At this year’s virtual annual European Society for Medical Oncology (ESMO) congress on 16–21 September, results from the Phase III DESTINY-Breast03 study for Daiichi Sankyo and AstraZeneca’s Enhertu (trastuzumab deruxtecan) were presented. Patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer, who had previously been treated with Herceptin (trastuzumab) and taxane chemotherapy, were randomised at a 1:1 ratio to receive either Enhertu or Kadcyla (trastuzumab emtansine), with progression-free survival (PFS) being assessed by a blinded independent central review as the primary endpoint.

First-line therapy for metastatic HER2-positive breast cancer consists of Perjeta (pertuzumab) in combination with Herceptin and taxane chemotherapy, as established by results from the CLEOPATRA trial in which the median PFS was 18.7 months. Second-line therapy consists of treatment with Kadcyla, as established after it showed a median PFS of 9.6 months in the EMILIA trial. The recent randomised KATE2 trial, however, showed a more conservative median PFS of 6.8 months for Kadcyla. In the Phase II DESTINY-Breast01 single-arm study, Enhertu demonstrated a median PFS of 19.4 months, calling into question which drug is a better option for second-line therapy.

The open-label, multicentre DESTINY-Breast03 study enrolled 524 patients across 54 countries. Median PFS was not reached, but 12-month PFS with Enhertu treatment was 75.8% compared to Kadcyla’s 34.1%, with a hazard ratio of 0.28. For the key secondary endpoint, the 12-month overall survival probability was 94.1% for Enhertu and 85.9% for Kadcyla, with a hazard ratio of 0.56. A total of 1.1% of patients treated with Enhertu had progressive disease compared to Kadcyla’s 17.5%. No drug-related deaths occurred in either arm, and adverse events were similar between arms, with grade three or higher treatment-related adverse events being experienced by 45.1% of patients receiving Enhertu treatment and 39.8% of patients receiving Kadcyla.

With these significant results from the first randomised Phase III study of Enhertu in breast cancer, Daiichi Sankyo and AstraZeneca believe that this study will lead to a shift in the treatment paradigm of HER2-positive metastatic breast cancer. This is echoed by key opinion leaders interviewed by GlobalData, who state that trial results support Enhertu’s superiority over Kadcyla, and that Enhertu will inevitably replace Kadcyla in the second-line metastatic setting. According to GlobalData’s recent patient-based forecast, sales of Kadcyla in the eight major markets (8MM), namely the US, France, Germany, Spain, Italy, UK, Japan and China, are expected to drop from $1.8bn next year to $589m in 2030 at a negative compound annual growth rate (CAGR) of 13% due to impending patent expiry, biosimilar erosion and competition from agents such as Enhertu. GlobalData forecasts Enhertu’s 8MM sales in HER2-positive breast cancer to rise from $306m next year to $1.43bn in 2030 at a CAGR of 21.2%.