Dr Sammons on the Significance of DESTINY-Breast09 for the HER2+ Breast Cancer Treatment Paradigm

"What DESTINY-Breast09 shows us is that ADCs keep moving up into earlier lines of therapy for our patients with metastatic HER2-positive breast cancer. The question will be: Are we now giving our patients a first-line ADC?"

Sarah Sammons, MD, associate director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute; as well as an assistant professor of medicine at Harvard Medical School, discussed how results from the phase 3 DESTINY-Breast09 trial (NCT04784715) fit into the larger, rapidly evolving treatment paradigm of antibody-drug conjugates (ADCs) in HER2-positive advanced/metastatic breast cancer.

Findings from DESTINY-Breast09 presented at the 2025 ASCO Annual Meeting showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with fam-trastuzumab deruxtecan-nxki (Enhertu) plus pertuzumab (Perjeta), with a 44% reduction in the risk of disease progression or death, compared with standard-of-care trastuzumab (Herceptin) plus pertuzumab and a taxane (THP; HR, 0.56; 95% CI, 0.44-0.71; P < .00001). The median PFS for the investigational arm was 40.7 months (95% CI, 36.5-not calculable [NC]) compared with 26.9 months (95% CI, 21.8-NC) for the THP arm, and the benefit with T-DXd was observed consistently across all prespecified subgroups, regardless of prior treatment status, hormone receptor status, and PI3K mutation status.

The findings from DESTINY-Breast09 underscore the increasing role of ADCs in earlier lines of therapy for patients with metastatic HER2-positive breast cancer, Sammons stated, adding that these results raise important clinical questions about the optimal duration of therapy with T-DXd plus pertuzumab. It remains to be determined whether patients should receive continuous therapy until disease progression or whether a more tolerable maintenance strategy could be developed to balance efficacy with potential adverse effects, Sammons continued. Additionally, it is necessary to explore how ADCs may be integrated into sequential treatment strategies and whether earlier use of ADCs could affect resistance patterns, Sammons stated.

ADCs, including T-DXd, are being investigated in earlier-stage HER2-positive breast cancer, Sammons noted. These trials are ongoing in both the neoadjuvant and adjuvant settings, including studies assessing ADCs for patients with residual disease after induction therapy with taxane- and trastuzumab-based regimens, she said. As ADCs continue to advance into earlier lines of therapy, careful attention to the balance between efficacy and tolerability will be essential to optimize outcomes for patients, Sammons concluded.

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