Evolving Treatment Paradigms in Advanced Breast Cancer: Key Trial Updates From SABCS 2025

Karissa Britten, MD Cedars Sinai Cancer | Vaishali Deenadayalan, MD Roswell Park Comprehensive Cancer Center

December 19, 2025

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Key Points

  • DESTINY-Breast09 supports earlier use of trastuzumab deruxtecan in metastatic HER2-positive breast cancer.

  • Sequencing decisions in HER2-positive disease have become more individualized, informed by data from HER2CLIMB-05 and patient-specific disease characteristics.

  • ASCENT-03 highlights the potential role of antibody–drug conjugates (ADCs) earlier in triple-negative breast cancer, particularly for patients ineligible for immunotherapy.

Emerging Data Reshaping First-Line HER2-Positive Treatment

In a discussion coinciding with the 2025 San Antonio Breast Cancer Symposium (SABCS 2025), Karissa Britten, MD, of Cedars-Sinai Cancer, spoke with Vaishali Deenadayalan, MD, of Roswell Park Comprehensive Cancer Center, about recent studies with potential practice-changing implications in HER2-positive and triple-negative breast cancer (TNBC).

One of the most notable updates discussed was emerging data from DESTINY-Breast09, which evaluated trastuzumab deruxtecan (T-DXd) in the first-line metastatic HER2-positive setting. Previously established in later lines of therapy, T-DXd demonstrated a meaningful progression-free survival benefit when moved earlier in treatment, including in combination with pertuzumab. These findings further support the expanding role of ADCs earlier in the disease course.

HER2-Positive Disease: Sequencing and Maintenance Decisions

Dr. Deenadayalan highlighted data from HER2CLIMB-05, which explored the addition of tucatinib to HER2-directed maintenance therapy. Patients with aggressive disease features, such as significant visceral involvement or co-mutations, including PIK3CA, may be better candidates for T-DXd–based approaches, whereas others may continue to benefit from trastuzumab- and pertuzumab-based maintenance regimens, particularly in hormone receptor–negative disease.

The Role of ADCs Across Breast Cancer Subtypes

The discussion extended beyond HER2-positive disease to advances in TNBC. Dr. Deenadayalan highlighted ASCENT-03, which evaluated sacituzumab govitecan in the frontline setting for patients ineligible for immunotherapy or with low PD-L1 expression. In addition, both clinicians noted increasing interest in moving ADCs into earlier-stage and adjuvant settings, with multiple ongoing trials aimed at improving long-term outcomes.