Expanded indication likely for Enhertu in breast cancer

PFS 40 months↑ in Asia trial…the potential for first-line therapy has been emphasized

Pre-operative adjuvant therapy demonstrated superior pathological complete response (pCR) rate compared to the existing standard of care (SOC)

The influence of Enhertu in breast cancer treatment is rapidly expanding. It has been confirmed that Enhertu, in combination with the targeted agent Perjeta, could be a first-line therapy for HER2-positive metastatic breast cancer. Furthermore, Enhertu succeeded in increasing the pathological complete response (pCR) rate by over 10% in the pre-operative adjuvant setting.

According to industry sources on December 8, clinical results for the combination of 'Enhertu (trastuzumab deruxtecan)' and Perjeta were presented at the European Society for Medical Oncology Asia (ESMO Asia 2025) annual meeting recently held in Singapore.

Enhertu, an antibody-drug conjugate (ADC) anticancer agent, is currently approved as a second-line monotherapy for HER2-positive metastatic breast cancer. The developers, AstraZeneca and Daiichi Sankyo, are testing Enhertu's potential as a first-line treatment by combining it with Perjeta, which is used in the current standard THP.

The DESTINY-Breast09 Phase 3 study enrolled 1,157 patients with previously untreated HER2-positive advanced breast cancer, including 346 Asian patients from Korea, Japan, China, Taiwan, and the Philippines.

The Asia cohort analysis results of the DESTINY-Breast09 Phase 3 study, evaluating the potential of Enhertu + Perjeta combination therapy as a first-line treatment, were presented at ESMO ASIA 2025, a three-day event held since December 5.

The Asian cohort was randomized to receive treatment in the Enhertu + Perjeta group, the Enhertu + placebo group (maintaining the blind), or the THP group.

The median Progression-Free Survival (PFS) based on Blinded Independent Central Review (BICR) for the Enhertu + Perjeta group was 40.7 months. This represents a 45% reduction in the risk of progression compared to the THP group (24.7 months), reproducing the trend confirmed in the global analysis within the Asian patient population.

The difference was also significant in terms of response rates. The confirmed Objective Response Rate (ORR) for the Enhertu + Perjeta group was 89.7%, compared to 84.3% for the THP group. The Complete Response (CR) rate was also higher at 17.8% compared to 12.8% in the control group. The Duration of Response (DOR) was 39.2 months and 26.3 months, respectively, sustaining the superiority of the Enhertu combination therapy.

The safety profile was similar to existing data. Adverse events over Grade 3 occurred in 63.4% of the Enhertu combination group versus 72.5% in the THP group, and serious adverse events occurred in 22.9% and 22.8%, respectively.

However, drug-related Interstitial Lung Disease (ILD)/pneumonitis occurred in 18.9% of the Enhertu combination group (mostly Grade 1/2), with Grade 5 cases reported in 0.6%. The ILD incidence in the THP group was relatively low at 1.8%.

The investigators assessed, "The results of this Asian analysis are highly significant as they further support the possibility that the Enhertu + Perjeta combination could become the new standard of care (SOC) for first-line treatment," and added, "While Perjeta-based antibody treatment has been the standard for HER2-positive breast cancer, the ADC Enhertu is rapidly expanding its influence into this area. Therefore, a shift in the treatment landscape is expected, noting that "

Enhertu improves response rate in the pre-operative adjuvant therapy setting

Enhertu's potential for expanded indication is also being confirmed in the pre-operative adjuvant therapy setting. Achieving pathological complete response (pCR) in advanced breast cancer is a key indicator for lowering recurrence risk and increasing long-term survival. However, even with the current SOC, with Herceptin, Perjeta, and cytotoxic chemotherapy, half of the patients fail to achieve pCR.

The Phase 3 DESTINY-Breast11 study was designed to overcome the limitations of existing neoadjuvant therapies, enrolling 927 patients with advanced HER2-positive breast cancer.

Professor Nadia Harbeck of LMU University Hospital, based in Munich, Germany, is presenting the results of Enhertu's DESTINY-Breast11 study at ESMO ASIA 2025.

The clinical results showed that the pCR rate for the Enhertu combination group was 67.3%, which was 11.2 percentage points higher than the standard treatment group (ddAC-THP: dose-dense Doxorubicin and Cyclophosphamide followed by THP combination therapy, at 56.3%). The investigators explained that a double-digit difference is highly significant in early breast cancer.

Consistent improvement was confirmed across patient subsets. In Hormone Receptor (HR) positive patients, the pCR for the Enhertu combination was 61.4%, approximately 9.1 percentage points higher than the ddAC-THP group (52.3%). The difference was even greater in HR negative patients.

Investigators assessed, "Increased pCR by over 10% indicates the potential for expanded utilization of Enhertu as a pre-operative adjuvant therapy. This could potentially minimize the required dose, which would not interfere with subsequent treatment options."