Dr Tarantino on the Evolution of TROP2-Directed ADCs in First-Line TNBC

“The first-line data from TROPION-Breast02…bring hope to the [TNBC] field, and the data with sacituzumab govitecan as well. Now we need to further raise the bar and develop novel ADCs with additional payloads and different treatment strategies to further improve outcomes for these patients.”

Paolo Tarantino, MD, PhD, a breast medical oncologist and advanced fellow at Dana-Farber Cancer Institute and Harvard Medical School, discussed the emergence of TROP2-directed antibody-drug conjugates (ADCs) in the first-line treatment of patients with metastatic triple-negative breast cancer (TNBC) and the sequencing questions their arrival raises.

Tarantino began by noting that 2 distinct TROP2-directed ADCs have now moved into the first-line setting: datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) based on data from the phase 3 TROPION-Breast02 trial (NCT05374512), and sacituzumab govitecan-hziy (Trodelvy) based on findings from the phase 3 ASCENT-03 (NCT05382299) and ASCENT-04 (NCT05382286) trials.

For both agents, analyses presented at the 2026 ASCO Annual Meeting demonstrated—beyond the primary end point of improved progression-free survival (PFS) vs chemotherapy—improvements in time to second progression, he stated. Tarantino characterized this as reassuring, particularly for the sacituzumab govitecan trials, for which no overall survival (OS) benefit has yet been demonstrated, whereas Dato-DXd has already shown both a PFS and an OS benefit. He noted that sufficient data exist to consider these agents standard first-line treatments.

Major questions for the field have consequently shifted, Tarantino explained. The first concerns patient selection between the 2 TROP2-directed ADCs, for which he emphasized that key differences in administration schedule and toxicity profile can guide shared decision-making with patients. The second question concerns second-line therapy after progression on a TROP2-directed ADC, Tarantino hypothesized that substantial cross-resistance exists between ADCs with topoisomerase-I payloads. Therefore, he recommended that patients receive traditional chemotherapy, such as a taxane, eribulin, or carboplatin, immediately after ADC progression. However, he noted that the field should remain open to giving additional ADCs in later lines because of these patients’ need for more options.

Tarantino further noted that ADCs are frequently effective in the brain, relevant since approximately one-third of patients develop brain metastases. Although he would not sequence ADCs back-to-back, he emphasized that the high overall response rate, median PFS, and median OS seen with Dato-DXd in TROPION-Breast02 bring hope, emphasizing the need to develop novel ADCs with additional payloads and strategies to further raise the bar.

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