Dr Tarantino on the Potential Relevance of the DESTINY-Breast09 Trial in HER2+ Breast Cancer

“I’m extremely excited for [the 2025 ASCO Annual Meeting] because of the many important abstracts, some of which are expected to shape practice for the coming years.”

Paolo Tarantino, MD, PhD, a clinical fellow at Dana-Farber Cancer Institute, discussed notable breast cancer research that will be presented at the 2025 ASCO Annual Meeting.

The phase 3 DESTINY-Breast09 study (NCT04784715) is evaluating fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), a HER2-directed antibody-drug conjugate (ADC), in combination with pertuzumab (Perjeta) as a first-line treatment for patients with HER2-positive metastatic breast cancer. This regimen is being compared with the longstanding standard of care established by the phase 3 CLEOPATRA trial (NCT00567190), which consists of a taxane plus trastuzumab (Herceptin) and pertuzumab.

Importantly, DESTINY-Breast09 introduces a novel therapeutic agent into the frontline setting and challenges the current treatment paradigm by potentially eliminating the need for induction chemotherapy with a taxane, Tarantino explained. Given that T-DXd is not associated with cumulative neurotoxicity, it may be suitable for prolonged administration, in contrast to taxanes, he noted. The results of this trial will help determine the efficacy and tolerability of this chemotherapy-sparing strategy in patients with HER2-positive disease, he said. Although the trial was positive, according to a news release published in April 2025, full data will be needed to assess the magnitude of clinical benefit of this regimen and its implications for routine practice, he emphasized.

Another key phase 3 study, ASCENT-04 (EudraCT 2021-005743-79), is evaluating sacituzumab govitecan-hziy (Trodelvy), a topoisomerase I–targeted ADC, combined with pembrolizumab (Keytruda) vs chemotherapy plus pembrolizumab in patients with PD-L1–positive metastatic triple-negative breast cancer (TNBC). This trial enrolled a patient population that currently achieves modest benefit with chemoimmunotherapy, according to Tarantino. Positive topline results suggest improved efficacy with the addition of the ADC, offering a promising new first-line strategy for the approximately 40% of patients with metastatic TNBC who have PD-L1–positive disease, he stated.

Furthermore, the phase 2 NEOSTAR trial (NCT03158129), which is investigating neoadjuvant sacituzumab govitecan in combination with pembrolizumab in early-stage TNBC, builds upon prior data showing the efficacy of sacituzumab govitecan as monotherapy in this patient population, including those with BRCA mutations, Tarantino reported. The field is also closely watching the development of sacituzumab tirumotecan (SKB264/MK-2870), another topoisomerase I–directed ADC.

Overall, these developments signal a clear trend in favor of upfront ADC use, Tarantino stated. This approach could increase the number of patients who can access these effective therapies earlier in their disease course, thereby improving overall outcomes, he concluded.

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