SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.
Clinical Context
TNBC accounts for roughly 10–15% of breast cancers and is characterized by its aggressive biology and lack of targetable receptors. Survival prospects in the metastatic setting are particularly poor and fewer than 20% of patients are alive at 5 years. Treatment options remain limited for patients with newly diagnosed, locally advanced unresectable or metastatic triple-negative breast cancer (TNBC) who are not candidates for PD-1/PD-L1 blockade, as approximately 60% of metastatic TNBCs are PD-L1–negative (CPS <10), excluding them from approved chemo-immunotherapy regimens. Aside from PARP inhibitors, which apply only to a minority with germline BRCA1/2 mutations, cytotoxic chemotherapy has remained the default first-line therapy despite short survival and limited durability. Compounding this unmet need, real-world data show that nearly half of patients never receive second-line therapy due to rapid progression or early mortality. Thus, optimizing first-line outcomes is essential, particularly for patients not eligible for immunotherapy.
TRODELVY® (Sacituzumab govitecan) is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Trop-2, a transmembrane calcium signal transducer, stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38. The Phase 3 ASCENT-03 trial provides important new evidence supporting Sacituzumab govitecan as a frontline therapeutic foundation for this high-risk group.
ASCENT-03 Trial Overview
ASCENT-03 was an International, open-label, randomized Phase 3 trial evaluating Sacituzumab govitecan versus investigator’s choice of chemotherapy (Paclitaxel, nab-Paclitaxel, or Gemcitabine/Carboplatin) in patients with untreated advanced or metastatic TNBC who were not candidates for PD-1/PD-L1 inhibitors. Most participants (about 99% in each arm) had PD-L1–negative disease. Eligibility also included PD-L1–positive patients previously treated with checkpoint inhibitors or those with comorbidities precluding immunotherapy. A total of 558 patients were enrolled globally and randomized 1:1 to receive Sacituzumab govitecan (279 patients) or chemotherapy (279 patients – 56% were selected to receive a taxane and 44% to receive Gemcitabine plus Carboplatin). Treatment continued until disease progression, or unacceptable toxicity. Crossover to Sacituzumab govitecan was permitted for patients in the chemotherapy arm after progression. The Primary endpoint was Progression-Free Survival (PFS) assessed by Blinded Independent Central Review. Key Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DOR), and Safety.
Efficacy: Meaningful Extension of Disease Control
Sacituzumab govitecan delivered a statistically robust and clinically meaningful improvement in PFS:
- Median PFS:
- 9.7 months with Sacituzumab govitecan
- 6.9 months with chemotherapy
- Risk reduction: 38% reduction in risk of progression or death (HR 0.62; 95% CI, 0.50–0.77; P<0.001)
Response rates were numerically similar between arms (48% vs. 46%), but Sacituzumab govitecan produced a notably longer median duration of response (12.2 vs. 7.2 months), underscoring the sustained disease control characteristic of Trop-2–targeted therapy.
Improved PFS with Sacituzumab govitecan was observed across most prespecified subgroups, including those with particularly poor prognostic indicators such as early recurrence after curative-intent therapy and the presence of liver metastases.
OS results were immature at the time of analysis and are confounded by crossover; however, the strong PFS signal aligns with survival benefits previously demonstrated in later-line settings (ASCENT) and in PD-L1–positive patients treated with Sacituzumab govitecan plus Pembrolizumab (ASCENT-04).
Safety and Tolerability
The toxicity profile of Sacituzumab govitecan was consistent with prior experience, without new safety signals. Grade ≥3 adverse events were 66% with Sacituzumab govitecan versus 62% with chemotherapy. Most common grade ≥3 events with Sacituzumab govitecan included neutropenia (43%), diarrhea (9%), leukopenia (7%). Despite comparable rates of high-grade events, Sacituzumab govitecan led to fewer dose reductions and considerably fewer discontinuations compared with chemotherapy (4% vs. 12%), suggesting improved treatment continuity. Neutropenia remains an important risk, and emerging regulatory guidance recommends considering primary G-CSF prophylaxis in patients with elevated risk for febrile neutropenia (e.g., age ≥65, prior neutropenia, poor performance status, comorbid organ dysfunction).
Positioning ASCENT-03 Within the Evolving TNBC Landscape
ASCENT-03 complements the ASCENT-04 findings, where Sacituzumab govitecan combined with Pembrolizumab demonstrated meaningful benefit in PD-L1–positive previously untreated metastatic TNBC. Together, these trials provide convergent evidence that Sacituzumab govitecan contributes substantially to disease control, regardless of PD-L1 status, and can serve as either a foundational monotherapy or as part of combination immunotherapy.
For the large subset of patients with PD-L1–negative disease, or those ineligible for checkpoint blockade, ASCENT-03 establishes Sacituzumab govitecan as a superior first-line option compared with standard chemotherapy.
Key Considerations and Limitations
- The trial’s open-label design introduces potential bias, although PFS assessment was safeguarded by Blinded Independent Central Review.
- Enrollment of PD-L1–positive patients and those previously treated with PD-1/PD-L1 inhibitors was limited, restricting generalizability to those subgroups.
- Despite specific efforts to enhance racial diversity, representation of Black patients remained low, highlighting ongoing disparities in TNBC clinical trial participation.
Conclusion
Sacituzumab govitecan significantly prolonged Progression-Free Survival compared with standard chemotherapy in the first-line treatment of advanced or metastatic TNBC among patients who are not candidates for PD-1/PD-L1 inhibitors. With durable responses, a manageable safety profile, and fewer treatment discontinuations than chemotherapy, Sacituzumab govitecan offers a meaningful advance for a population in critical need of more effective therapies.
As experience accumulates from ASCENT-03, ASCENT-04, and ongoing studies in early-stage disease, Sacituzumab govitecan is poised to reshape the treatment paradigm across the TNBC continuum.
Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer. Cortés J, Punie K, Barrios C, et al. N Engl J Med 2025;393:1912-1925
