Approximately 60% of patients with previously untreated metastatic triple-negative breast cancer (TNBC) are ineligible for programmed death-ligand 1 (PD-L1) inhibitor therapy, highlighting a significant unmet need in this population. Sacituzumab govitecan, an antibody–drug conjugate targeting TROP2, has previously demonstrated significant survival benefit versus chemotherapy in pretreated metastatic TNBC and as a combination with pembrolizumab vs chemotherapy plus pembrolizumab in PD-L1–positive metastatic TNBC. ASCENT-03 (NCT05382299) is a phase 3, global, randomized study aimed to evaluate the efficacy and safety of sacituzumab govitecan versus chemotherapy in patients with previously untreated advanced TNBC who are not candidates for PD-L1 inhibitors. Patients had centrally confirmed PD-L1–negative TNBC (combined positive score [CPS] <10) or PD-L1–positive TNBC (CPS ≥10) but were ineligible for PD-L1 inhibitors due to comorbidities. Participants were randomized 1:1 to receive sacituzumab govitecan (10 mg/kg intravenously on days 1 and 8 of 21-day cycles) or physician’s choice of chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin). The primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR), with secondary endpoints including overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety.
The study enrolled 558 patients (279 in each arm). As of April 2, 2025, after a median follow-up of 13.2 months, sacituzumab govitecan demonstrated a statistically significant improvement in median PFS compared with chemotherapy (9.7 months vs 6.9 months; hazard ratio, 0.62, 95% confidence interval [CI], 0.50-0.77; P<.0001). The subgroup analysis of PFS by BICR showed consistent benefit of sacituzumab govitecan over chemotherapy across key prespecified subgroups, including age, ECOG performance status, geographic region, disease status, PD-L1 expression, and chemotherapy selected prior to randomization. Sacituzumab govitecan also yielded a longer median DOR (12.2 months [95% CI, 9.7-13.8] vs 7.2 months [95% CI, 5.7-8.4]). OS data were immature at the time of analysis. Investigator-assessed PFS2, defined as the time from randomization to first documented progression on next-line therapy, was longer with sacituzumab govitecan vs chemotherapy (18.2 vs 14 months). Safety findings were consistent with the known profile of sacituzumab govitecan; neutropenia (43%) and diarrhea (9%) were the most common grade ≥3 treatment-emergent adverse events (TEAEs) compared with neutropenia (41%) and anemia (16%) in the chemotherapy arm. Importantly, sacituzumab govitecan demonstrated a lower rate of treatment discontinuation due to TEAEs compared with chemotherapy (4% vs 12%, respectively).
The ASCENT-03 trial establishes sacituzumab govitecan as a promising first-line treatment for patients with advanced TNBC who are unable to receive PD-L1 inhibitors. Its significant improvement in PFS, coupled with manageable safety and durable responses, supports its potential as a new standard of care in this underserved patient population. Further follow-up is warranted to assess overall survival outcomes.
Source: Cortés JC, Bardia A, Punie K, et al. Primary results from ASCENT-03: a randomized phase III study of sacituzumab govitecan (SG) vs chemotherapy (chemo) in patients with previously untreated advanced triple-negative breast cancer (TNBC) who are unable to receive PD-(L)1 inhibitors (PD-[L]1i). Presented at: ESMO Congress 2025. October 19, 2025; Berlin, Germany. Abstract LBA20.