With the release of data from studies such as DESTINY-Breast09 (DB-09), antibody–drug conjugates (ADCs) are gaining increasing prominence in the first-line treatment of HER2-positive metastatic breast cancer (MBC). However, while the traditional THP regimen (trastuzumab + pertuzumab + taxane) remains firmly established as the guideline-preferred standard, the question remains: has the “era of ADC dominance” truly begun? During the “Deep Dive” session at the 8th North–South Breast Cancer Forum, Professor Leiping Wang from Fudan University Shanghai Cancer Center addressed this question. She emphasized that although ADCs have opened the door to first-line therapy with impressive progression-free survival (PFS) benefits, their full integration into clinical practice still requires further validation, particularly in the context of refined disease management and treatment sequencing.The arrival of ADCs: a breakthrough in first-line therapy
Professor Leiping Wang: There is no doubt that the emergence of ADCs represents one of the most transformative developments in the treatment landscape of HER2-positive metastatic breast cancer. As of 2026, it is essential to critically examine whether ADCs have truly established themselves as first-line therapy.
From the standpoint of clinical evidence, ADCs have already secured a place in first-line treatment. At the 2025 ASCO Annual Meeting, the interim analysis of the DESTINY-Breast09 trial demonstrated that the combination of trastuzumab deruxtecan (T-DXd) plus pertuzumab significantly prolonged median PFS compared with the THP regimen (40.7 vs 26.9 months; HR 0.56; 95% CI 0.44–0.71; P < 0.00001), representing an absolute improvement of 13.8 months.
These findings provided strong support for the use of ADC-based combinations in the first-line setting. Subsequently, the U.S. Food and Drug Administration approved this combination in December 2025 for first-line treatment of HER2-positive breast cancer, and the NCCN Breast Cancer Guidelines (Version 2, 2026) incorporated ADC plus pertuzumab as a recommended option.
In this sense, ADCs have clearly “arrived.”
Why the ADC era has not fully arrived
Despite these advances, it may be premature to declare the arrival of a true “ADC era.” For such a designation, ADC-based regimens would need to become the preferred first-line standard rather than one of several recommended options.
According to the NCCN Guidelines (2026.V2), the THP regimen continues to hold its position as the category 1 preferred regimen, a status it has maintained for over 14 years. ADC-based combinations, by contrast, are currently listed as “other recommended regimens.”
The continued dominance of THP is supported by increasingly refined maintenance strategies. For example, the PATINA study demonstrated that in patients with HR+/HER2+ (triple-positive) disease, the addition of endocrine therapy and CDK4/6 inhibitors to dual HER2 blockade resulted in remarkably prolonged PFS, with total effective treatment duration potentially exceeding four years.
While this duration appears numerically superior to that reported in DB-09, several factors must be considered. First, such outcomes apply only to hormone receptor–positive patients. Second, the median follow-up in DB-09 remains relatively short (less than 30 months), and the reported median PFS of 40.7 months is still evolving. Third, although endocrine therapy was permitted in DB-09, only a small proportion of eligible patients received it. Broader and more optimized use of endocrine therapy—potentially combined with CDK4/6 inhibitors during maintenance—may further enhance outcomes in ADC-treated patients.
In China, additional first-line options have emerged based on the PHILA study, where a combination of small-molecule tyrosine kinase inhibitors (TKIs) such as pyrotinib with trastuzumab and chemotherapy provides another effective strategy. Notably, TKIs offer advantages such as oral administration and activity against brain metastases.
Where ADCs show clear strengths
ADCs have demonstrated notable efficacy in specific patient subgroups. In the DB-09 trial, the hazard ratio for patients with brain metastases was 0.30, suggesting substantial benefit, although the sample size was limited and warrants cautious interpretation. Nonetheless, accumulating evidence from studies such as DESTINY-Breast12 indicates that brain metastases are not a barrier to ADC use.
In addition, ADCs have shown promising activity in patients with PIK3CA mutations, a subgroup typically associated with poorer prognosis. These findings provide a potential new first-line strategy for this high-risk population.
Unresolved questions: sequencing and the “SONIA debate”
A key unresolved issue is treatment sequencing. If ADCs are used upfront as a highly potent “early strike,” does this limit options for subsequent lines of therapy? Although DB-09 demonstrated some advantage in second progression-free survival (PFS2), the relatively low crossover rate to T-DXd in the THP arm complicates interpretation.
This dilemma echoes the “SONIA question” in HR+/HER2– breast cancer, regarding whether CDK4/6 inhibitors should be used in the first or second line. Similarly, the optimal positioning of ADCs—whether as first-line therapy or reserved for later use—remains a topic of ongoing debate.
From a safety perspective, ADC-related adverse events such as gastrointestinal toxicity and fatigue are present but generally manageable, and overall quality-of-life data suggest acceptable tolerability.
Clinical perspective: a pragmatic approach to ADC use
Professor Wang summarized her clinical perspective as follows: For patients with aggressive disease or features of treatment resistance, ADC-based combinations are recommended, as more intensive therapy may achieve rapid and effective disease control and prevent early progression that could preclude subsequent treatment.
For patients with de novo stage IV disease and limited metastatic burden, ADC-based regimens may also be preferred, as deeper responses may be achievable. In selected cases, combining systemic therapy with local treatment could potentially lead to outcomes exceeding expectations.
Conclusion
In light of consistent and even more favorable results observed in the Chinese subgroup of DB-09, the era of ADC-based first-line therapy for HER2-positive metastatic breast cancer has clearly begun.
However, replacing the long-established THP regimen as the universal standard will require further evidence, including results from ADC monotherapy arms, longer follow-up data, optimized sequencing strategies, and improved management of adverse events.
In summary, ADCs have arrived—but the era of their full dominance is still on the horizon.
Expert profile
Leiping Wang, MD
Professor of Medical Oncology Fudan University Shanghai Cancer Center
Professor Wang specializes in the systemic treatment of breast cancer, with a focus on optimizing individualized therapeutic strategies in advanced disease.
