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

AstraZenecaAnnouncement

14/03/2022 07:16

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RNS Number : 5902E  AstraZeneca PLC  14 March 2022

14 March 2022 07:05 GMT

 

Lynparza approved in the US 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

 

New data show Lynparza demonstrated overall survival benefit in early breast
cancer

 

AstraZeneca and MSD's Lynparza (olaparib) has been approved in the US for the
adjuvant treatment of patients with germline BRCA-mutated (gBRCAm)
HER2-negative high-risk early breast cancer who have already been treated with
chemotherapy either before or after surgery.

 

The approval by the US Food and Drug Administration (FDA) was based on results
from the OlympiA Phase III trial presented during the 2021 American Society of
Clinical Oncology Annual Meeting and published in The New England Journal of
Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2105215) .(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, second cancers or death, by 42%
versus placebo (based on a hazard ratio  HR  of 0.58; 95% confidence interval
 CI  0.46-0.74; p<0.0001).

 

New updated results from the OlympiA trial also showed Lynparza demonstrated a
statistically significant and clinically meaningful improvement in the key
secondary endpoint of overall survival (OS), reducing the risk of death by 32%
versus placebo (based on a HR of 0.68; 95% CI 0.50-0.91; p=0.0091). The safety
and tolerability profile of Lynparza in this trial was in line with that
observed in prior clinical trials. The OS data will be presented at an
upcoming European Society for Medical Oncology virtual plenary on 16 March
2022.

 

Breast cancer is the most diagnosed cancer worldwide with an estimated 2.3
million patients diagnosed in 2020.(2) Almost 91% of all breast cancer
patients in the US are diagnosed at an early stage of disease and BRCA
mutations are found in approximately 5-10% of patients.(3,4)

 

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 of olaparib is great news for patients
with a specific inherited form of breast cancer. Most breast cancers are
identified in the early stages and many patients will do very well, but for
those with higher risk disease at diagnosis, the risk of cancer returning can
be unacceptably high and new treatment options are needed. OlympiA has shown
that identifying a BRCA1/2 mutation in women with high risk disease opens the
additional option of eligibility for olaparib treatment, which reduces the
risk of recurrence and improves survival for these breast cancer patients."

 

Dave Fredrickson, Executive Vice President, Oncology Business Unit,
AstraZeneca, said: "This important approval gives early-stage breast cancer
patients in the US with a germline BRCA mutation a new targeted therapy option
in the adjuvant setting starting today. Lynparza reduces the risk of disease
recurrence in these high-risk patients and now new data confirm it also
significantly extends patients' lives versus placebo. These data underline the
importance of germline BRCA testing as soon as possible after diagnosis to
identify patients that may be eligible for Lynparza."

 

Roy Baynes, Senior Vice President and Head of Global Clinical Development,
Chief Medical Officer, MSD Research Laboratories, said: "For patients with
germline BRCA-mutated, HER2-negative high-risk early breast cancer, who often
present with more aggressive disease, today's approval is an important step
forward. Compared to placebo, Lynparza as adjuvant treatment offers these
patients the potential to live longer without their cancer recurring. We thank
the patients, caregivers and healthcare providers for their participation in
the OlympiA trial."

 

Lynparza is now indicated for the adjuvant treatment of adult patients with
deleterious or suspected deleterious gBRCAm HER2-negative high-risk early
breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy.
Patients are to be selected for treatment based on an FDA-approved companion
diagnostic test for Lynparza.

 

Lynparza is approved in the US, EU, Japan and several 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 US, AstraZeneca will receive a
regulatory milestone payment from MSD of $175m, anticipated to be booked as
Collaboration Revenue by the Company during the first 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.(5) 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).(3)

 

Despite advances 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(6), and patients with gBRCA mutations are more likely to be
diagnosed at a younger age than those without these mutations.(7)

 

Breast cancer is one of the most biologically diverse tumour types with
various factors fuelling its development and progression.(8) The discovery of
biomarkers in the development of breast cancer has greatly impacted scientific
understanding of the disease.(9)

 

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.(10)

 

The primary endpoint of the trial is iDFS defined as time from randomisation
to date of first locoregional or distant recurrence or new cancer or death
from any cause.(11)

 

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.(12)

 

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.(11-14)

 

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
germline BRCAm, HER2-negative metastatic breast cancer (in the EU this
includes locally advanced breast cancer); for germline BRCAm 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 first approval 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
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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.   Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of
Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A
Cancer Journal for Clinicians. 2020;0:1-41.

3.   American Cancer Society. Breast Cancer Facts & Figures 2019-2020.
Available at
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2019-2020.pdf
(https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2019-2020.pdf)
. Accessed January 2021.

4.   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 January 2021.

5.   Union for International Cancer Control. Early-stage breast cancer -2014
Review of Cancer Medicines on the WHO List of Essential Medicines. 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 January 2021.

6.   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 Mar 20; 34(9):927-935.

7.   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).

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

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

10.  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 January 2021.

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

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

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

14. 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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