# Metastatic triple-negative breast cancer

Source: https://onco.cc/cancers/tnbc-metastatic/  
OnCo record `tnbc-metastatic` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Triple-negative breast cancer that has spread is not curable, but its treatment has been transformed since 2020. By PD-L1 score, first treatment is pembrolizumab with chemotherapy or with sacituzumab govitecan, or datopotamab deruxtecan or sacituzumab govitecan alone; BRCA carriers can take a PARP inhibitor tablet; and trastuzumab deruxtecan reaches the third of tumours with low HER2.

## Summary

Metastatic triple-negative disease spreads early to lung, liver and brain and grows fast, so the first line matters more than in other breast cancers. At relapse the tumour is retested, because receptors can change, and three results steer treatment: PD-L1 by combined positive score (10 or more in roughly four in ten patients), germline BRCA status and the HER2 immunohistochemistry score that identifies HER2-low disease. Until 2018 the options were taxanes, anthracyclines, platinum, capecitabine and eribulin, with platinum favoured in BRCA carriers after the TNT trial.

Immunotherapy came first. IMpassion130 showed atezolizumab with nab-paclitaxel delays progression in PD-L1-positive disease and won an accelerated approval that was withdrawn in 2021 when IMpassion131 with paclitaxel failed. KEYNOTE-355 (847 patients) showed pembrolizumab with chemotherapy extends survival in tumours with a combined positive score of 10 or more (hazard ratio 0.73) and became the first-line standard for that group. The TROP2 antibody-drug conjugates then moved into the first line: ASCENT-04 showed sacituzumab govitecan with pembrolizumab beats chemotherapy with pembrolizumab in PD-L1-positive disease, ASCENT-03 showed sacituzumab govitecan beats chemotherapy in PD-L1-negative disease, and TROPION-Breast02 (644 patients) showed datopotamab deruxtecan extends overall survival from 18.7 to 23.7 months in patients who cannot have immunotherapy, the first first-line antibody-drug conjugate to do so; all three were approved in 2026.

Later lines were transformed earlier. ASCENT (529 patients with at least two prior lines) showed sacituzumab govitecan nearly doubles survival against chemotherapy (12.1 against 6.7 months, hazard ratio 0.48), the first antibody-drug conjugate approval in triple-negative disease in 2020. For germline BRCA carriers OlympiAD (302 patients) and EMBRACA (431) showed olaparib and talazoparib extend progression-free survival over chemotherapy (7.0 against 4.2 months, hazard ratio 0.58; 8.6 against 5.6 months, hazard ratio 0.54) without a significant survival gain. DESTINY-Breast04 included a small HER2-low triple-negative cohort that pointed the same way as the main result, and trastuzumab deruxtecan is an option for the third of tumours that are HER2-low; the bispecific antibody-drug conjugate izalontamab brengitecan posted a positive phase 3 in 2026. Whether a second topoisomerase-payload conjugate works after the first, how to select patients for TROP2 drugs, and what to do about brain metastases, present in up to a third to nearly half of patients, are the open questions.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Advanced triple-negative breast cancer; Stage IV TNBC; Recurrent triple-negative breast cancer
- Tags: subtype-page
- Group: breast
- Burden: Many women with early triple-negative disease relapse, most within three years, joining those diagnosed with spread from the outset; median survival was about a year to eighteen months on chemotherapy alone and now approaches two years in first-line trials.
- Subtypes: PD-L1-positive basal-like disease (combined positive score 10 or more; pembrolizumab combinations); PD-L1-negative or immunotherapy-ineligible disease (antibody-drug conjugate first); Germline BRCA-mutant metastatic triple-negative disease (olaparib, talazoparib, platinum); HER2-low triple-negative disease (trastuzumab deruxtecan); Early relapse within twelve months of curative chemotherapy (excluded from many first-line trials); Triple-negative disease with brain metastases
- Biomarkers: PD-L1 by 22C3 combined positive score (10 or more for pembrolizumab); Germline BRCA1 and BRCA2 (PARP inhibitors); HER2 immunohistochemistry to identify HER2-low disease; Repeat receptor testing on a metastatic biopsy (receptor conversion); TROP2 expression (not required for TROP2 antibody-drug conjugates); Tumour mutational burden and microsatellite instability (tumour-agnostic immunotherapy)

## Standard of care

- First line, combined positive score 10 or more: Pembrolizumab with chemotherapy (KEYNOTE-355) or with sacituzumab govitecan (ASCENT-04). ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [KEYNOTE-355](https://onco.cc/trials/keynote-355/), [Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/), [ASCENT-04 / KEYNOTE-D19](https://onco.cc/trials/ascent-04/), [Combined positive score (CPS)](https://onco.cc/terms/cps/))
- First line, PD-L1-negative or immunotherapy-ineligible: Datopotamab deruxtecan (TROPION-Breast02) or sacituzumab govitecan (ASCENT-03); a taxane or platinum where antibody-drug conjugates are unavailable. ([Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [TROPION-Breast02](https://onco.cc/trials/tropion-breast02/), [Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/), [ASCENT-03](https://onco.cc/trials/ascent-03/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Carboplatin](https://onco.cc/drugs/carboplatin/))
- Germline BRCA carriers: Olaparib (OlympiAD) or talazoparib (EMBRACA) after or instead of first-line chemotherapy; platinum chemotherapy is also more active. ([Olaparib](https://onco.cc/drugs/olaparib/), [OlympiAD](https://onco.cc/trials/olympiad/), [Talazoparib](https://onco.cc/drugs/talazoparib/), [EMBRACA](https://onco.cc/trials/embraca/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Germline BRCA mutation (gBRCA)](https://onco.cc/terms/gbrca-mutation/))
- Second line and beyond: Whichever TROP2 antibody-drug conjugate has not been used (ASCENT); trastuzumab deruxtecan for HER2-low tumours (DESTINY-Breast04); izalontamab brengitecan where available; eribulin, capecitabine or gemcitabine with carboplatin. ([Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/), [ASCENT](https://onco.cc/trials/ascent/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [DESTINY-Breast04](https://onco.cc/trials/destiny-breast04/), [Izalontamab brengitecan](https://onco.cc/drugs/izalontamab-brengitecan/), [Eribulin](https://onco.cc/drugs/eribulin/), [Capecitabine](https://onco.cc/drugs/capecitabine/), [Gemcitabine](https://onco.cc/drugs/gemcitabine/))
- Brain metastases: Stereotactic radiosurgery or whole-brain radiotherapy with continued systemic therapy; antibody-drug conjugates have early evidence of intracranial activity. ([Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/))

## State of the art

- Antibody-drug conjugates are first-line therapy for every PD-L1 group, alone or with pembrolizumab.
- Median survival in first-line trials approaches two years, roughly double the chemotherapy era.
- PARP inhibitors give BRCA carriers a chemotherapy-free option.
- A bispecific antibody-drug conjugate has succeeded in phase 3.

## Open problems

- Cross-resistance between antibody-drug conjugates sharing a topoisomerase I payload.
- No biomarker selects patients for TROP2 drugs.
- Brain metastases remain undertreated and are excluded from most trials.
- Access: the new first-line drugs cost many times more than chemotherapy.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Triple-negative_breast_cancer
- ASCENT (NEJM 2021): https://doi.org/10.1056/NEJMoa2028485
- KEYNOTE-355 (NEJM 2022): https://doi.org/10.1056/NEJMoa2202809
- OlympiAD (NEJM 2017): https://doi.org/10.1056/NEJMoa1706450

## Connected records

- drugs: [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Capecitabine](https://onco.cc/drugs/capecitabine/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [Eribulin](https://onco.cc/drugs/eribulin/), [Gemcitabine](https://onco.cc/drugs/gemcitabine/), [Ivonescimab](https://onco.cc/drugs/ivonescimab/), [Izalontamab brengitecan](https://onco.cc/drugs/izalontamab-brengitecan/), [Olaparib](https://onco.cc/drugs/olaparib/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Patritumab deruxtecan](https://onco.cc/drugs/patritumab-deruxtecan/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/), [Sacituzumab tirumotecan](https://onco.cc/drugs/sacituzumab-tirumotecan/), [Talazoparib](https://onco.cc/drugs/talazoparib/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/)
- trials: [ASCENT](https://onco.cc/trials/ascent/), [ASCENT-03](https://onco.cc/trials/ascent-03/), [ASCENT-04 / KEYNOTE-D19](https://onco.cc/trials/ascent-04/), [BL-B01D1-307](https://onco.cc/trials/bl-b01d1-307/), [DESTINY-Breast04](https://onco.cc/trials/destiny-breast04/), [EMBRACA](https://onco.cc/trials/embraca/), [IMpassion130](https://onco.cc/trials/impassion130/), [IMpassion131](https://onco.cc/trials/impassion131/), [IZABRIGHT-Breast01](https://onco.cc/trials/izabright-breast01/), [KEYNOTE-355](https://onco.cc/trials/keynote-355/), [OlympiAD](https://onco.cc/trials/olympiad/), [TROPION-Breast02](https://onco.cc/trials/tropion-breast02/), [TROPION-Breast05](https://onco.cc/trials/tropion-breast05/)
- technologies: [Dual-payload ADC](https://onco.cc/technologies/dual-payload-adc/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [TROP2 PET](https://onco.cc/technologies/trop2-pet/)
- terms: [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Combined positive score (CPS)](https://onco.cc/terms/cps/), [Germline BRCA mutation (gBRCA)](https://onco.cc/terms/gbrca-mutation/)
- cancers: [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)

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