REG - AstraZeneca PLC - Enhertu approved in US for 1L HER2+ metastatic BC

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RNS Number : 6717L  AstraZeneca PLC  16 December 2025

16 December 2025

 

Enhertu plus pertuzumab approved in the US as first new treatment in a decade
for the 1st-line treatment of patients with HER2-positive metastatic breast
cancer

 

Based on DESTINY-Breast09 Phase III trial results that showed AstraZeneca and
Daiichi Sankyo's Enhertu in combination with pertuzumab reduced the risk of
disease progression or death by 44% vs. THP with a median progression-free
survival of more than three years

 

AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) in
combination with pertuzumab has been approved in the US for the 1st-line
treatment of adult patients with unresectable or metastatic HER2-positive
breast cancer, as determined by a Food and Drug Administration (FDA)-approved
test.

 

The approval follows Priority Review
(https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-plus-pertuzumab-granted-priority-review-us-1st-line-treatment-patients-with-her2-positive-metastatic-breast-cancer.html)
and Breakthrough Therapy Designation by the FDA and is based on the results of
the DESTINY-Breast09 Phase III trial. The data were presented at the 2025
American Society of Clinical Oncology (ASCO) Annual Meeting and published in
The New England Journal of Medicine
(https://www.nejm.org/doi/full/10.1056/NEJMoa2508668) .(1)

 

Sara Tolaney, MD, MPH, Chief of the Division of Breast Oncology, Dana-Farber
Cancer Institute and principal investigator for the trial, said: "Trastuzumab
deruxtecan plus pertuzumab is the only 1st-line treatment approved in more
than a decade to demonstrate a statistically significant improvement in
progression-free survival over the current standard regimen for patients with
HER2-positive metastatic breast cancer. With a median progression-free
survival exceeding three years, versus approximately two years with THP,
trastuzumab deruxtecan combined with pertuzumab should become a new 1st-line
standard of care in this setting."

 

Dave Fredrickson, Executive Vice President, Oncology Haematology Business
Unit, AstraZeneca, said: "With this approval, we are bringing Enhertu to the
earliest setting for HER2-positive metastatic breast cancer, where optimising
efficacy has an important impact on long‑term outcomes. The treatment
approach with Enhertu plus pertuzumab in DESTINY-Breast09 sets a new benchmark
of more than three years without disease progression or death for patients in
this setting."

 

Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi
Sankyo, said: "Since its initial approval six years ago, Enhertu has
transformed the treatment of HER2-positive metastatic breast cancer. With this
approval of Enhertu in the 1st-line HER2-positive metastatic setting, Enhertu
once again offers significant improvements in progression-free survival and
has practice-changing potential when used in combination with pertuzumab."

 

In the trial, Enhertu in combination with pertuzumab reduced the risk of
disease progression or death by 44% versus a taxane, trastuzumab and
pertuzumab (THP) (based on a hazard ratio of 0.56; 95% confidence interval
 CI  0.44-0.71; p<0.0001) as a 1st-line treatment for patients with
HER2-positive metastatic breast cancer. Median progression-free survival (PFS)
was 40.7 months with Enhertu plus pertuzumab compared to 26.9 months for THP.
The PFS benefit for Enhertu plus pertuzumab versus THP was consistent across
subgroups.(1)

 

The safety profile of Enhertu plus pertuzumab in DESTINY-Breast09 was
consistent with the known profiles of each individual therapy with no new
safety concerns identified.

 

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.

 

This application was approved under the FDA's Real-Time Oncology Review
(RTOR), an initiative by the FDA to ensure safe and effective treatments are
available to patients as early as possible.

 

This US regulatory submission was also reviewed under Project Orbis, which
provides a framework for concurrent submission and review of oncology
medicines among participating international partners. As part of Project
Orbis, the Enhertu plus pertuzumab 1st-line regimen is under review by
Switzerland's Swissmedic (SMC) and Singapore's Health Sciences Authority
(HSA). Separate regulatory applications are also under review in other
countries.

 

Financial considerations
Following this approval in the US, an amount of $150m is due from AstraZeneca
to Daiichi Sankyo as a milestone payment for the 1st-line unresectable or
metastatic HER2-positive breast cancer indication. Sales of Enhertu in the US
are recognised by Daiichi Sankyo. For further details on the financial
arrangements, please consult the collaboration agreement from 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)
.

 

Notes

 

HER2-positive metastatic breast cancer

Breast cancer is the second most common cancer and one of the leading causes
of cancer-related deaths worldwide.(2) More than two million breast cancer
cases were diagnosed in 2022, with more than 665,000 deaths globally.(2) In
the US, more than 300,000 cases of breast cancer are diagnosed annually with
more than 42,000 deaths.(3) While survival rates are high for those diagnosed
with early breast cancer, only about 30% of patients diagnosed with or who
progress to metastatic disease are expected to live five years following
diagnosis.(4)

 

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the
surface of many types of tumours including breast cancer.(5) HER2 protein
overexpression may occur as a result of HER2 gene amplification.(6)
Approximately one in five cases of breast cancer are considered
HER2-positive.(7)

 

HER2-positive metastatic breast cancer is an aggressive disease driven by
overexpression or amplification of HER2.(8) Approximately 10,000 patients are
treated each year in the 1st-line HER2-positive metastatic setting in the
US.(9) While HER2-targeted therapies have improved outcomes, prognosis remains
poor with most patients experiencing disease progression within two years of
1st-line treatment with THP, which has been the standard of care for more than
a decade.(6,10-12) Approximately 25% to 30% of patients do not receive any
treatment following 1st-line therapy due to discontinuation or death.(13-15)

 

DESTINY-Breast09
DESTINY-Breast09 is a global, multicentre, randomised, open-label, Phase III
trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) either alone
or in combination with pertuzumab versus standard of care THP as a 1st-line
treatment in patients with HER2-positive metastatic breast cancer.

 

Patients were randomised 1:1:1 to receive either Enhertu monotherapy with a
pertuzumab matching placebo; Enhertu in combination with pertuzumab; or THP.
Randomisation was stratified by prior treatment (de novo metastatic disease
versus progression from early-stage disease), hormone receptor (HR) status and
PIK3CA mutation status.

 

The primary endpoint of DESTINY-Breast09 is PFS as assessed by
blinded-independent central review in the Enhertu monotherapy and Enhertu
combination arms. Secondary endpoints include investigator-assessed PFS,
overall survival, objective response rate, duration of response,
pharmacokinetics and safety. The investigational arm assessing Enhertu
monotherapy versus THP remains blinded to patients and investigators and will
continue to the final PFS analysis.

 

DESTINY-Breast09 enrolled 1,157 patients across multiple sites in Africa,
Asia, Europe, North America and South America. For more information about the
trial, visit ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT04784715)
.

 

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) in combination with pertuzumab is approved in the US as a
1st-line treatment for adult patients with unresectable or metastatic
HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-approved
test based on the results from the DESTINY-Breast09
(https://clinicaltrials.gov/study/NCT04784715) trial.

 

Enhertu (5.4mg/kg) is approved in more than 90 countries/regions worldwide
for the treatment of adult patients with unresectable or metastatic
HER2-positive (IHC 3+ or ISH+) breast cancer who have received a 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/study/NCT03529110) trial.

 

Enhertu (5.4mg/kg) is approved in more than 85 countries/regions 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/study/NCT03734029) trial.

 

Enhertu (5.4mg/kg) is approved in more than 55 countries/regions worldwide
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 60 countries/regions 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) and/or DESTINY-Lung05
(https://clinicaltrials.gov/study/NCT05246514) trials. Continued approval in
China and the US for this indication may be contingent upon verification and
description of clinical benefit in a confirmatory trial.

 

Enhertu (6.4mg/kg) is approved in more than 70 countries/regions worldwide
for the treatment of adult patients with locally advanced or metastatic
HER2-positive (IHC 3+ or IHC 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/study/NCT03329690) , DESTINY-Gastric02
(https://clinicaltrials.gov/study/NCT04014075) and/or DESTINY-Gastric06
(https://clinicaltrials.gov/study/NCT04989816) trials. Continued approval in
China for this indication may be contingent upon verification and description
of clinical benefit in a confirmatory trial.

 

Enhertu (5.4mg/kg) is approved in more than 10 countries/regions worldwide 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 efficacy results from the
DESTINY-PanTumor02 (https://clinicaltrials.gov/study/NCT04482309) ,
DESTINY-Lung01 (https://clinicaltrials.gov/study/NCT03505710) and
DESTINY-CRC02 (https://www.clinicaltrials.gov/study/NCT0474483) trials.
Continued approval for this indication may be 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 a monotherapy, in combination or
sequentially with other cancer medicines 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 patients with 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. 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.
(https://www.linkedin.com/company/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.   Tolaney SM, et al. Trastuzumab Deruxtecan plus Pertuzumab for
HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2025; DOI:
10.1056/NEJMoa2508668.

2.   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.

3.   American Cancer Society. Key Statistics for Breast Cancer. Available
at:
https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html
(https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html)
. Accessed December 2025.

4.   National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer
Subtypes. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html
(https://seer.cancer.gov/statfacts/html/breast-subtypes.html) . Accessed
December 2025.

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

6.   Pillai R, et al. HER2 mutations in lung adenocarcinomas: A report from
the Lung Cancer Mutation Consortium. Cancer. 2017;1;123(21):4099-4105.

7.   Ahn S, et al. HER2 status in breast cancer: changes in guidelines and
complicating factors for interpretation. J Pathol Transl Med.
2019;54(1):34-44.

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

9.   AstraZeneca. Investor Relations: Epidemiology. Available at:
https://www.astrazeneca.com/content/dam/az/Investor_Relations/Epidemiology-data-2024.xlsx
(https://www.astrazeneca.com/content/dam/az/Investor_Relations/Epidemiology-data-2024.xlsx)
. Accessed December 2025.

10.  Swain SM, et al. Pertuzumab, trastuzumab, and docetaxel for
HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from
a double-blind, randomised, placebo-controlled, Phase III study. Lancet
Oncol. 2020;21(4):519-530.

11.  Blumenthal G, et al. First FDA Approval of Dual Anti-HER2 Regimen:
Pertuzumab in Combination with Trastuzumab and Docetaxel for HER2-Positive
Metastatic Breast Cancer. Clin Can Res. 2013;19(18).

12.  Tripathy D, et al. De Novo Versus Recurrent HER2-Positive Metastatic
Breast Cancer: Patient Characteristics, Treatment, and Survival from the
SystHERs Registry. Oncologist. 2020;25(2):e214-e222.

13.  Hartkopt AD, et al. Attrition in the First Three Therapy Lines in
Patients with Advanced Breast Cancer in the German Real-World PRAEGNANT
Registry. Geburtshilfe Frauenheilkd. 2024;84(5):459-469.

14.  Cottu P, et al. Attrition between lines of therapy and real-world
outcomes of patients with HER2-positive metastatic breast cancer in Europe: a
cohort study leveraging electronic medical records. Breast Cancer Res Treat.
2025;209:419-430.

15.  Lam C, et al. Treatment patterns and associated outcomes among patients
with HER2+ metastatic breast cancer in the United States: an observational
cohort study. Oncologist. 2025;30(4).

 

 

Matthew Bowden

Company Secretary

AstraZeneca PLC

 

 

 

 

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