelling its development and progression.(13) The discovery of
biomarkers in the development of breast cancer has greatly impacted scientific
understanding of the disease.(14)

 

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.(15)

 

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.(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 alterations that can lead
to cancer. Cancers with BRCA mutations are more likely to be sensitive to PARP
inhibitors including Lynparza.(16-19)

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. Enhertu has received approval in
the US in previously treated HER2-low 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 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
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.

 

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.   Ganjoho. Projected Cancer Statistics. Available at
https://ganjoho.jp/reg_stat/statistics/stat/short_pred_en.html
(https://ganjoho.jp/reg_stat/statistics/stat/short_pred_en.html) . Accessed
August 2022.

4.   Heer E, et al. Global burden and trends in premenopausal and
postmenopausal breast cancer: a population-based study. Lancet Glob Health.
2020;8(8):e1027-37.

5.   Healthline. What Does It Mean to Have HER2-Negative Breast Cancer?
Available at
https://www.healthline.com/health/breast-cancer/her2-negative#:~:text=Most%20breast%20cancers%20are%20HER2,t%20produce%20too%20much%20HER2
(https://www.healthline.com/health/breast-cancer/her2-negative#:~:text=Most%20breast%20cancers%20are%20HER2,t%20produce%20too%20much%20HER2)
. Accessed August 2022.

6.   Winter C, et al. Targeted sequencing of BRCA1 and BRCA2 across a large
unselected breast cancer cohort suggests that one-third of mutations are
somatic. Ann. Oncol. 2016 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.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.

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

9.   Hattori M, et al. A systematic literature review of prognostic factors
in patients with HR+/HER2− advanced breast cancer in Japan. Jpn J Clin
Oncol. 2021;51(10):1498-508.

10.  Hayashi N, et al. Annual report of the Japanese breast cancer registry
for 2017. Breast Cancer. 2020;27(5):803-9.

11.  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).

12.  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.

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

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

15.  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.

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

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

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

19. 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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