After failure of tyrosine kinase inhibitor (TKI) therapy, treatment options for patients with HER2-positive metastatic breast cancer (MBC) mainly include next-generation anti-HER2 antibody–drug conjugates (ADCs) or dual HER2 blockade with pertuzumab and trastuzumab plus chemotherapy (HP+C). Although our previous work indicated meaningful clinical benefit from novel anti-HER2 ADCs in TKI-refractory disease, comparative evidence between these agents and HP-based chemotherapy is lacking. This study aimed to evaluate and contrast the clinical outcomes and tolerability of these two strategies in patients with prior TKI exposure. We retrospectively reviewed patients with HER2-positive MBC who had received TKIs and were subsequently treated with either novel anti-HER2 ADCs or HP in combination with chemotherapy between January 2019 and August 2023. Progression-free survival (PFS) was the primary outcome. Secondary outcomes included objective response rate (ORR), clinical benefit rate (CBR), and treatment-related adverse events. A total of 150 patients were analyzed, with 83 receiving novel anti-HER2 ADCs and 67 treated with HP plus chemotherapy. Within the ADC cohort, 36 patients were administered trastuzumab deruxtecan (T-DXd), while 47 received other investigational ADCs. Median PFS was 7.0 months in the ADC group and 8.9 months in the HP+C group. The ADC cohort achieved a higher ORR than the HP+C cohort (51.8% vs. 26.9%), whereas CBR was comparable between groups (69.9% vs. 65.7%). Subgroup analysis demonstrated superior PFS in patients treated with T-DXd compared with those receiving HP combined with chemotherapy. Severe (grade 3–4) toxicities were predominantly hematologic and gastrointestinal in both treatment arms. In patients with HER2-positive MBC who progress after TKI therapy, both novel anti-HER2 ADCs and HP combined with chemotherapy provide clinically meaningful disease control with manageable safety profiles. Anti-HER2 ADCs, particularly T-DXd, may represent the preferred therapeutic approach following TKI failure. However, HP combined with chemotherapy remains a reasonable alternative in circumstances where access to ADCs is limited.
