Trial Insights from TROPiCS-02 and DESTINY-Breast06 in HR+/HER2– Breast Cancer

The optimal sequencing of antibody-drug conjugates (ADCs) in the treatment of metastatic hormone receptor (HR)–positive, HER2-negative breast cancer is a critical area of investigation. Recent data from the phase 3 TROPiCS-02 (NCT03901339) and DESTINY-Breast06 (NCT04494425) trials offer valuable insights into this evolving landscape.1,2

In a recent discussion with CancerNetwork®, Kit Yu Lu, MD, an oncology/hematology oncologist and specialist in breast cancer, at the University of Pittsburgh Medical Center, provided key takeaways regarding how these trials inform the sequencing of agents like sacituzumab govitecan-hziy (Trodelvy) and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu).

Lu highlighted the significant findings from the DESTINY-Breast06 trial, which demonstrated the efficacy of T-DXd as a first-line treatment following endocrine resistance in patients with HR-positive/HER2-negative metastatic breast cancer. The trial showed a superior progression-free survival (PFS) of 13.2 months with T-DXd compared with 8.1 months for standard first-line chemotherapy in this setting.

However, Lu pointed out the current lack of head-to-head comparisons between T-DXd in this first-line setting and other ADCs, such as sacituzumab govitecan, making direct efficacy comparisons challenging. Current guidelines now support the use of T-DXd in the first line after endocrine failure.

In contrast, Lu discussed the TROPiCS-02 trial, which evaluated sacituzumab govitecan in patients with HR-positive/HER2-negative metastatic breast cancer who had progressed after endocrine therapy and 1 to 2 prior lines of chemotherapy. Notably, the current indication for sacituzumab govitecan requires at least 1 prior line of chemotherapy. Lu’s analysis of these pivotal trials underscores the evolving treatment paradigms and the need for further research to definitively establish the optimal sequencing strategies for ADCs in this patient population. The differing eligibility criteria and trial designs necessitate careful consideration when integrating these agents into clinical practice.

Transcript:

Destiny-Breast06 has now shown that you can use T-DXd in the first-line setting after a patient has become endocrine refractory. In that trial, it showed that T-DXd was better in terms of PFS compared with standard first-line chemotherapy. What we don’t know is how that will fare if it’s compared head-to-head with sacituzumab govitecan. The current guidelines and standards are that we can utilize T-DXd in the first-line setting. Whereas in TROPiCS-02, [treatment] was after endocrine therapy progression and 1 to 2 lines of chemotherapy. Unfortunately, right now, the only indication we have is at least 1 [prior] line of chemotherapy for sacituzumab govitecan.

References

1. Enhertu approved in the US as first HER2-directed therapy for patients with HER2-low or HER2-ultralow metastatic breast cancer following disease progression after one or more endocrine therapies. News release. FDA. January 27, 2025. Accessed May 19, 2024. https://tinyurl.com/5n8ab8sk
2. U.S FDA approves Trodelvy in pre-treated HR+/HER2- metastatic breast cancer. News release. Gilead. February 3, 2023. Accessed May 19, 2025. https://bwnews.pr/3Y0bftX