In Part 2 of this series, we focus on Enhertu (trastuzumab deruxtecan), the DXd-based ADC from AstraZeneca and Daiichi Sankyo that has already transformed the treatment of advanced HER2-positive and HER2-low breast cancer. At ESMO 2025, Enhertu delivered pivotal readouts in early-stage HER2-positive breast cancer, raising the prospect that ADCs could reshape treatment algorithms even in settings where cure is the goal.
Specifically, we examine two key trials:
- DESTINY-Breast05, in which adjuvant Enhertu outperformed Kadcyla (T-DM1) in patients with residual invasive disease after neoadjuvant therapy
- DESTINY-Breast11, where neoadjuvant Enhertu plus THP (taxane, trastuzumab, pertuzumab) achieved a higher pathological complete response (pCR) rate than the traditional anthracycline-containing THP regimen, pointing to a potential anthracycline-free regimen
Together, these trials suggest that Enhertu could bookend the neoadjuvant–adjuvant sequence in high-risk early HER2-positive disease. At the same time, they raise new questions about safety, retreatment and how far we should go in replacing chemotherapy with ADCs in curative settings.
Why Enhertu in early disease matters now
HER2-positive breast cancer was once considered one of the most aggressive subtypes, but with trastuzumab, pertuzumab and T-DM1, it has become a disease where cure is realistic for many patients. Enhertu has already displaced Kadcyla in the second-line advanced setting and is moving into earlier lines of metastatic disease. The ESMO 2025 data extend that story into early-stage disease.
The key shift is conceptual: ADCs are no longer just salvage therapies for advanced disease. They are now being tested—and in Enhertu’s case, succeeding—as backbone components of curative-intent regimens. This has implications not only for efficacy, but also for how we think about acceptable toxicity and long-term risk.
DESTINY-Breast05: adjuvant Enhertu vs. Kadcyla in high-risk patients
DESTINY-Breast05 enrolled patients with high-risk HER2-positive early breast cancer who had residual invasive disease after standard neoadjuvant therapy. In this setting, adjuvant Kadcyla has been the standard of care based on prior trials showing improved outcomes compared with continued trastuzumab.
In the ESMO 2025 readout, adjuvant Enhertu achieved a ~53% reduction in the risk of invasive disease recurrence or death compared with Kadcyla, as measured by invasive disease-free survival (IDFS). Event rates were roughly halved: around 6% in the Enhertu arm versus about 12% in the Kadcyla arm at the time of the interim analysis. Early overall survival data, while immature, suggested a trend toward a substantial reduction in the risk of death as well.
These numbers strongly support Enhertu as a new benchmark in this high-risk population. However, the safety profile needs to be weighed carefully. The overall rates of grade 3 or higher treatment-emergent adverse events were similar between the two arms, but Enhertu was associated with a higher incidence of drug-related interstitial lung disease (ILD), including rare fatal cases. In a curative setting, even a small absolute increase in life-threatening toxicity carries significant ethical and practical weight.
DESTINY-Breast11: toward an anthracycline-free neoadjuvant regimen
DESTINY-Breast11 explored the neoadjuvant use of Enhertu in combination with THP—an anthracycline-free regimen—versus a standard anthracycline-containing THP regimen in patients with high-risk HER2-positive early breast cancer.
The key finding was a higher pathological complete response (pCR) rate in the Enhertu+THP arm—about 67%—versus roughly 56% with standard chemo-THP, corresponding to an absolute difference of around 11 percentage points. In the curative early-stage setting, this magnitude of pCR improvement is clinically meaningful, especially when considered alongside toxicity.
Anthracyclines are well known for cumulative cardiotoxicity and other long-term adverse effects. In DESTINY-Breast11, the anthracycline-free Enhertu+THP arm showed fewer grade 3 or higher adverse events overall and a lower incidence of left ventricular dysfunction compared with the anthracycline-containing regimen. However, ILD/pneumonitis remained an important safety signal with Enhertu, even if the absolute incidence was relatively modest.
Taken together, the data support Enhertu+THP as a potential new neoadjuvant option that improves pCR while avoiding anthracyclines, particularly attractive for younger patients, those with pre-existing cardiac risk, or settings where long-term cardiac safety is a priority.
Safety trade-offs: ILD versus anthracycline-related toxicity
The emerging picture in early-stage HER2-positive disease is not “Enhertu is safer than chemo,” but rather that we are trading one toxicity profile for another. Anthracyclines carry well-established risks of cardiomyopathy and secondary malignancies; Enhertu introduces the risk of ILD/pneumonitis and other ADC-specific events.
In advanced disease, the benefit of Enhertu is often so large that many clinicians and patients are willing to accept ILD risk when managed with careful monitoring and early intervention. In early disease, where many patients may already be cured with existing regimens, the balance is less straightforward. The bar for tolerating life-threatening toxicity is higher, and long-term follow-up will be crucial to fully understand the net benefit.
Practically, treatment decisions will likely hinge on individual patient factors—age, comorbidities, baseline cardiac function, pulmonary status—and on shared decision-making that incorporates patient values regarding risk and benefit.
How treatment algorithms could evolve
Current algorithms typically involve neoadjuvant chemo plus anti-HER2 therapy, followed by adjuvant Kadcyla in patients with residual invasive disease. If regulatory approvals follow the DESTINY-Breast05/11 data, several shifts may occur:
- For high-risk patients, neoadjuvant Enhertu+THP could become a preferred option, especially when anthracyclines are undesirable.
- In patients with residual disease after neoadjuvant therapy, adjuvant Enhertu could replace Kadcyla as the default choice.
- Clinicians may consider, at least in theory, double exposure to Enhertu—both neoadjuvant and adjuvant—in selected patients, although this strategy is not directly supported by current trial designs.
The last point highlights a major evidence gap: DESTINY-Breast05 compared adjuvant Enhertu to Kadcyla after standard neoadjuvant therapy, not after neoadjuvant Enhertu. Whether patients who receive Enhertu up front should receive it again in the adjuvant setting if they have residual disease is an open question, with no randomized data yet to guide practice.
New clinical questions: retreatment and total exposure
At ESMO, investigators and discussants repeatedly raised the question of Enhertu retreatment. If a patient receives four cycles of Enhertu in the neoadjuvant setting and still has residual invasive disease, does that imply resistance, or is there still a rationale to re-use Enhertu as adjuvant therapy?
Sponsors and some experts have argued that short neoadjuvant exposure does not necessarily equate to full resistance, and that retreatment may be reasonable. Others caution that residual disease could signal insufficient sensitivity to Enhertu and that exposing patients to further ILD risk without clear incremental benefit may be hard to justify. Until more data accumulate—whether from post-hoc analyses, new trials or real-world evidence—these decisions will likely be individualized and somewhat heterogeneous across centers.
Market impact: a second round of Kadcyla-to-Enhertu replacement
In the second-line advanced setting, Enhertu has already claimed more than 70% of the U.S. market share, with Kadcyla relegated to a small minority of patients. The early-stage adjuvant setting is smaller in absolute numbers, but commercially important due to treatment duration and pricing.
If Enhertu secures approval as adjuvant therapy in high-risk patients with residual disease, a rapid shift away from Kadcyla in this niche seems likely. Coupled with a potential move into the neoadjuvant setting, this would represent a “second wave” of Kadcyla displacement, this time in the curative early-stage arena. Strategically, it underscores how ADC class leaders can extend their franchises by progressively migrating from late-line to early-stage disease.
Implications for Japanese practice and industry
For clinicians in Japan and elsewhere, the Enhertu data highlight the need to adapt to faster cycles of standard-of-care change driven by global trials. In early HER2-positive breast cancer, even modest improvements in pCR or IDFS can translate into meaningful long-term gains, but only if new regimens are implemented thoughtfully and safely.
For Japanese pharma and biotech, Enhertu’s trajectory—from metastatic salvage therapy to potential neoadjuvant and adjuvant backbone—offers a blueprint for how targeted agents and ADCs can expand their impact over time. The key lesson is that success in advanced disease is only the first step; to compete globally, companies must also consider when and how to move into earlier lines and stages, and how to manage the stricter safety and cost-effectiveness thresholds that apply there.
My Thoughts
To me, the Enhertu story in early HER2-positive breast cancer is a turning point in the long-running debate over whether ADCs can truly replace chemotherapy in curative settings. DESTINY-Breast05 and 11 show that, at least in some high-risk populations, ADC-based regimens can deliver superior efficacy and, in the case of anthracycline-free approaches, more favorable toxicity profiles in certain dimensions. At the same time, the ILD signal forces us to confront a more nuanced question: not simply “Is this drug effective?” but “What level of life-threatening toxicity is acceptable when many patients might already be cured with existing regimens?” For Japanese innovators, the challenge is not to copy Enhertu, but to think carefully about where their own ADCs or other modalities should enter the disease course, and with what safety profile. Designing drugs and regimens that are viable in early disease will require a very deliberate balance of potency, selectivity and tolerability, as well as earlier engagement with regulators, payers and patient groups. If that balance can be struck, the move of ADCs into curative-intent settings may create new opportunities for focused, high-quality players—not just for the current global giants.
This article has been edited by the Morningglorysciences team.
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