REG - AstraZeneca PLC - Enhertu improved pCR in early-stage breast cancer

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RNS Number : 5793H  AstraZeneca PLC  07 May 2025

07 May 2025

 

Enhertu followed by THP before surgery showed statistically significant and
clinically meaningful improvement in pathologic complete response in patients
with high-risk HER2-positive early-stage breast cancer in DESTINY-Breast11
Phase III trial

 

AstraZeneca and Daiichi Sankyo's Enhertu followed by THP

showed an improved safety profile vs. standard of care

 

First Phase III trial to demonstrate benefit of Enhertu in early breast cancer

 

Positive high-level results from the DESTINY-Breast11 Phase III trial showed
Enhertu (trastuzumab deruxtecan) followed by paclitaxel, trastuzumab and
pertuzumab (THP) demonstrated a statistically significant and clinically
meaningful improvement in pathologic complete response (pCR) rate versus
standard of care (dose-dense doxorubicin and cyclophosphamide followed by THP
 ddAC-THP ) when used in the neoadjuvant setting (before surgery) in patients
with high-risk, locally advanced HER2-positive early-stage breast cancer.
Pathologic complete response is defined as no evidence of invasive cancer
cells in the removed breast tissue and lymph nodes following treatment.

 

The secondary endpoint of event-free survival (EFS) was not mature at the time
of analysis; however, EFS data showed an early positive trend favouring
Enhertu followed by THP compared to standard of care. The trial will continue
to follow EFS.

 

Approximately one in three patients with early-stage breast cancer are
considered high risk, as they are more likely to experience disease recurrence
and have a poor prognosis.(1,2) Achieving pCR in early-stage HER2-positive
breast cancer is associated with improved long-term outcomes.(2,3) The current
standard of care in many regions of the world in this neoadjuvant setting
involves combination chemotherapy regimens.(2) These regimens often include
anthracyclines, which can be challenging for patients to tolerate and may
result in long-term cardiovascular side effects.(4) Further, nearly half of
patients who receive neoadjuvant treatment do not achieve pCR, reinforcing the
need for new treatment options.(2,3)

 

Susan Galbraith, Executive Vice President, Oncology Haematology R&D,
AstraZeneca, said: "The clinically meaningful improvement in pathologic
complete response and the safety data seen in DESTINY-Breast11 highlight the
potential of Enhertu to challenge the current standard of care in early-stage
HER2-positive breast cancer. Enhertu is already an important treatment option
in the metastatic setting, and these data have the potential to allow this
medicine to move into early stages of disease where cure is possible."

 

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "There are still
many patients with early-stage breast cancer who do not achieve a pathologic
complete response with treatment in the neoadjuvant setting, increasing the
risk of disease recurrence. These topline results from DESTINY-Breast11
demonstrate that Enhertu followed by THP could offer patients with
HER2-positive breast cancer a promising new treatment approach prior to
surgery, setting more patients on a path towards a potential cure."

 

Enhertu followed by THP showed an improved safety profile compared to
ddAC-THP. The safety profiles of Enhertu and THP were consistent with the
known profiles of each individual medicine with no new safety concerns
identified. Rates of interstitial lung disease were similar across the Enhertu
followed by THP and the ddAC-THP arms as determined by an independent
adjudication committee.

 

Following a recommendation by the Independent Data Monitoring Committee,
patient enrolment in a third arm of the trial evaluating Enhertu alone was
closed after a previous interim efficacy assessment of the trial arms.

 

Data from DESTINY-Breast11 will be presented at an upcoming medical meeting
and shared with regulatory authorities.

 

Enhertu is a specifically engineered HER2-directed DXd antibody drug conjugate
(ADC) discovered by Daiichi Sankyo and being jointly developed and
commercialised by AstraZeneca and Daiichi Sankyo.

 

Enhertu has demonstrated improved outcomes in six Phase III breast cancer
trials across different subtypes and stages of disease, including the recently
announced DESTINY-Breast09
(https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-combination-improved-pfs-in-1l-her-positive-mbc.html)
Phase III trial in the 1st-line HER2-positive metastatic setting. Enhertu is
also being studied in several ongoing breast cancer trials including the
DESTINY-Breast05 Phase III trial which is evaluating Enhertu in the high-risk
adjuvant early HER2-positive setting.

 
Notes

 

HER2-positive early breast cancer

Breast cancer is the second most common cancer and one of the leading causes
of cancer-related deaths worldwide.(5) More than two million breast cancer
cases were diagnosed in 2022, with more than 665,000 deaths globally.(5)

( )

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the
surface of many types of tumours including breast cancer.(6) HER2 protein
overexpression may occur as a result of HER2 gene amplification and is often
associated with aggressive disease and poor prognosis in breast cancer.(7)
Approximately one in five cases of breast cancer are considered
HER2-positive.(8)

 

DESTINY-Breast11

DESTINY-Breast11 is a global, multicentre, randomised, open-label, Phase III
trial evaluating the efficacy and safety of neoadjuvant Enhertu (5.4mg/kg)
monotherapy or Enhertu followed by THP vs. the standard of care regimen in
patients with high-risk (lymph node positive  N1-3  or primary tumour stage
T3-4), locally advanced or inflammatory HER2-positive early-stage breast
cancer.

 

Patients were randomised 1:1:1 to receive either eight cycles of Enhertu
monotherapy; four cycles of Enhertu followed by four cycles of THP; or four
cycles of ddAC (dose-dense doxorubicin and cyclophosphamide) followed by four
cycles of THP.

 

The primary endpoint of DESTINY-Breast11 is pCR (absence of invasive disease
in the breast and lymph nodes). Secondary endpoints include EFS, invasive
disease-free survival, overall survival and safety.

 

DESTINY-Breast11 enrolled 927 patients across multiple sites in Asia, Europe,
North America and South America. For more information about the trial, visit
ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT05113251) .

 

Enhertu

Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo's proprietary
DXd ADC Technology, Enhertu is the lead ADC in the oncology portfolio of
Daiichi Sankyo and the most advanced programme in AstraZeneca's ADC scientific
platform. Enhertu consists of a HER2 monoclonal antibody attached to a
number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via
tetrapeptide-based cleavable linkers.

 

Enhertu (5.4mg/kg) is approved in more than 75 countries worldwide for the
treatment of adult patients with unresectable or metastatic HER2-positive
(immunohistochemistry [IHC 3+ or in-situ hybridisation  ISH +) breast cancer
who have received a (or one or more) prior anti-HER2-based regimen, either in
the metastatic setting or in the neoadjuvant or adjuvant setting, and have
developed disease recurrence during or within six months of completing therapy
based on the results from the DESTINY-Breast03
(https://clinicaltrials.gov/ct2/show/NCT03529110)  trial.

 

Enhertu (5.4mg/kg) is approved in more than 75 countries worldwide for the
treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+
or IHC 2+/ ISH-) breast cancer who have received a prior systemic therapy in
the metastatic setting or developed disease recurrence during or within six
months of completing adjuvant chemotherapy based on the results from
the DESTINY-Breast04 (https://clinicaltrials.gov/ct2/show/NCT03734029) trial.

 

Enhertu (5.4mg/kg) is approved in more than 30 countries for the treatment of
adult patients with unresectable or metastatic hormone receptor (HR)-positive,
HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane
staining) breast cancer, as determined by a locally or regionally approved
test, that have progressed on one or more endocrine therapies in the
metastatic setting based on the results from the DESTINY-Breast06
(https://clinicaltrials.gov/study/NCT04494425) trial.

 

Enhertu (5.4mg/kg) is approved in more than 50 countries worldwide for the
treatment of adult patients with unresectable or metastatic non-small cell
lung cancer (NSCLC) whose tumours have activating HER2 (ERBB2) mutations, as
detected by a locally or regionally approved test, and who have received a
prior systemic therapy based on the results from the DESTINY-Lung02
(https://www.clinicaltrials.gov/study/NCT04644237?term=DESTINY-Lung02&rank=1)
 and/or DESTINY-Lung05 (https://clinicaltrials.gov/study/NCT05246514)
 trials. Continued approval in China and the US for this indication is
contingent upon verification and description of clinical benefit in a
confirmatory trial.

 

Enhertu (6.4mg/kg) is approved in more than 65 countries worldwide for the
treatment of adult patients with locally advanced or metastatic HER2-positive
(IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma
who have received a prior trastuzumab-based regimen based on the results from
the DESTINY-Gastric01 (https://clinicaltrials.gov/ct2/show/NCT03329690)
, DESTINY-Gastric02 (https://clinicaltrials.gov/ct2/show/NCT04014075)
 and/or DESTINY-Gastric06 (https://clinicaltrials.gov/study/NCT04989816)
 trials. Continued approval in China for this indication will depend on
whether a randomised controlled confirmatory clinical trial can demonstrate
clinical benefit in this population.

 

Enhertu (5.4mg/kg) is approved in the US and other countries for the
treatment of adult patients with unresectable or metastatic HER2-positive (IHC
3+) solid tumours who have received prior systemic treatment and have no
satisfactory alternative treatment options based on the results from
the DESTINY-PanTumor02
(https://classic.clinicaltrials.gov/ct2/show/NCT04482309) , DESTINY-Lung01
(https://clinicaltrials.gov/study/NCT03505710)  and DESTINY-CRC02
(https://www.clinicaltrials.gov/study/NCT04744831?term=DESTINY-CRC02&rank=1)
 trials. Continued approval for this indication in the US is contingent upon
verification and description of clinical benefit in a confirmatory trial.

 

Enhertu development programme
A comprehensive global clinical development programme is underway evaluating the efficacy and safety of Enhertu as monotherapy or in combination or sequentially with other anti-cancer therapies across multiple HER2-targetable cancers.
 
Daiichi Sankyo collaboration
 AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu in
March 2019 (https://www.astrazeneca.com/media-centre/press-releases/2019/astrazeneca-and-daiichi-sankyo-enter-collaboration-for-novel-her-2-targeting-antibody-drug-conjugate.html)
 and Datroway (datopotamab deruxtecan) in
July 2020 (https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-daiichi-sankyo-enter-collaboration-to-develop-and-commercialise-new-antibody-drug-conjugate.html#!)
, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and Datroway.

 

AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology, AstraZeneca is
challenging, and redefining, 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.

 

With Enhertu, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes
in previously treated HER2-positive, HER2-low and HER2-ultralow metastatic
breast cancer, and are exploring its potential in earlier lines of treatment
and in new breast cancer settings.

 

In HR-positive breast cancer, AstraZeneca continues to improve outcomes with
foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and
aims to reshape the HR-positive space with first-in-class AKT
inhibitor, Truqap (capivasertib), the TROP2-directed
ADC, Datroway (datopotamab deruxtecan), and next-generation oral SERD and
potential new medicine camizestrant.

 

PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has
been studied in early and metastatic breast cancer patients with an
inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the
US and Canada) continue to research Lynparza in these settings and to
explore its potential in earlier disease. AstraZeneca is also exploring the
potential of saruparib, a potent and selective inhibitor of PARP1, in
combination with camizestrant in BRCA-mutated, HR-positive, HER2-negative
advanced breast cancer.

 

To bring much-needed treatment options to patients with triple-negative breast
cancer, an aggressive form of breast cancer, AstraZeneca is collaborating with
Daiichi Sankyo to evaluate the potential of Datroway alone and in
combination with immunotherapy Imfinzi (durvalumab).

 

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's innovative medicines are
sold in more than 125 countries and used by millions of patients worldwide.
Please visit astrazeneca.com (http://www.astrazeneca.com/)  and follow the
Company on social media @AstraZeneca
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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.   National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer
Subtypes. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed May
2025.

2.   Spring LM, et al. Pathologic Complete Response after Neoadjuvant
Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A
Comprehensive Meta-analysis. Clin Cancer Res. 2020; 26(12): 2838-2848.

3.   Antonini M, et al. Pathologic Complete Response and Breast Cancer
Survival Post-Neoadjuvant Chemotherapy: A Systematic Review and Meta-Analysis
of Real-World Data. Heliyon. 2025;ePub ahead of print: e43069

4.   Swain SM, et al. Pertuzumab, trastuzumab, and standard anthracycline-
and taxane-based chemotherapy for the neoadjuvant treatment of patients with
HER2-positive localized breast cancer (BERENICE): a phase II, open-label,
multicenter, multinational cardiac safety study. Ann Oncol. 2018;29(3):646-653

5.   Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of
incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer
J Clin. 2024;10.3322/caac.21834.

6.   Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in
Cancers: Overexpression and Therapeutic Implications. Mol Biol Int.
2014;852748.

7.   Tarantino P, et al. ESMO expert consensus statements (ECS) on the
definition, diagnosis, and management of HER2-low breast cancer. J An Onc.
2023;34(8):645-659.

8.   Ahn S, et al. HER2 status in breast cancer: changes in guidelines and
complicating factors for interpretation. J Pathol Transl Med. 2019;54(1):34

 

Matthew Bowden

Company Secretary

AstraZeneca PLC

 

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