DESTINY-Breast06: T-DXd Beats Chemo in HER2-Low HR+ mBC

A survival benefit was seen in patients with hormone receptor–positive (HR-positive), HER2-low or -ultralow metastatic breast cancer (mBC) who were treated with trastuzumab deruxtecan (T-DXd) compared with all physicians’ choice of chemotherapy subgroups, according to findings from the DESTINY-Breast06 clinical trial.

More than 860 patients who had received at least 1 line of endocrine therapy (ET) were randomly selected to receive either T-DXd (5.4 mg/kg every 3 weeks) or a physician’s choice of chemotherapy (capecitabine [CAPE], nab-paclitaxel, or paclitaxel). The study, led by Carlos H. Barrios, MD, Hospital São Lucas-PUCRS, Porto Alegre, Brazil, evaluated the antibody-drug conjugate for efficacy and safety. Results from the phase 3, open-label trial were presented during the 2025 European Society for Medical Oncology (ESMO) Breast Cancer Annual Congress held in Munich, Germany.

Primary endpoints included progression-free survival (PFS), confirmed objective response rate (cORR), time from randomization to second progression or death (PFS2), and safety by choice of chemotherapy before randomization in the intent-to-treat (ITT; HER2-low and -ultralow) population.

The T-DXd group included 436 patients, and the physician’s choice group had 430 patients (59.8% CAPE; 24.4% nab-paclitaxel; 15.8% paclitaxel).

Compared with physician’s choice, T-DXd showed an increased median PFS, cORR, and median PFS2. Results revealed a median PFS of 13.3 months in the T-DXd group versus 8.5 months in the CAPE group. When comparing T-DXd and nab-paclitaxel, median PFS was 12.9 months versus 8.3 months. Furthermore, T-DXd was also favored over paclitaxel (median PFS 16.1 months vs 6.3 months, respectively).

In addition, cORR was higher in patients who received T-DXd compared with those who received CAPE, nab-paclitaxel, and paclitaxel (57.9% vs 30.7%; 56.3% vs 37.1%; 56.7% vs 23.5%, respectively).

T-DXd also showed greater median PFS2 compared with all chemotherapy groups (22.6 months vs 16.4 months [CAPE]; 17.3 months vs 14.5 months [nab-paclitaxel]; and 18.2 months vs 12.4 months [paclitaxel]).

“These findings support T-DXd as a treatment option in HR-positive, HER2-low/ultralow mBC with prior ET but no chemotherapy, as previously reported in the ITT population,” Barrios said.

Safety outcomes of T-DXd were consistent with previous research, Barrios said. The most common adverse event (AE) from T-DXd was nausea, which was experienced by 69.8% of patients. With physician’s choice, the most common AEs were palmar-plantar erythrodysesthesia syndrome (57.4%, CAPE) and alopecia (45.5%, nab-paclitaxel; 50.7%, paclitaxel). Moreover, patients in all groups reported grade 3 or greater drug-related AEs (40.6%, T-DXd; 29.3%, CAPE; 27.7%, nab-paclitaxel; and 44.8%, paclitaxel).

Reference

Barrios CH. DESTINY-Breast06 (DB-06) post-hoc analysis by physician’s choice of chemotherapy (TPC): Efficacy and safety of trastuzumab deruxtecan (T-DXd) vs TPC in hormone receptor–positive (HR+), HER2-low or -ultralow metastatic breast cancer (mBC). Abstract 299MO. Presented at the 2025 ESMO Breast Cancer Annual Congress, May 14-17, 2025; Munich, Germany.