Efficacy of sacituzumab govitecan, a Trop-2-directed antibody–drug conjugate, in metastatic triple-negative breast cancer
- Open Access
- 14.01.2026
- short review
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Summary
ADCs in oncology: precision delivery of cytotoxic agents to tumors
In oncology, antibody–drug conjugates (ADCs) have gained importance, especially in breast cancer management. They consist of a monoclonal antibody (IgG) linked to a low-molecular-weight cytotoxic payload via a chemical linker. The antibody delivers the cytotoxic agent specifically to tumor cells, aiming to restrict chemotherapy effects to the tumor site and reduce systemic exposure. An ideal target antigen should be highly expressed in tumor tissue, minimally or not at all in healthy tissues, localized on the cell surface, and accessible to the antibody. Efficient internalization is essential for intracellular delivery and activity of the payload [1, 2].
Redefining treatment paradigms in TNBC: the role of Trop-2 in mTNBC
Trophoblast cell-surface antigen 2 (Trop-2), a calcium signal transducer, promotes tumor growth. Using anti-Trop‑2 antibodies with selective affinity for distinct maturation states enabled identification of two spatially distinct Trop‑2 pools: one on the plasma membrane, the other in the cytoplasm. Membrane-localized Trop‑2 was differentially associated with tumor aggressiveness and delineated biologically distinct breast cancer subgroups. These findings suggest that Trop‑2 localization and maturation status may hold prognostic value and influence cancer progression [3].
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TNBC: a molecularly distinct and therapeutically challenging entity
Triple-negative breast cancer (TNBC) remains a therapeutic challenge due to its molecular heterogeneity, aggressive course, and lack of established molecular targets. Trop‑2, a transmembrane glycoprotein overexpressed in many epithelial malignancies, has emerged as a clinically relevant target in TNBC. Sacituzumab govitecan (SG), a Trop-2-directed ADC linked to the topoisomerase I inhibitor SN-38, has been integrated into treatment algorithms for advanced TNBC, independent of Trop‑2 expression, with a manageable safety profile [4]. In addition to HER2, Trop‑2 is another important antigen as a target for ADCs. Trastuzumab deruxtecan (T-DXd) is now an established option for TNBC patients with low HER2 expression—a subgroup previously considered HER2-negative. This shift was driven by trials such as DESTINY-Breast04, which showed significant progression-free survival (PFS) and overall survival (OS) benefits in HER2-low metastatic breast cancer, redefining HER2-negative disease and establishing T‑DXd as a standard therapy [5, 6].
Results and clinical impact of the ASCENT trial
The ASCENT trial was a randomized, open-label, phase III study evaluating SG in patients with metastatic TNBC (mTNBC) who had received at least two prior chemotherapy regimens for advanced disease. Patients were randomized 1:1 to receive SG or treatment of physician’s choice (TPC), which included eribulin, vinorelbine, gemcitabine, or capecitabine. Treatment continued until progression or unacceptable toxicity. The primary endpoint was PFS; OS and objective response rate (ORR) were secondary endpoints [7].
Trop‑2 expression was not required for study inclusion, but post hoc analyses explored associations between Trop‑2 and HER2 expression and treatment outcomes in the intention-to-treat (ITT) population. Trop‑2 expression was assessed using immunohistochemistry (IHC), quantified by H‑score and the proportion of membrane-positive tumor cells. Patients were stratified into quartiles based on Trop‑2 expression. HER2 expression was assessed using local IHC and in situ hybridization (ISH) data and classified as HER2-low (IHC 1+ or 2+/ISH-) or HER2‑0 [7, 8].
In line with the final efficacy analysis in the primary study population overall subgroups, SG demonstrated a significant improvement in median PFS with 4.8 months vs. 1.7 months with TPC; hazard ratio (HR): 0.41, 95% confidence interval (CI): 0.33–0.52, and median OS: 11.8 months with SG vs. 6.9 months with TPC, HR: 0.51, 95% CI: 0.42–0.63 [7, 8].
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Trop‑2 data were available in ~60% of patients. Most showed moderate to high Trop‑2 expression (H-score ≥ 130). Efficacy outcomes in this subgroup closely matched those in the full ITT cohort, supporting the representativeness of the biomarker-evaluable population. Treatment with SG improved PFS and ORR across all Trop‑2 expression levels, including patients with low expression. A trend toward better OS and ORR was observed with higher Trop‑2 expression, suggesting a possible association between target expression and efficacy.
However, no statistically significant interaction was found between treatment and Trop‑2 expression for PFS (P = 0.24–0.73). For OS, the interaction was borderline significant (P = 0.04–0.05), with a trend across H‑score quartiles (P = 0.054). Importantly, SG showed clinical benefit regardless of Trop‑2 expression, underlining its broad applicability [7].
HER2 status was assessed in 78% of the ITT population. Among these, 21% were HER2-low and 71% were HER2‑0. Both subgroups experienced improved PFS and OS with SG, in line with the overall study results. Furthermore, SG led to a higher ORR compared to TPC in both HER2‑0 and HER2-low patients. Trop‑2 was highly expressed across tumor samples irrespective of HER2 status, supporting the utility of SG beyond molecular subgroups [7].
Limitations of the study include the exploratory design of subgroup analyses, small sample sizes within subgroups, reliance on archival tissue, and the absence of a pre-specified analysis plan [7].
Overall, SG demonstrated improved outcomes in pretreated mTNBC patients, independent of Trop‑2 IHC expression across all analyzed subgroups. These findings support SG as a standard therapeutic option in this setting.
Safety profile
The most frequently reported treatment-related adverse events (TRAEs) of any grade were neutropenia (63% with SG vs. 43% with TPC), followed by diarrhea (59% vs. 12%), nausea (57% vs. 26%), alopecia (46% vs. 16%), fatigue (45% vs. 30%), and anemia (34% vs. 24%). Serious TRAEs occurred in 15% of patients receiving SG (n = 39) and in 8% of patients receiving chemotherapy (n = 19).
Dose reductions due to adverse events were comparable between groups, occurring in 22% of patients in the SG group and 26% in the chemotherapy group. Treatment discontinuation due to adverse events was infrequent and similar in both groups, reported in 5% of patients (n = 12) in each arm.
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Treatment with SG led to more substantial and clinically meaningful improvements in health-related quality of life (QoL) than TPC [12].
ASCENT-04: first-line sacituzumab govitecan plus pembrolizumab in patients with mTNBC and PD-L1-positive tumors
Recently, data from the ASCENT-04 trial, a global phase III study, were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, which showed that the combination of a Trop-2-directed ADC and immunotherapy is superior to the traditional regimen of chemotherapy plus immunotherapy in the first-line treatment of advanced TNBC. This marks a significant advancement in the TNBC treatment landscape [13].
The ASCENT-04 trial enrolled patients with PD-L1-positive (combined positive score [CPS] ≥ 10), locally advanced unresectable or metastatic TNBC, previously untreated in the advanced setting and with a disease-free interval (DFI) ≥ 6 months. Participants received either SG plus pembrolizumab or chemotherapy plus pembrolizumab. Crossover to SG was allowed upon progression. The primary endpoint was PFS assessed by blinded independent central review (BICR), with secondary endpoints including OS, ORR, duration of response (DoR), safety, and QoL. Sacituzumab govitecan plus pembrolizumab significantly improved median PFS (11.2 vs. 7.8 months; HR: 0.65; P < 0.001), meeting the primary endpoint with early and durable benefit. The ORR (60% vs. 53%), CR (13% vs. 8%), and DoR (16.5 vs. 9.2 months) rates were also higher. Data on OS are still immature but trending positively.
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The combination had a manageable safety profile, with no new safety signals. Grade ≥ 3 AEs were similar (71% vs. 70%), but fewer patients discontinued treatment (12% vs. 31%). ASCENT-04 challenges the role of chemotherapy in first-line mTNBC and supports ADC–immunotherapy combinations as a promising alternative [14].
ASCENT-03: first-line sacituzumab govitecan in patients with mTNBC without indication for immunotherapy
ASCENT-03 is a global, open-label, randomized phase III trial investigating SG as first-line therapy in patients with locally advanced inoperable or metastatic TNBC without indication for immunotherapy. The trial enrolled 558 patients with centrally confirmed TNBC (ER/PR < 1%, HER2-negative) and either PD-L1-negative tumors (CPS < 10) or PD-L1-positive tumors (CPS ≥ 10) who previously received anti-PD-(L)1 therapy in the curative setting. Eligible patients (ECOG 0–1, ≥ 6 months since last curative treatment) were randomized 1:1 to receive either SG in standard dosing or physician’s choice chemotherapy (gemcitabine/carboplatin, paclitaxel, or nab-paclitaxel). The primary endpoint was PFS by BICR; secondary endpoints included OS, ORR, safety, and QoL.
Patients were stratified by recurrence pattern and geographic region.
Compared with chemotherapy, SG significantly improved PFS, with a median PFS of 9.7 months (95% CI: 8.1–11.1) in the SG group versus 6.9 months (95% CI: 5.6–8.2) in the chemotherapy group, corresponding to a stratified HR of 0.62 (95% CI: 0.50–0.77; P < 0.001). Confirmed objective responses were observed in 48% of patients treated with SG and in 46% of those receiving chemotherapy. Responses were more durable with SG, with a median duration of response of 12.2 months compared to 7.2 months.
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Grade ≥ 3 adverse events were observed in approximately two thirds of patients in both treatment groups (66% with SG vs. 62% with chemotherapy). Severe neutropenia and leukopenia occurred frequently in both arms. Diarrhea was more common in the SG arm, whereas anemia was observed more often with chemotherapy. Discontinuation due to treatment-related adverse events was less frequent with SG (4% vs. 12%).
Overall, SG demonstrated a clinically meaningful improvement in PFS compared to chemotherapy in patients with advanced TNBC who were not candidates for PD-1/PD-L1 inhibitor therapy [15].
Toxicity management
Sacituzumab govitecan is classified as a high emetogenic agent [15, 16]; therefore, a two-drug antiemetic prophylaxis is mandatory. This should include a 5-hydroxytryptamine type 3 (5HT3) receptor antagonist in combination with dexamethasone. The addition of an NK1 receptor antagonist may be considered for patients at higher risk of nausea and vomiting, forming a three-drug antiemetic regimen. In addition, patients should be provided with take-home antiemetic medication (e.g., ondansetron) to manage delayed or breakthrough symptoms.
In the event of diarrhea, oral loperamide should be prescribed. The recommended initial dose is 4 mg, followed by 2 mg after each subsequent loose stool, up to a maximum of 16 mg per day. Also, the PRIMED study demonstrated that prophylactic loperamide significantly reduced the incidence and severity of SG-related diarrhea.
Future perspectives on ADCs and Trop-2-directed ADCs
TROPION-Breast02: datopotamab deruxtecan
In addition to SG, the Trop-2-directed ADC datopotamab deruxtecan (Dato-DXd) has emerged as a highly promising therapeutic option in mTNBC. Dato-DXd consists of a humanized anti-Trop‑2 IgG1 monoclonal antibody linked via a cleavable linker to a topoisomerase I inhibitor payload.
The randomized, global, open-label phase III TROPION-Breast02 trial evaluated Dato-DXd versus investigator’s choice chemotherapy (paclitaxel, nab-paclitaxel, capecitabine, eribulin, or carboplatin) as first-line treatment in patients with locally recurrent inoperable or metastatic TNBC for whom PD-1/PD-L1 inhibitor therapy was not an option. Patients were randomized 1:1 to receive Dato-DXd (6 mg/kg every 3 weeks) or chemotherapy, with dual primary endpoints of PFS by BICR and OS.
At the primary analysis, Dato-DXd met both dual primary endpoints, demonstrating a statistically significant and clinically meaningful improvement in PFS and OS compared with chemotherapy. Median PFS by BICR was 10.8 months with Dato-DXd versus 5.6 months with chemotherapy (HR: 0.57, 95% CI: 0.47–0.69; P < 0.0001). Median OS was 23.7 months versus 18.7 months, respectively (HR: 0.79, 95% CI: 0.64–0.98; P = 0.029).
Dato-DXd also resulted in substantially higher confirmed ORRs (62.5% vs. 29.3%) and more durable responses, with a median duration of response of 12.3 months compared with 7.1 months in the chemotherapy arm. Efficacy benefits were consistent across key prespecified subgroups, including patients with PD-L1-low tumors, visceral disease, and stable brain metastases.
The safety profile of Dato-DXd was manageable and consistent with its known toxicity spectrum. Rates of grade ≥ 3 treatment-related adverse events were comparable between arms (33% vs. 29%), while treatment discontinuation due to adverse events was lower with Dato-DXd (4% vs. 7%). The most frequent adverse events included stomatitis, nausea, alopecia, and fatigue, with specific adverse events of special interest such as ocular surface toxicity and stomatitis generally manageable with dose modifications and supportive care [18].
The positive results of TROPION-Breast02 therefore position Dato-DXd as a new first-line standard-of-care option in this setting and underscore the growing importance of Trop‑2 as a therapeutic target. Together with ongoing studies such as TROPION-Breast03 and TROPION-Breast05, these data highlight the transformative potential of next-generation ADCs to redefine treatment paradigms and improve outcomes for patients with TNBC and substantial unmet medical need [19‐21].
Conclusion
In the treatment of HER2-low metastatic triple-negative breast cancer (mTNBC), two antibody-drug conjugates (ADCs) are currently approved and clinically available: sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd). Based on the strength and specificity of available evidence, SG has traditionally been considered the preferred first ADC in this setting, largely driven by the phase III ASCENT trial, which exclusively enrolled patients with mTNBC and demonstrated a significant and clinically meaningful benefit over standard chemotherapy.
By contrast, the DESTINY-Breast04 trial evaluated T‑DXd in a broader HER2-low population, with only a limited subgroup of patients with triple-negative disease. Consequently, evidence supporting T‑DXd specifically in mTNBC remains less robust, and current treatment strategies have generally favored SG as the initial ADC, followed by T‑DXd upon disease progression. Importantly, this sequencing is guided by immunohistochemical parameters (HER2 status) rather than by predictive biomarkers such as Trop‑2 expression. Both agents share a similar cytotoxic payload, delivering a topoisomerase I inhibitor, raising potential concerns regarding cross-resistance.
To date, prospective data addressing the efficacy of T‑DXd following progression on SG, or vice versa, are lacking, and the optimal sequencing of these ADCs remains undefined. Notably, subgroup analyses from ASCENT demonstrated that patients with low Trop‑2 expression still derived benefit from SG compared with chemotherapy, albeit with a reduced magnitude of effect. These findings generate the hypothesis that patients with HER2-low, Trop-2-low mTNBC may derive greater benefit from HER2-targeted ADCs such as T‑DXd, suggesting that alternative sequencing strategies—potentially administering T‑DXd prior to SG—warrant prospective evaluation.
Beyond these two agents, the therapeutic landscape of mTNBC is rapidly evolving. The phase III TROPION-Breast02 trial has demonstrated that the Trop-2-directed ADC datopotamab deruxtecan (Dato-DXd) significantly improves both PFS and OS compared with chemotherapy when used as first-line treatment in patients with locally recurrent inoperable or metastatic TNBC who are not eligible for PD-1/PD-L1 inhibitor therapy. These results establish Dato-DXd next to SG as a new first-line standard of care option in this population and further underscore the central role of Trop-2-directed ADCs in TNBC.
Collectively, these data highlight a paradigm shift toward ADC-based strategies across multiple lines of therapy in TNBC. However, the increasing number of available ADCs with overlapping payloads emphasizes the urgent need for biomarker-driven patient selection and prospective trials addressing optimal sequencing, resistance mechanisms, and cross-ADC efficacy to fully individualize treatment and maximize long-term benefits.
Conflict of interest
G. Rinnerthaler: employment: none; leadership: none; stock and other ownership interests: none; honoraria: AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Seagen, Stemline; consulting or advisory role: AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Novartis, Pfizer, Stemline; speakers bureau: none; research funding (institution): AstraZeneca, Daiichi Sankyo, Stemline; patents, royalties, other intellectual property: none; expert testimony: none; travel, accommodations, expenses: Daiichi Sankyo, Gilead, Roche, Servier; other relationship: none. F. Berton declares that she has no competing interests.
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