Real-World Data Support Earlier T-DXd Use in HR+/HER2-Low Metastatic Breast Cancer
Key Clinical Summary
- In a US real-world cohort of 1232 patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC), earlier use of trastuzumab deruxtecan (T-DXd) was associated with longer real-world time to next treatment (rwTTNT) and treatment discontinuation (rwTTD).
- Median rwTTNT was longest in the second-line (2L) setting at 9.7 months, compared with 7.4 months in first-line (1L) and ≥ fourth-line (4L) settings.
- Outcomes were numerically better among patients without prior chemotherapy or with prior endocrine therapy (ET).
T-DXd demonstrates improved real-world outcomes when used earlier in the treatment sequence for HR+/HER2-low mBC, according to findings presented at the 2025 San Antonio Breast Cancer Symposium. The TRIO ARDENT study analyzed US electronic health record data to evaluate treatment patterns and effectiveness in routine oncology practice.
Study Findings
The retrospective study evaluated 1232 adults with HR+/HER2-low mBC treated with T-DXd between August 5, 2022, and January 1, 2025, using the Flatiron Health nationwide database. Patients were diagnosed with mBC on or after January 1, 2018.
Most patients received T-DXd in later lines, with 55.2% treated in 4L or beyond (≥4L), 27.2% in 3L, 10.2% in 2L, and 7.4% in 1L. Median follow-up ranged from 10.8 to 14.5 months across lines.
Overall, median rwTTNT was 7.4 months in 1L, 9.7 months in 2L, 7.9 months in 3L, and 7.4 months in ≥4L settings. Median rwTTD followed a similar pattern, at 7.1, 9.3, 7.8, and 7.1 months, respectively.
In subgroup analyses, patients receiving T-DXd without prior chemotherapy had numerically longer rwTTNT and rwTTD compared with those previously treated with chemotherapy. Similarly, patients who had received at least one prior line of endocrine therapy demonstrated longer median rwTTNT and rwTTD than those without prior ET.
The authors concluded that a general trend toward better outcomes was observed when T-DXd was initiated in earlier lines (≥2L), including among chemotherapy-naïve patients and those previously treated with endocrine therapy.
Clinical Implications
Approximately 50% of breast cancers are HER2-low with higher prevalence in HR+ disease. T-DXd received US approval in 2022 for patients with HER2-low mBC after prior chemotherapy in the metastatic setting or early relapse following adjuvant chemotherapy.
In this real-world US population study, the median rwTTNT of 9.7 months in the 2L setting was comparable to the progression-free survival reported in DESTINY-Breast04, despite inclusion of older patients and a higher proportion with brain metastases.
These findings support earlier integration of T-DXd in eligible patients with HR+/HER2-low mBC, consistent with current labeling. The data also provide insight into treatment sequencing in community oncology settings, which comprised the majority of participating sites.
“This study highlights that, when used in routine clinical practice, starting T-DXd earlier in eligible patients with HR+, HER2-low mBC improves outcomes compared with waiting until people have received more treatments,” the authors reported.
Conclusion
Real-world US data from the study indicate that earlier-line T-DXd use in HR+/HER2-low metastatic breast cancer is associated with numerically longer treatment duration and delayed need for subsequent therapy. These findings reinforce current treatment recommendations and inform sequencing decisions in clinical practice.
Reference
Brufsky A, Kaufman PA, Inoue-Choi M, et al. Real-world treatment utilization and outcomes of trastuzumab deruxtecan (T-DXd) among patients with hormone receptor–positive (HR+) HER2-low metastatic breast cancer (mBC) in the United States. Presented at: SABCS 2025; December 9, 2025; San Antonio, TX.
