Enhertu vs Herzuma for HER2-Positive Breast Cancer
For HER2-positive metastatic breast cancer, Enhertu (trastuzumab deruxtecan) is now the superior choice over Herzuma (trastuzumab) in second-line and beyond settings, while first-line treatment should use trastuzumab plus pertuzumab plus a taxane unless Enhertu-based regimens become standard based on the most recent 2025 evidence.
Treatment Line Determines the Optimal Agent
First-Line Treatment: Trastuzumab-Based Regimens Remain Standard
The combination of trastuzumab, pertuzumab, and a taxane is the established first-line treatment for HER2-positive advanced breast cancer unless contraindications to taxanes exist 1.
This regimen demonstrated a 34% reduction in risk of death (HR 0.66, P=0.0008) with median progression-free survival of 18.5 months versus 12.4 months compared to trastuzumab plus taxane alone 1.
However, the 2025 DESTINY-Breast09 trial showed that trastuzumab deruxtecan plus pertuzumab as first-line therapy achieved median progression-free survival of 40.7 months versus 26.9 months with standard trastuzumab/pertuzumab/taxane (HR 0.56, P<0.00001), representing a paradigm shift that will likely change first-line recommendations 2.
Chemotherapy should continue for 4-6 months or until maximal response, while HER2-targeted therapy continues until progression or unacceptable toxicity 1, 3.
Second-Line Treatment: Enhertu is Superior
If disease progresses during or after first-line HER2-targeted therapy, trastuzumab deruxtecan is now the recommended second-line treatment based on the most recent evidence 3.
The DESTINY-Breast02 trial (2023) demonstrated that trastuzumab deruxtecan achieved median progression-free survival of 17.8 months versus 6.9 months with treatment of physician's choice (capecitabine plus trastuzumab or capecitabine plus lapatinib), with HR 0.36 (P<0.0001) 4.
This represents a 64% reduction in risk of progression or death compared to continuing trastuzumab-based therapy 4.
If trastuzumab deruxtecan is unavailable, trastuzumab emtansine (T-DM1) should be offered as second-line treatment, though it is inferior to trastuzumab deruxtecan 1, 3.
Third-Line and Beyond: Continue HER2-Targeted Therapy
For patients who have not received T-DM1, it should be offered in third-line or beyond 1.
For patients who have not received pertuzumab, it may be considered, though evidence is limited 1.
After both pertuzumab and T-DM1, options include lapatinib plus capecitabine, other chemotherapy combinations with trastuzumab, or lapatinib plus trastuzumab 1.
Key Differences Between Enhertu and Herzuma
Mechanism and Efficacy
Enhertu (trastuzumab deruxtecan) is an antibody-drug conjugate that delivers cytotoxic payload directly to HER2-positive cells, providing superior efficacy compared to naked antibody trastuzumab (Herzuma) 5, 6.
Enhertu demonstrated 60.3% confirmed overall response rate in heavily pretreated patients who had received two or more prior anti-HER2 regimens, with median duration of response of 14.8 months 6.
Herzuma (trastuzumab biosimilar) functions identically to reference trastuzumab, blocking HER2 signaling but without cytotoxic payload 7.
Safety Profile Differences
Interstitial lung disease (ILD)/pneumonitis is the critical safety concern with Enhertu, occurring in 10-12% of patients, including rare grade 5 (fatal) events 4, 2, 6.
Enhertu requires careful monitoring for ILD symptoms (cough, dyspnea, fever) and prompt dose interruption or discontinuation if ILD is suspected 5, 6.
Cardiac toxicity is a concern with both agents, but trastuzumab (Herzuma) has lower rates of severe hematologic toxicity compared to Enhertu 7, 4.
Common adverse events with Enhertu include nausea (73%), vomiting (38%), alopecia (37%), and fatigue (36%), which are more frequent than with trastuzumab alone 4.
Special Considerations for Hormone Receptor-Positive Disease
For patients with both hormone receptor-positive and HER2-positive disease, HER2-targeted therapy plus chemotherapy provides the strongest evidence for survival benefit 1, 3.
Endocrine therapy plus trastuzumab or lapatinib may be considered in highly selected cases with low disease burden, but studies have not shown overall survival benefit with this approach 1.
Studies of chemotherapy with HER2-targeted therapy have shown overall survival benefit, while studies of endocrine therapy with HER2-targeted therapy have not 1.
Treatment Duration and Monitoring
HER2-targeted therapy should continue until disease progression or unacceptable toxicity, not just until completion of chemotherapy 1, 3.
Left ventricular ejection fraction must be evaluated prior to initiation and every 3 months during therapy with any HER2-targeted agent 1, 7.
For patients who completed trastuzumab-based adjuvant treatment more than 12 months before recurrence, follow first-line recommendations; if less than 12 months, follow second-line recommendations 1, 3.
Critical Pitfalls to Avoid
Never discontinue HER2-targeted therapy when chemotherapy is completed—continue until progression or unacceptable toxicity 1, 3.
Never ignore symptoms of interstitial lung disease with Enhertu (new or worsening cough, dyspnea, fever)—this requires immediate evaluation and potential treatment discontinuation 5, 4, 6.
Never combine trastuzumab with anthracyclines concurrently due to significantly increased cardiac dysfunction risk 1, 8.
Never assume HER2 status remains unchanged—re-biopsy accessible metastatic lesions when feasible, as receptor status can change during disease progression 3.
Never use trastuzumab alone in first-line metastatic setting—dual HER2 blockade with pertuzumab is now standard of care 1.