Current first-line ADC trials for metastatic TNBC largely excluded patients who relapsed after receiving the KEYNOTE-522 neoadjuvant chemo-immunotherapy regimen. This timing mismatch creates a critical evidence gap for an increasingly common clinical scenario, forcing clinicians to rely on real-world data.

After a triple-negative breast cancer patient progresses on a first-line TROP2 antibody-drug conjugate (ADC), experts advise against immediately sequencing another ADC. Due to suspected cross-resistance, the recommended strategy is to return to traditional chemotherapy agents like taxanes or carboplatin, which remain effective options, before considering another ADC in later lines.

The apparent lack of survival benefit for datopotamab in North American patients is likely an artifact. Better access to other effective antibody-drug conjugates after progression in the control arm diluted the survival advantage, highlighting how regional care standards can confound trial outcomes.

Advances like immunotherapy and Antibody-Drug Conjugates (ADCs) in early-stage Triple-Negative Breast Cancer (TNBC) are so effective that fewer patients are relapsing. This success paradoxically makes it harder to enroll patients in trials for metastatic disease, shifting the trial population toward those with de novo metastatic cancer.

Clinicians lack evidence to guide treatment for triple-negative breast cancer that relapses shortly after neoadjuvant chemo-immunotherapy. Pivotal trials for new ADCs like Dato-DXD included very few patients with prior immunotherapy, creating a significant and common evidence gap in clinical practice.

Patients with triple-negative breast cancer (TNBC) who recur after standard neoadjuvant chemo-immunotherapy (per the KEYNOTE-522 trial) represent a new, challenging population. There is virtually no clinical data to guide treatment, particularly on whether re-challenging with immunotherapy alongside an ADC is effective.

In the TROPION-Breast02 trial, a survival benefit for Dato-DXD was seen mainly in regions without later-line access to TROP2 ADCs. Western patients often received an ADC second-line, muting the first-line survival difference and showing how post-progression therapy access can confound trial results.

When choosing between TROP2-directed ADCs like sacituzumab govitecan and datopotamab deruxtecan, the decision often hinges on side effect profiles and scheduling convenience, not superior efficacy. Datopotamab has more oral/ocular issues but is given every three weeks, while sacituzumab causes more neutropenia and requires visits two out of every three weeks.

A unique advantage of the ADC datopotamab deruxtecan is its non-myelosuppressive profile. This makes it an especially attractive option for patients whose bone marrow is compromised or 'tired' after receiving intensive prior chemotherapy, a common real-world clinical scenario not always captured in trials.