Authors: *François Cherifi1
1. Medical Oncology Department, Cancer Centre François Baclesse, Caen, France
*Correspondence to [email protected]
Disclosure: Cherifi has received grants from Novartis and Gilead, with payment to the institution; consulting fees from Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pharmaand; and support for attending meetings and/or travel from Roche, Gilead, and Chugai.
Citation: EMJ Oncol. 2025;13[1]:23-26. https://doi.org/10.33590/emjoncol/SEBR8422
INTRODUCTION
TNBC remains the most aggressive subtype of breast cancer, and is characterised by the absence of oestrogen receptor, progesterone receptor, and HER2 expression, as well as by a high likelihood of early relapse and visceral spread.1 Despite progress with immune checkpoint inhibitors, response remains variable and unpredictable. Moreover, a substantial proportion of patients with metastatic TNBC are ineligible for PD-L1-based therapy due to PD-L1-negative status or comorbidities.2 For these individuals, chemotherapy has long represented the default first-line option, offering modest benefit with a median progression-free survival (PFS) of less than 6 months and a median overall survival (OS) rarely exceeding 18 months.1,3
The emergence of ADCs has reshaped therapeutic strategies in pretreated TNBC, with SG and datopotamab deruxtecan (Dato-DXd) both demonstrating robust antitumour activity in later-line settings. The 2025 congress season marked a major inflexion point for the field: the ASCENT-04/KEYNOTE-D19 study presented at ASCO 2025 established SG plus pembrolizumab as a new standard of care for PD-L1-positive, previously untreated metastatic TNBC.4 Simultaneously, two Phase III trials presented at ESMO 2025, TROPION-Breast02 (Dato-DXd versus chemotherapy) and ASCENT-03 (SG versus chemotherapy), reported practice-changing results in patients who are PD-L1 negative or immunotherapy ineligible.5,6
DATOPOTAMAB DERUXTECAN IN TROPION-BREAST02
The TROPION-Breast02 trial5 was a randomised, open-label, Phase III study evaluating Dato-DXd, a trophoblast cell surface antigen 2 (TROP2)-directed ADC with a DXd payload, versus the investigator’s choice of chemotherapy in patients with locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option. Eligible patients had received no prior systemic therapy for advanced disease and were randomised 1:1 to Dato-DXd 6 mg/kg intravenously every 3 weeks or to standard single-agent chemotherapy. The dual primary endpoints were PFS by blinded independent central review and OS.
At the August 2025 data cutoff, Dato-DXd significantly improved PFS compared with chemotherapy, reducing the risk of progression or death by 43% (hazard ratio [HR]: 0.57; 95% CI: 0.47–0.69; p<0.0001). Median PFS was 10.8 months with Dato-DXd versus 5.6 months with chemotherapy. The trial also demonstrated a significant OS improvement (HR: 0.79; median OS: 23.7 versus 18.7 months). The objective response rate was 62.5% with Dato-DXd versus 29.3% with chemotherapy, with complete responses in 9.0% versus 2.5% of patients. Median duration of response exceeded 1 year. Safety findings were consistent with prior reports, with stomatitis, nausea, and dry eye as the most common adverse events. Despite a median treatment duration twice that of chemotherapy, Grade ≥3 toxicities and treatment discontinuations were comparable.
SACITUZUMAB GOVITECAN IN ASCENT-03
The ASCENT-03 trial6 evaluated SG, a TROP2-directed ADC conjugated to SN-38, versus physician’s choice chemotherapy in previously untreated, locally advanced inoperable or metastatic TNBC not eligible for PD-L1 therapy. A total of 558 patients were randomised 1:1 to SG or to chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine/carboplatin). SG achieved a statistically significant and clinically meaningful PFS improvement, with a 38% reduction in risk of progression or death (HR: 0.62; 95% CI: 0.50–0.77; p<0.0001). Median PFS was 9.7 months with SG versus 6.9 months with chemotherapy. Twelve-month PFS rates were 41% and 24%, respectively.
Although OS data were immature, a numerical improvement was observed (median OS: 21.5 versus 20.2 months). Median duration of response was longer with SG (12.2 versus 7.2 months). Safety analysis showed manageable toxicity consistent with prior studies, including neutropenia, diarrhoea, and alopecia. Treatment-related discontinuations were lower with SG (4%) than with chemotherapy (12%).
EVOLVING THERAPEUTIC LANDSCAPE AND CLINICAL IMPLICATIONS
The 2025 congress data mark the advent of a new era in TNBC therapy. The parallel success of ASCENT-03 and TROPION-Breast02 represents a decisive shift toward ADCs as front-line standards in TNBC, displacing traditional taxane- based chemotherapy.
ASCENT-04 (SG plus pembrolizumab) and likely TROPION-Breast057 (Dato-DXd in combination with durvalumab) serve PD-L1-positive disease, while SG or Dato-DXd monotherapy serve PD-L1-negative or immunotherapy-ineligible populations, heralding an ADC-dominant paradigm for first-line TNBC management.
EXPERT PERSPECTIVE
The ESMO 2025 data consolidate a unified ADC paradigm in metastatic TNBC. For clinicians, the challenge now lies not in whether to use an ADC, but which ADC to use first. SG and Dato-DXd both target TROP2, but differ in linker chemistry and payload composition, influencing their pharmacologic profiles and toxicity spectra.8,9 Dato-DXd’s improved tolerability and prolonged PFS make it an attractive option for patients prioritising quality of life, while SG, alone or with pembrolizumab, remains the most clinically validated agent across disease settings. Future research will likely explore long-term outcomes, sequencing and cross-resistance between ADCs, and biomarker-driven personalisation.
