18 October marked the presentation of the highly anticipated DESTINY-Breast05 and DESTINY-Breast11 trials at the 2025 European Society for Medical Oncology (ESMO) Congress, held through 17-21 October. These pivotal studies investigated AstraZeneca and Daiichi Sankyo’s Enhertu, a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate with a topoisomerase II-targeting payload, in the neoadjuvant and adjuvant settings of HER2-positive (HER2+) breast cancer (BC). The results signal a major shift for Enhertu from the metastatic to the curative-intent setting.
The DESTINY-Breast11 trial was designed to determine whether four cycles of Enhertu followed by four cycles of a taxane in combination with Roche’s Herceptin (trastuzumab) and Perjeta (pertuzumab), the standard regimen called THP, could improve pathological complete response (pCR) rated, compared with the longstanding standard of four cycles of dose dense anthracycline (ddAC) followed by four cycles of THP in the neoadjuvant HER2+ BC setting. A third arm of eight cycles of Enhertu monotherapy was initially open but closed early when interim analysis showed a low probability of outperforming the control arm. High-risk patients that are both hormone receptor-positive (HR) and HR-negative were selected for this trial.
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Investigators reported that the Enhertu-THP arm of the trial reached a pCR rate of 67.3% versus 56.3% in the ddAC-THP arm, a difference of 11.2% (95% confidence intervals [CI]: 4.0-18.3). Patients who achieve a pCR are known to have markedly lower relapse risk making this a meaningful prognostic endpoint. There was also an early positive trend in event free survival at data cutoff, with 96.9% in the Enhertu-THP arm versus 93.1% in the ddAC-THP arm, though the data is still immature. The Enhertu-THP arm had overall improved safety compared to the ddAC-THP arm with grade 3 or higher treatment-related adverse (TRAEs) being observed in 37.5% of patients in the experimental arm and 55.8% of patients in the control arm. Drug-related interstitial lung disease (ILD) was low in the experimental arm with 4.4% of patients receiving Enhertu-THP experiencing ILD compared to 5.1% of control arm patients.
In the adjuvant setting, DESTINY-Breast-05 randomised patients with residual invasive disease after neoadjuvant therapy to receive Enhertu or the standard of care, Roche’s Kadcyla (trastuzumab emtansine), both administered for 14 cycles. The study met its primary endpoint, showing a marked improvement in invasive disease-free survival with Enhertu at 92.4% compared to 83.7% with Kadcyla (hazard ratio [HR] 0.47, 95% CI 0.34-0.66). Overall survival data was not yet mature, however, was trending positively in favour of Enhertu with a HR of 0.61 (95% CI: 0.34-1.10). Safety signals were similar across both arms with 50.6% of patients in the Enhertu arm experiencing grade 3 or higher TRAEs compared to 51.9% of patients who received Kadcyla. Notably, 10.8% of patients who received Enhertu experienced ILD compared to 2.5% of patients receiving Kadcyla, and this led to an increase in drug discontinuation for Enhertu, which was 17.9% compared to 12.9% for Kadcyla.
Together, DESTINY-Breast11 and DESTINY-Breast-05 redefine the treatment landscape for early HER2-positive breast cancer but also create sequencing uncertainty. Physicians will now have to determine the optimal setting for Enhertu as a neoadjuvant treatment, an adjuvant treatment, or both. One limitation of DESTINY-Breast11 is that the control arm used ddAC, a regimen that has fallen out of favour in many regions. Modern neoadjuvant standards increasingly rely on non-anthracycline regimens such as docetaxel/carboplatin plus trastuzumab and pertuzumab (TCHP), which offer comparable efficacy with reduced cardiotoxicity. As a result, the apparent safety advantage of Enhertu-THP over ddAC-THP may not fully reflect clinical practice. However, the improvement in pCR and the lack of ILD events will likely result in significant uptake of this regimen. Greater complexity arises in adjuvant therapy decisions for patients who receive Enhertu-THP but still have residual disease. In such cases, clinicians will need to weigh whether to re-challenge with Enhertu, which carries cumulative toxicity and potential resistance to its topoisomerase I payload, or to switch to Kadcyla, which delivers a different emtansine microtubule-inhibitor payload. Many oncologists believe that Kadcyla may remain preferred in this residual-disease subgroup, both to minimise overlapping toxicity and to avoid possible cross-resistance.
The key takeaway from these studies is that the question for clinicians is no longer whether to use Enhertu in early HER2-positive breast cancer, but when. This represents highly positive news for AstraZeneca and Daiichi Sankyo, a sentiment reflected in leading data and analytics company GlobalData’s analyst consensus forecast, which projects Enhertu’s annual sales at $14.3bn, compared with $1.0bn for Kadcyla. AstraZeneca and Daiichi’s drug has completely dominated the HER2+ BC space and it is likely that sometime soon, every patient diagnosed with HER2+ BC will receive Enhertu sometime during their treatment.
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