HER2-positive metastatic breast cancer, caused by the overexpression of the HER2 protein, accounts for 15% to 20% of all metastatic breast cancers and is a relatively aggressive type.
The advent of therapies targeting HER2 has improved survival rates, but in many cases the disease still worsens within an average of two years after starting first-line treatment. The THP regimen (a combination of a taxane, trastuzumab, and pertuzumab), which has been the standard of care for more than 10 years, also has not overcome these limitations.
Among these, Enhertu (ingredient name trastuzumab deruxtecan), an Antibody-Drug Conjugate (ADC) jointly developed by AstraZeneca and Daiichi Sankyo, is drawing attention after delivering overwhelming results over the THP regimen in a global phase 3 trial.
There is also talk that the market for HER2-positive breast cancer therapies could be reshaped. According to the market research firm Mordor Intelligence, the market for HER2-positive targeted therapies is expected to grow to $13.4 billion (about 18.78 trillion won) by 2030.
◇ New first-line standard? Enhertu combination beats 'standard' THP
The trial (DESTINY-Breast09) enrolled 1,157 patients worldwide with HER2-positive advanced or metastatic breast cancer who had received neoadjuvant or adjuvant therapy and had no recurrence for at least six months. Patients were randomly assigned to three groups: Enhertu monotherapy; Enhertu plus pertuzumab combination therapy (T-DXd+P); and the THP regimen. Patients who had received endocrine therapy after metastasis were also included.
The primary endpoint was progression-free survival (PFS). AstraZeneca said, "If adverse events occurred during Enhertu treatment, patients were switched to trastuzumab to continue therapy, and after a certain point endocrine therapy could be added as designed."
In an interim analysis first presented on Jun. 6 at the American Society of Clinical Oncology annual meeting (ASCO 2025), the Enhertu plus pertuzumab combination showed a record-high result in PFS. The median PFS was 40.7 months for the Enhertu combination group and 26.9 months for the THP control group. In other words, the Enhertu combination extended the period without disease progression by more than about 14 months.
The difference in progression-free survival rates was also clear. The 6-, 12-, and 18-month progression-free survival rates in the Enhertu combination group were 93.0%, 85.9%, and 70.1%, respectively. The THP control group recorded 87.8%, 72.4%, and 52.1%.
The risk of disease progression or death was also 44% lower in the Enhertu combination group than in the THP control group. Objective response rate (ORR), the proportion of patients whose tumors shrank by a prespecified amount after anticancer treatment, and complete response rate (CR), in which the tumor completely disappears and is generally interpreted as a cure, were 85.1% and 15.1%, respectively, higher than in the THP control group (78.6% and 8.5%). The median duration of response (DoR) was also 39.2 months in the Enhertu combination group, more than one year longer than in the THP group (26.4 months).
Subgroup results for Asian patients, presented on Dec. 6 (local time) at the European Society for Medical Oncology Asia (ESMO Asia 2025), were broadly consistent.
Comparing the Enhertu combination group (174 patients) with the THP control group (172 patients), the median PFS was 40.7 months and 27.4 months, respectively. The 24-month progression-free survival rates were 73.7% and 52.8%, similar to the overall cohort. The risk of disease progression or death was 45% lower in the Enhertu combination group than in the THP control group.
ORR and CR in the Enhertu combination group were 89.7% and 17.8%, respectively, while the THP control group recorded 84.3% and 12.8%. The median DoR was also 39.2 months in the Enhertu combination group, more than one year longer than the THP control group's 26.3 months.
◇ Effect confirmed… but "it's early to make it first-line for all patients"
Park Kyunghwa, a professor of medical oncology at Korea University Anam Hospital, said the results are meaningful in meeting "unmet needs" in the field.
Park said, "The THP regimen has been established as the first-line standard of care over the past 10 years and is covered by national health insurance, which has greatly extended overall survival," adding, "Even so, there are limitations in preventing or treating brain metastases, which occur in about 25% of patients." Park also said, "In cases with resistance-driving genes such as a 'PIK3CA mutation,' PFS can be shorter than in patients without the mutation."
Park added, "This trial included about 10% of patients with brain metastases and patients with PIK3CA mutations, and all showed consistently superior efficacy compared with the THP regimen. This confirms a clear treatment benefit in special patient groups."
As for why outcomes improved even in patients with brain metastases, Park pointed to Enhertu's pharmacologic properties. Park said, "The payload of Enhertu, an anticancer substance with cytotoxicity, is an exatecan derivative known to have excellent diffusion, enabling it to cross the blood-brain barrier (BBB)," adding, "T-DM1, also an ADC-class anticancer drug, is effective in patients with brain metastases, but exatecan's diffusion is far superior to that of emtansine, the payload in T-DM1."
However, Park cautioned against unconditional expectations. Park said, "The Enhertu combination may not be suitable as first-line therapy for all patients," adding, "For patients who are HER2-positive and also hormone receptor–positive (HR+), the THP regimen can be considered first. Combining the THP regimen with Pfizer's CDK4/6 inhibitor Ibrance (ingredient name palbociclib) can also maintain long-term survival."
Kim Sungbae, a professor of medical oncology at Asan Medical Center, also said, "Over the past 15 years, no regimen has surpassed THP in the first-line setting," adding, "The superiority of the Enhertu combination in this trial is significant in itself." However, Kim also said, "THP still works well, and Enhertu can cause interstitial lung disease (ILD) in roughly 10% of patients," emphasizing, "For the Enhertu combination to become established as first-line therapy, a stepwise strategy is needed."
Kim said, "For example, there is still no evidence as to whether the THP regimen can be used after using Enhertu in combination with pertuzumab," adding, "In theory, if stronger treatment fails, weaker treatment would not be expected to work, but in reality that is not always the case. That is why we need to try multiple strategies and accumulate data."