Dr Mardones on the Potential Effect of TROP2 ADCs on the First-Line TNBC Paradigm

It is nice to have options that are lessening the burden of toxicity for patients [with TNBC] in the frontline setting. Not to say that these [TROP2-directed] ADCs don’t come with their own set of [toxicities], but I do think [they] lower the incidence…of neuropathy, which can be life-changing for patients.

Mabel Mardones, MD, a breast medical oncologist at Rocky Mountain Cancer Centers, discussed how the incorporation of datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) and sacituzumab govitecan-hziy (Trodelvy) into the first-line treatment paradigm for metastatic triple-negative breast cancer (TNBC) could affect survival and safety outcomes.

Data from multiple phase 3 studies reported in 2025 are poised to shift the standard-of-care (SOC) in the frontline TNBC setting, Mardones began. This includes the phase 3 TROPION-Breast02 trial (NCT05374512), in which Dato-DXd improved overall survival (OS) and progression-free survival (PFS) compared with investigator’s choice of chemotherapy in patients with locally advanced or metastatic TNBC who were ineligible for immunotherapy. A statistically significant PFS improvement was also reported for sacituzumab govitecan vs chemotherapy in patients with previously untreated, locally advanced unresectable, or metastatic TNBC who were ineligible for immunotherapy in the phase 3 ASCENT-03 trial (NCT05382299).

Furthermore, data from the phase 3 ASCENT-04 trial (NCT05382286) demonstrated that sacituzumab govitecan plus pembrolizumab (Keytruda) improved PFS vs chemotherapy plus pembrolizumab in patients with PD-L1–positive advanced or metastatic TNBC.

With current frontline SOC options yielding an approximate median OS between 15 to 16 months, Mardones explained that novel approaches such as the use of TROP2-directed antibody-drug conjugates (ADCs) are intended to further boost these survival outcomes. Along with improved efficacy outcomes, TROP2-directed ADC–based regimens could also yield improved safety and tolerability in the first-line setting compared with chemotherapy-based treatment, she added.

Although ADCs carry their own adverse effect (AE) profile, Mardones noted that these agents could lower the rates of neuropathy. Neutropenia is an AE to watch with these ADCs, she said, explaining that incorporating primary prophylaxis with granulate colony–stimulating factors into clinical practice will be key for preventing neutropenia if and when these agents are utilized, Mardones concluded.