The Trastuzumab Deruxtecan (Enhertu) Era in HER2-Positive Breast Cancer

ContributorsProf. Dr. Mustafa ÖzdoğanAuthor · Medical review · Editorial approval

PublishedNov 11, 2025

UpdatedOct 17, 2026

3 min read

The Trastuzumab Deruxtecan (Enhertu) Era in HER2-Positive Breast Cancer

In this article

DESTINY-Breast09, DESTINY-Breast05 and DESTINY-Breast11 show that the antibody–drug conjugate trastuzumab deruxtecan (T-DXd)enhances clinical benefit across a broad spectrum, from first-line metastatic treatment to early-stage disease treated with curative intent. Study designs and key numerical findings are outlined below.

DESTINY-Breast09 – PFS

40.7 months vs 26.9 months (HR 0.56) – 1st-line metastatic HER2+

DESTINY-Breast05 – 3-year IDFS

92.4% vs 83.7% (HR 0.47) – post-neoadjuvant residual disease

DESTINY-Breast11 – pCR

67.3% vs 56.3% (T-DXd→THP vs ddAC→THP) – neoadjuvant

DESTINY-Breast09 (Phase III)

1st-line metastatic HER2+

Design

T-DXd ± Pertuzumab vs THP

Randomized, open-label; primary endpoint: PFS

Main Result

PFS 40.7 vs 26.9 months

HR 0.56; CR 15.1% vs 8.5%

Clinical message: Superior to THP in the first line; an opportunity to plan for longer PFS.

DESTINY-Breast05 (Phase III)

Early-stage • post-neoadjuvant (residual +)

Design

T-DXd vs T-DM1

Primary: IDFS; secondary: DFS, DRFI, BMFI

Main Result

3y IDFS 92.4% vs 83.7%

HR 0.47; DRFI HR ~0.49

Safety: ILD 9.6% (T-DXd) vs 1.6% (T-DM1) – protocol-based monitoring recommended.

Clinical message: Marked superiority to T-DM1 in the adjuvant setting; a contribution to the chance of cure.

DESTINY-Breast11 (Phase III)

Early-stage • neoadjuvant (high-risk)

Design

T-DXd→THP vs ddAC→THP

Primary: pCR (breast + nodes)

Main Result

pCR 67.3% vs 56.3%

RCB 0+I: 81.3% vs 69.1%; EFS data immature

Safety: ≥G3 AE 37.5% vs 55.8%; ILD ~4–5%; lower LV dysfunction.

Clinical message: Higher pCR; potential to reduce chemotherapy burden and anthracycline use.

Comparative Summary Table

Study	Setting / Population	Treatment Arms	Primary Endpoint	Key Findings	Clinical Message
DB09	1st-line metastatic HER2+	T-DXd ± Pertuzumab vs THP	PFS	PFS 40.7 vs 26.9 months; HR 0.56; CR 15.1%	Candidate for a new first-line standard
DB05	Early-stage, residual (+), adjuvant	T-DXd vs T-DM1	IDFS	3y IDFS 92.4% vs 83.7%; HR 0.47; DRFI HR ~0.49	Marked superiority in the curative-intent setting
DB11	Early-stage, high-risk, neoadjuvant	T-DXd→THP vs ddAC→THP	pCR	pCR 67.3% vs 56.3%; RCB 0+I 81.3% vs 69.1%	A strong signal for early ADC use

Note: Maturation of OS/EFS data will consolidate its place in the treatment algorithm.

Looking Ahead

A strategic shift: T-DXd has the potential to redefine the standard in 1st-line metastatic and adjuvant/neoadjuvant settings.
Subgroup nuances: The pCR increase is marked in HR-negative subgroups; early intensification may be needed in patients at high risk of brain metastases.
Safety/monitoring: Protocol-based ILD screening, cardiac function monitoring and hematologic toxicity management are important.

Disclaimer: This summary is a brief review of research data. Clinical decisions should be based on the patient’s individual characteristics and multidisciplinary team assessment.

Sources

DESTINY-Breast09 press release/abstract: AstraZeneca
DESTINY-Breast05 press release/abstract: Daiichi Sankyo (US)
DESTINY-Breast11 press release/abstract: AstraZeneca

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