Enhertu (fam-trastuzumab deruxtecan-nxki or T-DXd) has shown promising results in slowing down or stopping the growth of certain types of breast cancer, regardless of whether patients have specific gene changes, according to a presentation from the 2025 ASCO Annual Meeting.

In an exploratory analysis of the phase 3 DESTINY-Breast06 trial, treatment with Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd) was efficacious regardless of baseline PI3K/AKT pathway, ESR1, or BRCA1/2 mutation status in patients with hormone receptor (HR)–positive, HER2-low or HER2-ultralow metastatic breast cancer after at least one prior line of endocrine-based therapy.

“Findings in the biomarker-evaluable population were consistent with those in the [intention-to-treat] population, and provide evidence that [Enhertu] is an effective treatment across patients with HR-positive, HER2-low or HER2-ultralow [metastatic breast cancer] after 1 or more endocrine-based therapies regardless of PI3K/AKT pathway, ESR1 or BRCA1/2 mutation status,” wrote lead study author Rebecca Dent, MD, MSc, of the Division of Medical Oncology at the National Cancer Centre Singapore in Singapore, with coauthors in the presentation.

Biomarker-evaluable patient responses

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In the biomarker-evaluable population (625 patients), the median progression-free survival (PFS) – or the time from treatment to disease worsening or progression – was 13.9 months in patients treated with Enhertu, compared with 8.2 months in patients treated with physician’s choice of chemotherapy. The confirmed objective response rate (ORR) – or the percentage of patients whose tumors shrink or disappear after treatment – was 59.4% versus 33.9%, respectively. 

PI3K/AKT mutations 

PI3K/AKT pathway mutations were observed in 281 patients (45%) who were biomarker evaluable. For patients with PI3K/AKT pathway wildtype, the median PFS was 13.1 months with Enhertu treatment, compared with 8.1 months with chemotherapy. Also in this group of patients, overall response rates (ORRs) were 60.9% versus 27.3%, respectively. 

For those with a PI3K/AKT pathway mutation, the median PFS was 13.2 months with Enhertu, compared with 7.1 months with chemotherapy. Also in this group of patients, the ORRs were 57.6% vs 41.5%, respectively.

In those with PI3K/AKT pathway wildtype disease, the median second progression-free survival (PFS2), which is the time from the start of second-line treatment to disease progression or worsening, was 19.2 months with Enhertu and 14.9 months with chemotherapy. In those with mutation status, the median PFS2 was 19.5 months versus 13.6 months, respectively.

ESR1 mutations

ESR1 mutations were observed in 322 patients (51.5%) of the biomarker-evaluable population. For those with ESR1 wildtype disease, the median PFS with Enhertu was 15.2 months, compared with 8.1 months with chemotherapy. The confirmed ORRs were 58.6% vs 35.8%, respectively. 

In those with an ESR1 mutation, the median PFS was 11.3 months with Enhertu, compared with 7.0 months with chemotherapy. The confirmed ORRs were 60.2% vs 32.1%, respectively.

In those with ESR1 wildtype disease, the median PFS2 was 20.0 months with T-Enhertu versus 14.6 months with chemotherapy. In those with ESR1 mutation, the median PFS2 was 19.4 months, compared with 13.7 months, respectively.

BRCA1/2 mutations

BRCA1/2 mutations were observed in 48 patients (7.7%) of the biomarker-evaluable population. In those with wildtype status, the median PFS was 12.9 months with Enhertu and 8.2 months with chemotherapy. The confirmed ORRs were 58.1% vs 33.3%, respectively. 

In those with a BRCA1/2 mutation, the median PFS was 21.4 months in the Enhertu group, versus 5.6 months in the chemotherapy group. The confirmed ORRs were 80.0% vs 39.3%, respectively.

In those with BRCA1/2 wildtype disease, the median PFS2 was 19.2 months with Enhertu, compared with 14.9 months with chemotherapy. In those with mutation status, the median PFS2 was 33.7 months vs 11.8 months, respectively. 

Study background

A total of 866 patients were enrolled in the trial, 625 of whom were included in the biomarker-evaluable population.

In the DESTINY-Breast06 trial, patients were randomly assigned, in a 1:1 ratio, to receive either 5.4 milligrams per kilograms of Enhertu once every 3 weeks or physician’s choice of chemotherapy, including either capecitabine, nab-paclitaxel, or paclitaxel. 

Eligible patients in the trial had HR-positive metastatic breast cancer with HER2-low or HER2-ultralow disease and were chemotherapy-naïve in the metastatic breast cancer setting. 

The trial’s primary end point was PFS in HER2-low patients. Secondary and exploratory end points included PFS in the intention-to-treat population, overall survival, PFS2, safety, and biomarkers.

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