AstraZeneca and Daiichi Sankyo’s star drug Enhertu has delivered a double knockout, showing its ability to stave off early breast cancer in two pivotal clinical trials.
First, in another major head-to-head win against Roche’s rival antibody-drug conjugate Kadcyla, Enhertu significantly pared down the risk of invasive disease recurrence or death by 53% when used as an adjuvant therapy after surgery in HER2-positive early breast cancer. The patients had residual invasive disease following neoadjuvant treatment and are considered at high risk of recurrence.
At the time of the analysis, 12.5% of patients who got Kadcyla have developed invasive disease or died, versus 6.2% among Enhertu takers. The data, from the Destiny-Breast05 study, will be presented during a presidential symposium at the 2025 European Society for Medical Oncology Congress.
Data were similar for the secondary endpoint of disease-free survival, with Enhertu showing a 53% improvement and a lower rate of recurrence or death at 6.4% at the data cutoff, compared with 12.6% for Kadcyla.
In a separate study dubbed Destiny-Breast11 also presented at ESMO 2025, neoadjuvant Enhertu, used on top of the THP regimen (the chemo Taxol, Herceptin and Perjeta), helped significantly more patients achieve no sign of cancer cells in resected tissues during surgery compared with the traditional chemo-THP regimen.
Specifically, 67.3% of patients in the Enhertu arm achieved what’s known as a pathological complete response, versus 56.3% of those in the control arm. Again, the patients had high-risk, HER2-positive early breast cancer.
The 11-percentage-point absolute difference is “a big deal” in the eyes of experts in this potentially curative setting, Abderrahmane Laadem, M.D., Daiichi’s head of oncology late-stage development, said in an interview with Fierce Pharma.
“The generally manageable safety profile and the superior efficacy data suggested that [Enhertu] should replace [Kadcyla] as the new standard of care for patients with HER2-positive, residual invasive breast cancer after neoadjuvant therapy,” Evandro de Azambuja, M.D., Ph.D., from the Jules Bordet Institute in Belgium, said in an Oct. 18 ESMO press release.
Investigators said the Destiny-Breast11 results support neoadjuvant Enhertu-THP “as a potential new anthracycline-free regimen with improved efficacy and less toxicity” in high-risk HER2-positive early breast cancer.
Grade 3 or higher adverse events happened in 37.5% of patients who got neoadjuvant Enhertu-THP versus 55.8% in the chemo-THP arm. The traditional chemo regimen includes doxorubicin, an anthracycline, a class that’s associated with serious heart toxicity. In Destiny-Breast11, left ventricular dysfunction was recorded in 1.9% of patients in the experimental arm versus 9% in the control group.
In the adjuvant trial, grade 3 or above treatment-emergent adverse events were similar between Enhertu and Kadcyla, at 50.6% and 51.9%, respectively. The rate of adjudicated drug-related interstitial lung disease, a side effect of interest for Enhertu and all ADCs based on Daiichi’s DXd technology, was higher for the Enhertu arm at 9.6% versus 1.6% for Kadcyla. These included two deaths (0.2%) for Enhertu, but none for Kadcyla. Nevertheless, deaths associated with overall adverse events occurred in 0.4% and 0.6% of patients, respectively.
As for the neoadjuvant study, adjudicated interstitial lung disease or pneumonitis occurred in 4.4% and 5.1% of patients in Enhertu-THP and chemo-THP, respectively.
“In conjunction, these two studies establish [Enhertu] as a critical treatment option for early-stage HER2-positive breast cancer, ultimately providing a new tool for treatment tailoring for what was once considered the most aggressive subtype of breast cancer, and which today represents the one with the highest chance of cure,” Paolo Tarantino, M.D., from the Dana-Farber Cancer Institute, said in the Oct. 18 ESMO release.
After Enhertu beat Kadcyla head-to-head in second-line HER2-positive breast cancer, the AZ/Daiichi ADC has taken over 70% of the U.S. second-line market share, leaving about 10% to Kadcyla and the rest a “smorgasbord of stuff,” Daiichi’s head of the global oncology business, Ken Keller, said in an interview with Fierce.
For the adjuvant setting, if Enhertu is approved following the head-to-head win, “it’s hard to imagine this not being a rapid switchover,” Keller said.
For high-risk patients with residual disease, adjuvant Kadcyla is used ubiquitously, with little room for further overall market expansion, Keller said. About 40% of Kadcyla’s U.S. sales are coming from adjuvant breast cancer, he noted. In 2024, Kadcyla’s sales were 765 million Swiss francs in the U.S., or 38% of the drug’s total haul.
In both trials, data remained immature for some of the longer-term endpoints. In the Destiny-Breast05 adjuvant trial, Enhertu is linked to a very preliminary 39% reduction in the risk of death versus Kadcyla, produced at below 5% data maturity, according to Keller.
In the Destiny-Breast11 neoadjuvant study, the Enhertu regimen showed an early 44% improvement on event-free survival, again at below 5% data maturity.
While these data are highly immature, Keller argued that they add to the overall confidence to Enhertu as the star ADC gradually moves into earlier treatment settings.
A new question
Strong data aside, the two new early-stage readouts have created a new question. Because Destiny-Breast05 was conducted in patients who had residue disease after receiving traditional neoadjuvant therapy—such as the chemo-THP regimen in the control arm of Destiny-Breast11—it’s unclear whether the findings can apply to Enhertu-THP. Namely, if Enhertu-THP is approved as a neoadjuvant therapy, doctors will face the practical question of whether to use Enhertu again in the adjuvant setting if patients still have residue disease. For regulators, it means whether to specify—and therefore restrict—the drug’s adjuvant use in its label.
Enhertu is only proposed to be used for four cycles in the neoadjuvant setting, AstraZeneca’s oncology R&D head Susan Galbraith, Ph.D., noted.
“If you’ve only had four cycles of Enhertu and you’ve had a really good response, I don’t think that that says that you’re going to necessarily be resistant to Enhertu for a re-challenge in that setting,” Galbraith said.
Daiichi’s Laadem cited similar feedback from scientific advisers. He said the experts told him they “wouldn’t flinch too much about retreating” patients with Enhertu if they have residual disease following neoadjuvant Enhertu.
“The key that they highlighted is, it’s only four cycles; this is not like I treated to progression,” he said.
Both Galbraith and Laadem acknowledged that, while this argument makes sense, this scenario is not what the Enhertu trials were designed to address. The possibility exists that residual disease simply means neoadjuvant Enhertu doesn’t work, and AZ and Daiichi currently do not have the data to counter that argument.
Even if this question won’t affect Enhertu’s broad approvability, it will affect the drug’s overall treatment duration in the real world.
This treatment duration question has also turned up in Enhertu’s proposed first-line use in HER2-positive advanced breast cancer. Even though the drug is designed to be given until disease progression in the Destiny-Breast09 trial, doctors have floated the idea of using a sans-Enhertu regimen during the maintenance phase of treatment.
Enhertu’s first-line application is under FDA priority review, with a decision expected by Jan. 23, 2026. Its neoadjuvant application has just been accepted by the FDA, with a target action date set for May 18, 2026. The adjuvant readout was newer, as AZ and Daiichi are still talking to the agency.