An Open-label, Randomized, Phase 3 Study to Evaluate Patritumab Deruxtecan Monotherapy versus Treatment of Physician’s Choice in Hormone Receptor-positive, HER2-negative Unresectable Locally Advanced or Metastatic Breast Cancer (HERTHENA-Breast04)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Oct 2025 → ongoing

Decision date (initial)

2025-09-29

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Sharp & Dohme LLC · DAIICHI SANKYO COMPANY, LIMITED

External identifiers

EU CT number

2025-520582-51-00

WHO UTN

U1111-1317-5490

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacokinetic, Pharmacogenomic, Safety, Pharmacogenetic, Efficacy

1. To compare patritumab deruxtecan (HER3-DXd) to TPC with respect to PFS per RECIST 1.1 as assessed by BICR in all participants.
2. To compare HER3-DXd to TPC with respect to OS in all participants.

Secondary objectives 5

1. To compare HER3-DXd to TPC with respect to ORR per RECIST 1.1 as assessed by BICR in all participants.
2. To evaluate the efficacy of HER3-DXd and TPC with respect to DOR per RECIST 1.1 as assessed by BICR in all participants.
3. To compare HER3-DXd to TPC with respect to mean change from baseline in HRQoL using the EORTC QLQ-C30.
4. To compare HER3-DXd to TPC with respect to TTD in HRQoL using the EORTC QLQ-C30 in all participants.
5. To evaluate the safety and tolerability of HER3-DXd and TPC.

Conditions and MedDRA coding

Hormone receptor positive breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Has a diagnosis of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) invasive breast carcinoma that is either locally advanced disease not amenable to resection with curative intent (herein called unresectable) or metastatic disease not treatable with curative intent
2. Has centrally-confirmed HR+ and HER2- results and human epidermal growth factor receptor 3 (HER3) evaluable results from a biopsy obtained from a distant metastatic site or a locally advanced lesion on or after the most recent line of therapy (with certain exceptions)
3. Must have had progression or recurrence on prior cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor + endocrine therapy (ET) with one of the following: a. Radiographic disease progression, as assessed by the investigator, on CDK4/6 inhibitor + ET as first line (1L) for treatment of unresectable locally advanced or metastatic HR+/HER2- breast cancer. CDK4/6 inhibitor + ET must be the only line of therapy received in the advanced setting, or b. Disease recurrence, either radiographic and/or confirmed histologically via biopsy as assessed by the investigator, while on adjuvant ET in combination with a CDK4/6 inhibitor or within 24 months from the date of last dose of adjuvant CDK4/6 inhibitor
4. Is determined by the investigator to be a candidate for at least 1 treatment of physician’s choice (TPC) option
5. Has measurable disease per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as assessed by the local site investigator/radiology
6. Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy
7. Has an Eastern Cooperative Oncology Group performance status of 0 or 1 assessed within 7 days before randomization

Exclusion criteria 17

1. Has breast cancer amenable to treatment with curative intent
2. Is eligible to receive additional endocrine-based treatment in the advanced setting as determined by the investigator. Patients with alterations/mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PI3KCA), phosphatase and tensin homolog (PTEN), alpha-serine/threonine kinase (AKT), or estrogen receptor 1 (ESR1) who are deemed suitable for second line (2L) treatment with ET in combination with targeted therapy, where available, are not eligible
3. Has a known germline BReast CAncer gene (BRCA) mutation (deleterious or suspected deleterious) where poly adenosine diphosphate-ribose polymerase (PARP) inhibitor(s) is a potential treatment option (i.e., available and not medically contraindicated)
4. Has current visceral crisis or is at risk for impending visceral crisis that has or may cause imminent organ compromise and/or other life-threatening complications
5. Has any of the following: a pulse oximeter reading <92% at rest, or requires intermittent supplemental oxygen, or requires chronic supplemental oxygen
6. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
7. Has clinically significant corneal disease
8. Has received prior chemotherapy for unresectable locally advanced or metastatic breast cancer
9. Has history of (noninfectious) pneumonitis/interstitial lung disease (ILD) that required steroids, has current pneumonitis/interstitial lung disease, or has suspected ILD/pneumonitis
10. Has ≥Grade 2 peripheral neuropathy
11. Has received prior treatment with an anti-HER3 antibody and/or antibody-drug conjugate that consists of a topoisomerase I inhibitor (e.g., T-DXd) or any other topoisomerase I inhibitor therapy
12. Has received prior systemic anticancer therapy within 4 weeks (or 5 half-lives, whichever is shorter) before randomization. Participants previously treated with ET plus a CDK4/6 inhibitor may participate as long as at least 2 weeks have elapsed since the last dose of therapy was administered.
13. Has received prior radiotherapy for non-central nervous system disease, or required corticosteroids for radiation-related toxicities, within 14 days of the first dose of study intervention
14. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
15. Has known additional malignancy that is progressing or has required active treatment within the past 3 years
16. Has severe hypersensitivity (≥Grade 3) to HER3-DXd and/or any of its excipients
17. Has severe hypersensitivity (≥Grade 3) to all the available TPC and/or any of their excipients

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Progression Free Survival (PFS)
2. Overall Survival (OS)

Secondary endpoints 12

1. Objective Response Rate (ORR)
2. Duration of Response (DOR)
3. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status-Quality of Life Score
4. Change from Baseline in EORTC QLQ-C30 Physical Functioning Score
5. Change from Baseline in EORTC QLQ-C30 Emotional Functioning Score
6. Change from Baseline in EORTC QLQ-C30 Pain Score
7. Time to First Deterioration (TTD) in EORTC QLQ-C30 Global Health Status-Quality of Life Score
8. TTD in EORTC QLQ-C30 Physical Functioning Score
9. TTD in EORTC QLQ-C30 Emotional Functioning Score
10. TTD in EORTC QLQ-C30 Pain Score
11. Number of Participants Who Experience an Adverse Event (AE)
12. Number of Participants Who Discontinue Study Treatment Due to an AE

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue, P. O. Box 2000 P. O. Box 2000

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Preeti K Sudheendra

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Preeti K Sudheendra

Third parties 9

Locations

7 EU/EEA countries · 46 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 69 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications