A Randomised Trial Comparing Trastuzumab Deruxtecan to CDK4/6 Inhibitors in Non-luminal A, ER-positive/HER2-low Metastatic Breast Cancer (DISCORDANT)

The objective of this trial, DBCG R25, will be to evaluate the effect of trastuzumab-deruxtecan versus standard of care on progression-free survival (PFS) in first-line for patients with non-Luminal A, ER-positive/HER2-negative metastatic breast cancer

Study Overview

• Status: Withdrawn
• Conditions: Metastatic Breast Cancer; ER-positive Breast Cancer; Luminal B; Her2 Enriched; Basal Like
• Intervention / Treatment: Drug: Trastuzumab deruxtecan (T-DXd); Drug: Ribociclib with ET; Drug: Abemaciclib with ET

Detailed Description

Study design and setting We will conduct an international, multicentre, open-label, randomised controlled trial. All oncological departments who treat patients with metastatic breast cancer can participate. The EU Clinical Trial Regulation will be applied.

Interventions Trial participants will be randomised to trastuzumab deruxtecan or standard treatment.

Trastuzumab deruxtecan

Patients randomised to trastuzumab deruxtecan will be treated as:

Trastuzumab deruxtecan until progression or intolerable toxicity, Trastuzumab deruxtecan: 5.4 mg/kg intravenous on day 1 of a 21 days cycle.

Standard

Patients randomised to standard will be treated as:

CDK4/6 inhibitor with an endocrine therapy until progression or intolerable toxicity CDK4/6 inhibitor: Physician's choice of ribociclib (600mg daily for 21 days in a 28 days cycle) or abemaciclib (150mg twice daily).

Endocrine therapy: letrozole (2.5mg daily), anastrozole (1mg daily), exemestane (25mg daily), tamoxifen (20mg daily) or fulvestrant (intramuscular 500mg every 4 weeks)

Other treatment Prophylactic antiemetics are allowed, including corticosteroids. Prophylactic antibiotics are allowed if deemed necessary for the patient. G-CSF is allowed when needed.

All other symptomatic treatment to perform best of care is allowed as long as name, administration and length is documented in the chart. Bone targeted agents are allowed. No other antineoplastic treatment is allowed.

Radiological evaluation Patients will initially be scanned every 9-12 weeks as per investigator's or co-investigator's discretion with minimum a CT of the thorax and abdomen or a FDG-PET/CT. Patients with response can have this interval extended. Upon progression treatment/control is to be done according to department preferences, but subsequent treatment and day of death must be registered.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women aged 18 or above.
• Radiologically/pathologically verified metastatic breast cancer.
• ER-positive (1% or more) and HER2-low (HER2 1+ or HER2 2+/ISH-neg)10,11.
• PAM50 Luminal B, HER2-enriched or Basal-like.
• Performance status 0-1.
• Evaluable disease

Exclusion Criteria:

• Patients who are incapable of understanding the written material received
• Patients with inaccessible tumour tissue
• Other malignant disease within 5 years (in situ cervix and non-melanoma skin cancer excluded)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trastuzumab-deruxtecan; Trastuzumab deruxtecan until progression or intolerable toxicity: 5.4 mg/kg intravenous on day 1 of a 21 days cycle.	Drug: Trastuzumab deruxtecan (T-DXd); Trastuzumab deruxtexan every three weeks; Other Names: Enhertu
Active Comparator: Immunohistochemistry guided treatment (standard); - CDK4/6 inhibitor with an endocrine therapy until progression og intolerable toxicity; CDK4/6 inhibitor: Physician's choice of ribociclib (600mg daily for 21 days in a 4 week schedule) or abemaciclib (125mg twice daily).; Endocrine therapy: letrozole (2.5mg daily), anastrozole (1mg daily), exemestane (25mg daily), tamoxifen (20mg daily) or fulvestrant (intramuscular 500mg every 4 weeks)	Drug: Ribociclib with ET; Ribociclib with endocrine therapy; Drug: Abemaciclib with ET; Abemaciclib with endocrine therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary outcome	Progression-free survival (ITT)	Up to 4 years after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival in ITT cohort	Up to 4 years after inclusion
PFS by subtype	PFS by subtype (Luminal B, HER2-enriched and Basal-like)	Up to 4 years after inclusion
OS by subtype	OS by subtype (Luminal B, HER2-enriched and Basal-like)	Up to 4 years after inclusion
Quality of life	Quality of life EORTC QLQ-C30/BR23 during treatment and at progression.	During treatment, estimated 18-24 months
Toxicity	Toxicity on treatment (NCI-CTC v. 5.0)	During treatment, estimated 18-24 months

Collaborators and Investigators

• Sponsor: Danish Breast Cancer Cooperative Group

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2026
• Primary Completion (Actual): January 1, 2026
• Study Completion (Actual): January 1, 2026

Study Registration Dates

• First Submitted: August 23, 2024
• First Submitted That Met QC Criteria: September 3, 2024
• First Posted (Actual): September 19, 2024

Study Record Updates

• Last Update Posted (Actual): February 12, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Immunoconjugates; abemaciclib; trastuzumab deruxtecan; ribociclib
• Other Study ID Numbers: DBCG-R25-DISCORDANT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes