EU approves Enhertu as first HER2-targeted therapy for HR-positive, HER2-low metastatic breast cancer

Enhertu, the antibody-drug conjugate co-developed by AstraZeneca and Daiichi Sankyo, has been authorised in the European Union as a treatment for adult patients with hormone receptor-positive (HR-positive), HER2-low or HER2-ultralow unresectable or metastatic breast cancer. This approval makes Enhertu the first HER2-directed therapy to be available to patients across the spectrum of low HER2 expression. Crucially, it introduces a targeted treatment option for patients who have typically been categorised as HER2-negative and thus excluded from HER2-targeted interventions.

The European Commission‘s decision was based on data from the Phase III DESTINY-Breast06 clinical trial, which showed that Enhertu significantly outperformed chemotherapy in patients with HER2-low breast cancer who had not yet been treated with chemotherapy for their metastatic disease. The data revealed a progression-free survival (PFS) advantage of over five months compared to conventional therapy. This milestone approval expands the eligible patient population to include those with HER2-ultralow expression—a subset that has historically lacked access to precision therapies despite expressing minimal HER2 biomarkers.

What does HER2-low and HER2-ultralow classification mean for breast cancer patients?

The distinction between HER2-low and HER2-ultralow breast cancer has only recently gained traction in clinical oncology. Traditionally, HER2 status was treated as binary: tumours were either HER2-positive or HER2-negative. HER2-positive cancers, which account for around 15–20% of all breast cancers, are characterised by overexpression of the HER2 protein and are known to respond to therapies targeting the HER2 receptor. For years, HER2-negative cases were grouped together and treated primarily with endocrine therapies or, in later stages, chemotherapy.

However, growing evidence suggests that many HER2-negative tumours do, in fact, express HER2 at low levels—defined as immunohistochemistry (IHC) 1+ or 2+ with negative in-situ hybridisation (ISH). This category, termed HER2-low breast cancer, is thought to make up approximately half of all breast cancers, with HER2-ultralow tumours, which show even fainter HER2 staining, also representing a sizable share. These patients had previously received little benefit from HER2-directed therapies due to insufficient HER2 expression for traditional agents to be effective.

Enhertu’s mechanism of action—leveraging a HER2-directed monoclonal antibody linked to a topoisomerase I inhibitor via a cleavable linker—enables it to deliver cytotoxic payloads into cancer cells even with low or ultralow HER2 expression. The approval of Enhertu for these populations validates a new approach to classifying breast cancer and sets a precedent for using antibody-drug conjugates (ADCs) beyond conventional biomarker thresholds.

How did the DESTINY-Breast06 trial lead to the EU approval?

The DESTINY-Breast06 trial was a global, open-label Phase III study designed to evaluate Enhertu against chemotherapy in patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer. These patients had received at least one prior endocrine therapy and were no longer responding to hormonal treatment, yet had not undergone chemotherapy for metastatic disease. The trial enrolled 866 patients across Asia, Europe, North America, Oceania and South America, with HER2 status confirmed by central laboratory testing.

In patients with HER2-low metastatic breast cancer, Enhertu achieved a median PFS of 13.2 months versus 8.1 months for standard chemotherapy. This translated to a hazard ratio of 0.62 and a statistically significant improvement in outcomes. Across the broader trial population, which included HER2-ultralow patients, Enhertu maintained a consistent advantage with a hazard ratio of 0.64. These findings underscore the clinical benefit of targeting HER2 expression even at minimal levels.

The safety profile of Enhertu remained consistent with previous trials, with no new adverse signals identified. Common side effects were manageable and within expectations for the antibody-drug conjugate class, helping to further support its use as a frontline option after endocrine resistance develops.

Why is this approval important for AstraZeneca and Daiichi Sankyo?

The European approval of Enhertu in this expanded setting has significant strategic and financial implications for both AstraZeneca and Daiichi Sankyo. The authorisation unlocks access to a large, previously untapped patient population, potentially increasing Enhertu’s addressable market across Europe. With HR-positive, HER2-negative breast cancer accounting for around 70% of all breast cancer cases, and an estimated 85–90% of those demonstrating HER2-low or HER2-ultralow expression, the potential for Enhertu’s uptake is substantial.

As a result of this approval, AstraZeneca will make a $125 million milestone payment to Daiichi Sankyo, consistent with the 2019 global collaboration agreement. This payment will be capitalised and amortised over time. Daiichi Sankyo will record product sales in most EU territories, while AstraZeneca will report its share of gross profit as alliance revenue or direct product sales depending on regional responsibilities.

Investors have responded favourably to the news. AstraZeneca plc (LON: AZN) has held a steady trajectory near £10,000 per share, supported by a strong oncology pipeline and confidence in Enhertu’s commercial prospects. Market analysts have maintained a “Buy” rating, pointing to the company’s strategic positioning in targeted cancer therapeutics.

Daiichi Sankyo Co., Ltd. (TYO: 4568) has seen more than a 10% rise in its share price over the past month, with investor sentiment buoyed by Enhertu’s expanding label and strong clinical performance. With additional ADCs like Datroway (datopotamab deruxtecan) in the pipeline, Daiichi Sankyo is viewed as a key innovator in the space. Analysts have offered a “Hold to Buy” consensus depending on investment outlook, citing the momentum in HER2-low breast cancer and a growing number of regulatory approvals globally.

How does Enhertu fit into the evolving breast cancer treatment landscape?

Enhertu’s expansion into HER2-low and HER2-ultralow metastatic breast cancer is part of a broader movement to redefine breast cancer subtypes based on deeper biomarker granularity. With the success of DESTINY-Breast04 and DESTINY-Breast06 trials, the binary classification of HER2-positive versus HER2-negative is giving way to a more nuanced understanding of HER2 expression levels and their clinical significance.

This transformation has implications for both diagnostics and treatment. Pathology laboratories are increasingly adopting updated IHC scoring protocols to identify HER2-low and HER2-ultralow disease accurately. Oncologists are adjusting treatment pathways to incorporate HER2-directed ADCs earlier in the metastatic setting. Enhertu’s design allows it to release its cytotoxic payload even in tumours with low antigen density, a mechanism that sets it apart from earlier HER2-targeted therapies.

The ongoing development of Enhertu across other HER2-expressing solid tumours, including gastric, lung, and colorectal cancers, further strengthens its relevance. Regulatory bodies in Japan and other countries are currently reviewing submissions for HER2-low and HER2-ultralow indications, with additional data expected from related trials in 2025.

What does this mean for future cancer care?

The approval of Enhertu for HER2-low and HER2-ultralow metastatic breast cancer marks a critical turning point for precision oncology. It reflects the power of antibody-drug conjugates to target tumours previously considered unsuitable for HER2 therapies and signals a wider shift in how cancers are classified and treated. For patients, the decision opens the door to a more personalised treatment approach that goes beyond endocrine therapy and conventional chemotherapy.

For AstraZeneca and Daiichi Sankyo, Enhertu’s success reinforces their leadership in the rapidly growing ADC market. It also underscores the commercial viability of investing in treatments for biomarker-defined populations that had been overlooked due to legacy classification systems.

The therapeutic momentum behind HER2-low breast cancer, coupled with positive market reaction and ongoing global regulatory activity, suggests that Enhertu is not only addressing an urgent clinical need but is also shaping the next frontier in targeted cancer therapy.