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This article presents key findings from the ICARUS-BREAST01 phase 2 trial evaluating patritumab deruxtecan (HER3-DXd), an antibody–drug conjugate, in patients with hormone receptor-positive, HER2-negative (HR+HER2−) metastatic breast cancer who had progressed after CDK4/6 inhibitors and chemotherapy. The study reported a notable overall response rate (ORR) of 53.5% with manageable safety, and exploratory biomarker analyses suggest HER3 distribution and ESR1 mutation status may predict treatment response.
Study Background and Disease Burden
Hormone receptor-positive, HER2-negative advanced breast cancer comprises the majority of breast cancer cases and, despite advances, many patients develop resistance to frontline endocrine therapies combined with CDK4/6 inhibitors—a current standard of care. After progression on these regimens and chemotherapy, therapeutic options are limited and largely ineffective, underscoring the urgent need for novel targeted therapies.
Antibody–drug conjugates (ADCs) have revolutionized treatment paradigms in metastatic breast cancer, notably in HER2-positive subtypes. However, such advances have been lacking in HR+HER2− disease, partly due to the absence of reliably predictive biomarkers guiding ADC use. Patritumab deruxtecan is a promising ADC targeting the HER3 receptor, which is expressed variably in breast cancer and implicated in resistance pathways.
Study Design
The ICARUS-BREAST01 was an open-label, single-arm phase 2 clinical trial conducted from May 2021 to June 2023, enrolling 99 patients with HR+HER2− metastatic breast cancer. Eligible patients had previously progressed on CDK4/6 inhibitors and at least one line of chemotherapy.
Participants received intravenous patritumab deruxtecan at a dose of 5.6 mg/kg every three weeks. The primary endpoint was overall response rate (ORR) evaluated by RECIST criteria. Secondary endpoints included progression-free survival (PFS), safety and tolerability, and exploratory biomarker analyses focusing on tumor HER3 expression and ESR1 mutation status.
Key Findings
The trial met its primary endpoint with an ORR of 53.5% (90% confidence interval [44.8–62.1%]), indicating substantial antitumor activity in this heavily pretreated population. The median progression-free survival data, although not detailed in the summary, correlated positively with HER3 expression levels, suggesting clinical relevance of the target.
Safety analysis revealed a manageable adverse event profile consistent with the ADC class. Common treatment-emergent adverse events included fatigue (83%), nausea (75%), diarrhea (53%), and alopecia (40%). Most adverse events were of mild to moderate severity, with few reports of severe toxicity, supporting a favorable risk-benefit ratio.
Exploratory biomarker investigations provided intriguing insights. Baseline tumor samples showed that spatial HER3 distribution and absence of estrogen receptor 1 (ESR1) mutations may be associated with higher ORR. Furthermore, on-treatment biopsy samples indicated that effective patritumab deruxtecan activity could be linked with intratumoral ADC distribution and the activation of interferon signaling pathways, which could underpin immune-mediated responses.
These biomarker findings are preliminary and hypothesis-generating, warranting further validation in larger, randomized studies.
Expert Commentary
The results presented by Pistilli et al. represent a significant advance in treatment options for HR+HER2− metastatic breast cancer patients who have exhausted established therapies. The ORR observed exceeds expected historical outcomes for this refractory cohort, highlighting HER3 as a promising therapeutic target. Moreover, the exploration of biomarkers offers a much-needed step toward personalized use of ADCs in this subgroup.
Despite the encouraging data, limitations include the single-arm design without a comparator, relatively small sample size, and the need for long-term efficacy and safety follow-up. Additionally, the preliminary nature of biomarker correlations necessitates cautious interpretation pending validation.
Comparison with other ADCs approved for breast cancer, such as trastuzumab deruxtecan in HER2-low tumors, will be crucial to understand the relative clinical positioning of patritumab deruxtecan. Further phase 3 trials are essential to establish survival benefits and refine patient selection criteria.
Conclusion
Patritumab deruxtecan demonstrates promising clinical activity and manageable safety in patients with HR+HER2− advanced breast cancer after progression on CDK4/6 inhibitors and chemotherapy. The study highlights the potential of HER3-targeted ADC therapy to fill a significant treatment gap in this population. Exploratory biomarker analyses open avenues for future research aimed at optimizing patient selection and understanding mechanisms of response and resistance.
These encouraging results warrant larger, randomized trials to confirm efficacy and integrate patritumab deruxtecan into the therapeutic armamentarium for HR+HER2− metastatic breast cancer.
References
1. Pistilli, B., Mosele, F., Corcos, N. et al. Patritumab deruxtecan in HR+HER2− advanced breast cancer: a phase 2 trial. Nat Med (2025). https://doi.org/10.1038/s41591-025-03885-3
2. Cardoso, F., Paluch-Shimon, S., Senkus, E., et al. 5th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 5). Ann Oncol. 2020;31(12):1623-1649. doi:10.1016/j.annonc.2020.09.010
3. Modi, S., Saura, C., Yamashita, T., et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20.