SG was the first TROP2-targeted ADC to demonstrate meaningful clinical activity and receive global approval (Figure 1). Early evidence came from the phase I/II IMMU-132-01 trial, which included > 100 pre-treated metastatic triple-negative breast cancer (mTNBC) patients⁷. SG achieved an objective response rate (ORR) of 33.3%, a median duration of response (DOR) of 7.7 months, a median progression-free survival (mPFS) of 5.5 months, and a median OS (mOS) of 13.0 months, which established a proof-of-concept in this difficult-to-treat population (Table 2).

The pivotal phase III ASCENT trial confirmed SG efficacy. SG significantly outperformed physician’s choice chemotherapy in 529 patients with refractory mTNBC: ORR, 31.0% vs. 4.0%; mPFS, 4.8 vs. 1.7 months (HR = 0.41); and mOS, 11.8 vs. 6.9 months (HR = 0.51). Adverse events (AEs) were manageable, with neutropenia, diarrhea, and anemia the most common grade ≥ 3 toxicities^8,9. Eighty patients with refractory mTNBC achieved ORR 38.8% and mPFS 5.6 months in the Chinese EVER-132-001 bridging study, confirming the value of SG across populations. Furthermore, the phase III ASCENT-03 trial showed that SG significantly improved the mPFS [9.7 vs. 6.9 months (HR = 0.62)] in the first-line setting for mTNBC patients who were not candidates for immunotherapy when compared to chemotherapy, as reported at the 2025 European Society for Medical Oncology (ESMO) Congress; OS data were not mature.

The results of the pivotal phase III TROPiCS-02 trial showed that SG improved survival [mPFS: 5.5 vs. 4.0 months (HR = 0.66); mOS: 14.4 vs. 11.2 months (HR = 0.79)] of pretreated patients with HR+/HER2− metastatic breast cancer (mBC) when compared to chemotherapy¹⁰. Consistent benefits of SG were also shown in the phase III EVER-132-002 Asia bridging study. Building on its metastatic success, SG has been tested in earlier stages of disease. The NeoSTAR trial evaluated SG as neoadjuvant monotherapy in untreated early TNBC. Approximately two-thirds of patients responded radiographically with 30% achieving a pathologic complete response (pCR) without additional chemotherapy¹¹. The ongoing phase III SASCIA trial is further assessing SG as adjuvant therapy in HER2-negative breast cancer with residual disease after neoadjuvant treatment.

Taken together, SG has become a benchmark therapy in mBC and validated across pivotal, bridging, and early-stage trials, making SG the most extensively studied TROP2 ADC to date.

Following the food and drug administration (FDA) approval in 2025, Dato-DXd became the second TROP2-targeted ADC authorized for the treatment of unresectable or metastatic HR+/HER2− breast cancer. Early evidence came from the phase I TROPION-PanTumor01 trial, which showed favorable activity (ORR: 32% and 27%, respectively; mPFS: 4.4 and 8.3 months, respectively) and tolerable safety of Dato-DXd in both pretreated mTNBC and HR+/HER2− cohorts¹².

These findings were confirmed in phase III trials. The TROPION-Breast01 trial randomized pretreated HR+/HER2− mBC patients to Dato-DXd or chemotherapy. Dato-DXd significantly improved mPFS [6.9 vs. 4.9 months (HR = 0.63)] and ORR (36% vs. 23%; odds ratio: 1.95, 95% CI: 1.41–2.71) across almost all subgroups. OS was not statistically different at the interim analysis but sensitivity analyses suggested a trend toward benefit, especially in HER2 IHC 0 patients. Importantly, toxicity was generally favorable; specifically, grade ≥ 3 AEs occurred in 21% of patients treated with Dato-DXd vs. 45% of patients treated with chemotherapy and stomatitis, nausea, and fatigue were the main manageable side effects¹³. As reported at the 2025 ESMO Congress, the TROPION-Breast02 trial showed that Dato-DXd significantly improved mPFS [10.8 vs. 5.6 months (HR = 0.57)] and mOS [23.7 vs. 18.7 months (HR = 0.79)] at the 27.5-month follow-up evaluation in the first-line setting of immunotherapy-ineligible mTNBC compared to chemotherapy. Higher ORR (62.5% vs. 29.3%) and longer DOR (12.3 vs. 7.1 months) were also noted in the Dato-DXd group, grade ≥3 AEs were comparable (33% vs. 29%), and fewer patients discontinued therapy due to toxicity (4% vs. 7%)¹⁴.

Regional studies have confirmed the aforementioned results. Dato-DXd yielded an ORR of 39% and mPFS of 8.1 months with fewer grade ≥3 AEs than chemotherapy in the China cohort of TROPION-Breast01 trial. The China TROPION-PanTumor02 study resulted in an ORR of 34% and mOS of 13.5 months in patients with mTNBC. Cross-trial observations suggested that Dato-DXd may have a safer hematologic profile than SG with markedly lower rates of severe neutropenia. This distinction could be clinically meaningful in patient selection.

Overall, Dato-DXd has rapidly become a new standard for mBC, while continuing to expand into earlier treatment settings, especially in TNBC. The ongoing phase III TROPION-Breast 03/04/05 trial is expected to benefit more patients.

Sac-TMT is an emerging TROP2 ADC that has gained approval in China and is generating promising results in global development. The results of the phase III OptiTROP-Breast01 trial were presented at the 2024 American Society of Clinical Oncology (ASCO) meeting. This trial randomized 263 patients with pretreated mTNBC to Sac-TMT or chemotherapy. Sac-TMT significantly improved the mPFS [6.7 vs. 2.5 months (HR = 0.32)] and ORR (45% vs. 12%); the OS benefit was not reached compared to 9.4 months for chemotherapy (HR = 0.53)¹⁵. The phase III OptiTROP-Breast02 trial (n = 399) showed that Sac-TMT significantly improved the mPFS [8.3 vs. 4.1 months (HR = 0.35)] in pretreated HR+/HER2− mBC with a higher 6-month PFS (61.4% vs. 25.7%) and ORR (41.5% vs. 24.1%) when compared to chemotherapy; a favorable early trend in OS was observed (HR = 0.33). These robust results highlight the potential of Sac- TMT as a strong competitor in the TROP2 ADC class¹⁶.

Grade ≥ 3 AEs occurred in roughly 63% of patients in the Sac-TMT group. Hematologic toxicities, including neutrope- nia (35%), anemia (29%), and thrombocytopenia (13%), were the most common grade ≥ 3 AEs in patients treated with Sac- TMT. Stomatitis (any grade, 50%–60%) was the most common AE of special interest; 1 treatment-related death was reported. These data suggest that Sac-TMT offers a favorable efficacy–safety balance, although vigilance for hematologic and mucosal toxicities is warranted¹⁶.

In addition to the three leading ADCs, several next-generation TROP2 ADCs are in early development in an effort to improve potency, stability, and safety. ESG-401, a phase I/II trial of HER2-negative mBC with central nervous system (CNS) involvement, achieved an intracranial ORR of 38% and intracranial disease control rate of 75%, with responses even in heavily pretreated patients¹⁷. Other ADC candidates, including SHR-A1921, JS-108, and F0024, are under preclinical or early clinical evaluation, leveraging novel payloads and linker designs to expand therapeutic reach.

TROP2 ADCs have been reported to induce immunogenic cell death (ICD), releasing tumor-associated antigens that stimulate immune responses. ICIs, such as PD-1/PD-L1 inhibitors, complement this effect by preventing T cell exhaustion and sustaining immune activation. The BEGONIA trial evaluated Dato-DXd plus durvalumab in mTNBC with any PD-L1 expression. The final results showed an ORR of 81.8%, mPFS of 14 months, and median DOR of 17.6 months, which far exceeded historical monotherapy outcomes¹⁸. Consistent findings from the phase III ASCENT-04 trial demonstrated that adding SG to pembrolizumab was superior to chemotherapy plus pembrolizumab. The SG combination regimen improved the mPFS [11.2 vs. 7.8 months (HR = 0.65)], a prolonged median DOR (16.5 vs. 9.2 months), and led to fewer treatment discontinuations (12% vs. 31%), collectively affirming the potent therapeutic synergy between TROP2-ADCs and ICIs¹⁹.

The SACI-IO HR+ trial tested SG with or without pembrolizumab in HR+/HER2− disease. While the combination showed a modest improvement in mPFS [8.4 vs. 6.2 months (HR = 0.76)] and ORR (21% vs. 17%), the differences were not statistically significant. Safety profiles were comparable, although neutropenia was more frequent with the combination. Subgroup analyses based on TROP2 and PD-L1 expression may clarify which patients derive the greatest benefit²⁰.

TROP2 ADCs inflict substantial DNA damage via cytotoxic payloads. When combined with PARP inhibitors, which impair the ability of the cancer cell to repair such damage, this strategy may induce synthetic lethality, thereby boosting antitumor effects. SG is currently being tested in combination with talazoparib and rucaparib in phase II trials for mTNBC. Early data suggest that the regimen is well-tolerated and shows promising antitumor activity, particularly in patients with limited treatment options²¹. Dato-DXd is also under investigation with AZD9574, a selective PARP inhibitor, in advanced solid tumors (NCT05417594). These dual-DNA damage approaches may yield more durable responses, particularly in BRCA-mutated or DDR-deficient patients.

Resistance to CDK4/6 inhibitors is a major challenge in HR+/HER2− breast cancer. Combining these agents with TROP2 ADCs offers a complementary mechanism; specifically, CDK4/6 blockade induces cell cycle arrest, while ADCs deliver targeted cytotoxicity to TROP2-expressing cells. The ongoing NCT05113966 trial is exploring SG with a CDK4/6 inhibitor in patients with HR+/HER2− mBC who progressed on endocrine therapy and CDK4/6 inhibitors. This population has few treatment options and favorable results could establish a new standard in the post-CDK4/6 setting.

In addition to ICIs, PARP inhibitors, and CDK4/6 inhibitors, combining TROP2 ADCs with PI3K inhibitors or novel targeted agents are under early investigation. Collectively, these efforts aim to expand the reach of TROP2 ADCs, delay resistance, and improve outcomes across breast cancer subtypes.

Balancing efficacy with tolerability remains a central consideration in TROP2-ADC therapy. SG is predominantly associated with hematologic toxicity, particularly neutropenia, which can be mitigated through dose modification, treatment delay, or granulocyte colony-stimulating factor (G-CSF) support. Dato-DXd exhibits a distinct profile characterized by stomatitis, fatigue, and low rates of interstitial lung disease, which are generally manageable with symptomatic care and early intervention. Mucositis and hematologic toxicities are the most frequent toxicities associated with Sac-TMT, reflecting the high DAR and potent topoisomerase payload. Gastrointestinal events, such as diarrhea and nausea, remain common across agents but are effectively controlled with antiemetics, antidiarrheals, hydration, and dietary adjustments²². As TROP2 ADCs move into earlier disease settings and more diverse populations, proactive toxicity monitoring and supportive care will be essential to preserve treatment adherence and patient quality of life.

Several mechanisms of resistance have emerged. Down-regulation or mutation of the TACSTD2 gene reduces TROP2 surface expression, limiting ADC binding and uptake. Altered intracellular trafficking can prevent delivery of the conjugate to lysosomal compartments, thereby impairing payload release. In addition, enhanced activity of drug efflux pumps, such as ATP-binding cassette (ABC) transporters, may expel cytotoxic agents prematurely, reducing efficacy.

Emerging approaches to overcome resistance include dual-target ADCs co-recognizing TROP2 and HER3, payload diversification to evade ABC transporter efflux, and modulation of lysosomal trafficking through PI3K/AKT pathway inhibitors. Preclinical data suggest that combining TROP2 ADCs with PARP inhibitors or immune checkpoint blockade can restore cytotoxic activity in low-TROP2 or resistant clones, providing a rational path toward biomarker-guided combination therapy. Elucidating these mechanisms will be key to designing next-generation ADCs and combination strategies that overcome resistance, particularly in relapsed or refractory disease.

Effective biomarkers are urgently needed to optimize patient selection. Quantitative TROP2 expression correlates with clinical response to ADC therapy. Higher TROP2 H-scores were associated with improved ORR and PFS in the ASCENT and TROPION-Breast01 trial. Thus, TROP2 IHC may serve as a dual prognostic and predictive biomarker for patient selection. Ongoing research is investigating markers of DNA repair deficiency, immune activation, and drug resistance as potential predictors. Integrating such biomarkers into clinical decision-making could enable use of TROP2 ADCs in precision medicine, maximizing benefit while minimizing unnecessary exposure in patients unlikely to respond.

Innovations in ADC construction include more stable and tumor-specific linkers, which reduce premature payload release in circulation and minimize off-target toxicity. Newer cytotoxic payloads are being developed to overcome existing resistance mechanisms and to improve potency, even in low-antigen–expressing tumors²³. Simultaneously, antibody engineering is enhancing binding affinity and selectivity, enabling more precise delivery of the therapeutic payload to cancer cells.

A particularly exciting innovation involves the use of extracellular vesicles (EVs), including exosomes, to improve ADC delivery. EVs can be engineered to carry ADCs or ADC components directly to tumor sites with high specificity, bypassing some of the limitations of traditional delivery methods. These strategies hold promise for resistant or poorly accessible tumors, where conventional ADC penetration is limited.

The integration of personalized medicine principles into ADC development is transforming treatment paradigms. By aligning therapies with the molecular profile of each patient’s tumor, clinicians can enhance treatment efficacy while minimizing toxicity. This precision-guided approach is expected to become increasingly central in the deployment of TROP2 ADCs, particularly as more biomarkers and resistance mechanisms are uncovered.