Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most prevalent subtype of the disease, accounting for approximately 70% of all cases.¹ While first-line endocrine-based regimens demonstrate considerable efficacy, later-line single-agent chemotherapy has limited effectiveness, highlighting a significant unmet need.² In February 2025, trastuzumab deruxtecan received a positive recommendation from the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP).³ This endorsement expands its potential clinical application to patients with HR-positive, HER2-low, or HER2-ultralow metastatic breast cancer who have progressed following at least one line of endocrine therapy, offering a promising new therapeutic avenue in this challenging landscape.³

In HR-positive/HER2-negative breast cancer, estrogen binding to estrogen receptor (ER) drives tumor growth through receptor-regulated transcription.¹ Endocrine therapy (ET), including tamoxifen, aromatase inhibitors (AIs), and ovarian function suppression (OFS), is the cornerstone of treatment, with chemotherapy used as needed based on disease biology and extent.¹ However, treatment options remain limited for patients with disease progression, highlighting the need for novel targeted therapies.¹

Trastuzumab deruxtecan, a HER2-targeting antibody-drug conjugate (ADC), exerts potent cytotoxic effects by releasing a topoisomerase I inhibitor payload upon cleavage of its tetrapeptide-based linker.⁴ The CHMP has recommended approval of trastuzumab deruxtecan as a monotherapy for patients with metastatic HR-positive, HER2-low, or HER2-ultralow breast cancer who have progressed following at least one line of endocrine therapy.³ The decision is based on DESTINY-Breast06 trial data, which demonstrated a significant improvement in progression-free survival (PFS) compared to standard chemotherapy.² This HER2-directed therapy represents a breakthrough in treatment, offering an effective alternative to chemotherapy.²

The phase 3 DESTINY-Breast06 open-label trial enrolled 866 patients, with HR-positive, HER2-low disease (n=713) and HER2-ultralow disease (n=153).² The trial demonstrated a 38% reduction in the risk of disease progression or death with trastuzumab deruxtecan vs. chemotherapy in HER2-low metastatic breast cancer (HR=0.62; 95% CI: 0.52-0.75; p<0.001) with a median PFS of 13.2 months in the trastuzumab deruxtecan group compared to 8.1 months in the chemotherapy group.² Trastuzumab deruxtecan demonstrated superior PFS over chemotherapy across all subgroups, including patients with a HER2 immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization (ISH) results.² This advantage remained consistent regardless of prior CDK4/6 inhibitor use, previous taxane treatment for nonmetastatic disease, or the selected chemotherapy regimen.² Although overall survival (OS) data were immature at the time of analysis, the PFS results highlight trastuzumab deruxtecan’s significant potential.² In terms of safety, adverse events of grade 3 or higher occurred in 52.8% of patients in the trastuzumab deruxtecan group, compared to 44.4% in the chemotherapy group.² The three most frequently reported adverse events of grade 3 or higher in both treatment groups included neutropenia, leukopenia, and anemia.² Importantly, no new safety concerns for trastuzumab deruxtecan emerged in this trial, consistent with previous findings.²

In conclusion, the CHMP’s recommendation for trastuzumab deruxtecan represents a significant milestone in the treatment of HER2-low and HER2-ultralow metastatic breast cancer.^1,3 By offering a targeted therapy that has demonstrated superior efficacy over chemotherapy, trastuzumab deruxtecan has the potential to fill a critical gap in breast cancer treatment, signifying a transformative shift in the management of patients in this setting.¹