Sequencing Trastuzumab Deruxtecan and Sacituzumab Govitecan in Metastatic Breast Cancer

Both trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) are approved agents for metastatic breast cancer, and patients harboring HER2-low disease frequently qualify for both therapies. However, the optimal sequencing strategy between these two antibody–drug conjugates (ADCs) remains undefined.

To evaluate whether clinical outcomes differ by treatment order, a systematic review and meta-analysis (PROSPERO CRD420251250322) conducted in accordance with PRISMA searched PubMed/MEDLINE, Scopus, Cochrane CENTRAL, and major oncology conference proceedings through December 2025. The analysis focused on comparing outcomes of the second ADC based on the sequence administered: SG followed by T-DXd (SG→T-DXd) versus T-DXd followed by SG (T-DXd→SG). The primary endpoint evaluated was progression-free survival on the second ADC (PFS2). Hazard ratios (HRs) were collected from patient-level datasets, published effect sizes, or reconstructed Kaplan–Meier curves and pooled using a random-effects model, with heterogeneity assessed via the I² statistic. Study quality and certainty of evidence were formally evaluated using ROBINS-I and GRADE frameworks.

From 694 retrieved records, 17 retrospective studies were identified, seven of which contributed to the quantitative PFS2 meta-analysis, encompassing 292 patients in the SG→T-DXd cohort and 286 in the T-DXd→SG cohort. The pooled HR for PFS2 comparing T-DXd→SG versus SG→T-DXd was 1.54 (95% CI 0.98–2.40; I²=61%). In sensitivity analysis excluding one study, the HR was 1.72 (95% CI 1.23–2.41; I²=10%), while pooling covariate-adjusted estimates yielded an HR of 1.36 (95% CI 0.89–2.10). Median PFS2 was 3.3 months with the SG→T-DXd sequence and 2.8 months with the T-DXd→SG sequence.

Although point estimates numerically favored sequencing SG prior to T-DXd, the authors concluded that current evidence does not establish the clinical superiority of either sequence given the very low certainty of evidence and likely confounding by breast cancer subtype. Prospective, subtype-stratified studies remain necessary to clarify optimal ADC sequencing.