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TROP2 ADCs for Advanced HR-Positive/HER2-Negative and Triple-Negative Cancers: Translating New Data into Practice

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Released: August 25, 2026

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Explore pivotal phase III evidence supporting recent updated regulatory indications for TROP2 ADCs in metastatic HR-positive/HER2-negative and triple-negative breast cancer, with a focus on how new efficacy and safety data inform treatment selection. Learn about expert considerations when selecting therapy in the first-line and later-line settings based on eligibility for immunotherapy and the adverse event profile of available TROP-targeted ADCs. Finally, learn how to anticipate potential adverse event challenges limiting therapy persistence, as well as how to mitigate them and incorporate supportive care approaches.

Peter Schmid
Peter Schmid, MD, PhD, FRCP
TROP2 ADCs in Breast Cancer

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Key Takeaways
  • TROP2-directed ADCs have established roles in metastatic TNBC and HR-positive/HER2-negative breast cancer without TROP2 expression testing for current breast cancer indications.
  • Phase III data from TROPION-Breast02 and ASCENT-03 support first-line datopotamab deruxtecan and sacituzumab govitecan, respectively, for metastatic TNBC when PD-1/PD-L1 inhibitor therapy is not an option.
  • Key adverse events to anticipate and manage include stomatitis, ocular adverse reactions, and ILD/pneumonitis with datopotamab deruxtecan, and neutropenia and diarrhea with sacituzumab govitecan.

In this commentary, Peter Schmid, MD, PhD, FRCP, reviews how TROP2-directed antibody–drug conjugates (ADCs) are changing treatment for metastatic triple-negative breast cancer (TNBC) and hormone receptor (HR)-positive/HER2-negative breast cancer. He examines pivotal phase III data supporting recently expanded treatment options, current regulatory indications, practical considerations for selecting and sequencing TROP2 ADCs, and strategies for anticipating and managing characteristic adverse events (AEs) in routine care.

TROP2 ADCs Are Expanding Across Metastatic Breast Cancer
TROP2 is a cell-surface glycoprotein expressed in many epithelial cancers, including breast cancer, and has become an important target for ADC development. The currently available TROP2-directed ADCs pair an anti-TROP2 antibody with a topoisomerase I inhibitor payload. Although TROP2 expression provides the biologic rationale for this treatment class, current FDA-approved breast cancer indications for sacituzumab govitecan and datopotamab deruxtecan (Dato-DXd) do not require a TROP2 expression threshold or companion diagnostic for treatment selection.

The treatment landscape for TROP2-directed ADCs now spans both TNBC and HR-positive/HER2-negative disease. In the United States specifically, sacituzumab govitecan is approved for later-line metastatic TNBC and HR-positive/HER2-negative breast cancer and, starting June 2026, is also available as first-line monotherapy for adults with unresectable locally advanced or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor–based therapy; and in combination with pembrolizumab for first-line unresectable locally advanced or metastatic TNBC with PD-L1 combined positive score ≥10 as determined by an FDA-approved test. Dato-DXd is approved for unresectable or metastatic HR-positive/HER2-negative breast cancer after prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease and, starting May 2026, for unresectable or metastatic TNBC when PD-1/PD-L1 inhibitor therapy is not an option.

In the European Union (EU), first-line monotherapy with sacituzumab govitecan or Dato-DXd is authorized for patients with immunotherapy-ineligible metastatic TNBC. For first-line sacituzumab govitecan plus pembrolizumab in PD-L1–positive TNBC, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion in July 2026, and a European Commission decision remains pending as of August 2026.

First-line TNBC: Pivotal Data Move TROP2 ADCs in Earlier Disease Setting
For patients with previously untreated advanced TNBC who are not candidates for immunotherapy, the phase III TROPION-Breast02 trial randomized 644 patients to Dato-DXd 6 mg/kg every 3 weeks or investigator's choice of chemotherapy. The dual primary endpoints were blinded independent central review (BICR)–assessed progression-free survival (PFS) and overall survival (OS). Dato-DXd was shown to improve median PFS (10.8 vs 5.6 months; HR: 0.57; 99% CI: 0.44-0.73; P <.0001) and median OS (23.7 vs 18.7 months; HR: 0.79; 95.01% CI: 0.64-0.98; P = .029); the confirmed objective response rate (ORR) was 64% vs 30%. Common AEs included stomatitis (63%), nausea (48%), alopecia (43%), dry eye (26%), and keratitis (26%); serious AEs occurred in 17% of patients, and 1 patient (0.3%) experienced fatal interstitial lung disease (ILD)/pneumonitis. These results supported FDA approval in May 2026 and subsequent EU authorization for first-line Dato-DXd in adults with unresectable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.

The phase III ASCENT-03 trial evaluated sacituzumab govitecan 10 mg/kg intravenously on Days 1 and 8 of each 21-day cycle vs physician's choice chemotherapy in 558 patients with previously untreated, unresectable locally advanced or metastatic TNBC who were not candidates for PD-1/PD-L1 inhibitors. The trial met its primary endpoint, with median BICR-assessed PFS of 9.7 vs 6.9 months (HR: 0.62; 95% CI: 0.50-0.77; P <.001). Confirmed ORR was 48% vs 46%, but median duration of response was longer with sacituzumab govitecan (12.2 vs 7.2 months); OS data were immature at the primary analysis. Grade ≥3 AEs occurred in 66% vs 62% of patients, with neutropenia (43%) and diarrhea (9%) among the most frequent grade ≥3 events with sacituzumab govitecan. These findings supported first-line monotherapy approval in the US and EU for patients who are not candidates for PD-1/PD-L1 inhibitor therapy.

For previously untreated PD-L1–positive advanced TNBC, the phase III ASCENT-04/KEYNOTE-D19 trial randomized 443 patients to sacituzumab govitecan plus pembrolizumab or chemotherapy plus pembrolizumab. Median BICR-assessed PFS was 11.2 vs 7.8 months (HR: 0.65; 95% CI: 0.51-0.84; P <.001), ORR was 60% vs 53%, and median duration of response was 16.5 vs 9.2 months; OS data remained immature. Grade ≥3 AEs occurred in 71% vs 70% of patients, and treatment discontinuation because of AEs occurred in 12% vs 31%, respectively. These data supported the June 2026 FDA approval of sacituzumab govitecan plus pembrolizumab for first-line unresectable locally advanced or metastatic TNBC with PD-L1 combined positive score ≥10, as determined by an FDA-authorized test. In Europe, CHMP recommended this combination in July 2026, with the European Commission decision still pending as of August 2026.

HR-Positive/HER2-Negative Disease: Efficacy and Sequencing
TROP2 ADCs also provide established options after endocrine-based therapy in patients with HR-positive/HER2-negative metastatic breast cancer. In the phase III TROPION-Breast01 trial, 732 patients with inoperable or metastatic disease who had progressed on endocrine therapy and had received 1 or 2 prior chemotherapy regimens in the advanced disease setting were randomized to Dato-DXd or investigator's choice of chemotherapy. Dato-DXd improved the dual primary endpoint of BICR-assessed PFS (6.9 vs 4.9 months; HR: 0.63; 95% CI: 0.52-0.76; P <.0001). At the final analysis, the median OS was 18.6 vs 18.3 months (HR: 1.01; 95% CI: 0.83-1.22) and was not statistically different between the treatment groups. These data supported FDA regulatory approval of Dato-DXd for patients with pretreated HR-positive/HER2-negative unresectable or metastatic breast cancer.

Sacituzumab govitecan was established in a more heavily pretreated HR-positive/HER2-negative population in the phase III TROPiCS-02 trial. Among 543 patients who had received endocrine therapy, a taxane, a CDK4/6 inhibitor, and 2-4 prior chemotherapy regimens for metastatic disease, sacituzumab govitecan improved median PFS vs single-agent chemotherapy (5.5 vs 4.0 months; HR: 0.66; 95% CI: 0.53-0.83; P = .0003) and median OS (14.4 vs 11.2 months; HR: 0.79; 95% CI: 0.65-0.96; P = .020). In practice, sequencing should account for the labeled population, prior exposure to ADCs and chemotherapy, HER2 expression and other actionable biomarkers, comorbidities, previous toxicities, disease tempo, and patient preferences.

How Toxicity Profiles Can Help Differentiate TROP2 ADCs
For sacituzumab govitecan, neutropenia and diarrhea remain key risks, and the prescribing information carries boxed warnings for both of these AEs. Blood counts should be monitored periodically, treatment should be withheld for specified neutropenia thresholds or neutropenic fever, and primary G-CSF prophylaxis is recommended for patients at increased risk of febrile neutropenia. Febrile neutropenia may also require prompt anti-infective treatment. For diarrhea, healthcare professionals should evaluate for infectious causes, provide fluids and electrolytes as needed, initiate loperamide promptly when infection is excluded, and withhold or dose-reduce treatment for severe events according to the prescribing information.

Dato-DXd requires a different anticipatory workflow. Stomatitis/oral mucositis, ocular adverse reactions, and ILD/pneumonitis are the prominent labeled risks of this ADC. Current prescribing information advises a steroid-containing mouthwash at the start of treatment and instructs patients to hold ice chips or ice water in the mouth throughout the infusion. Patients are also advised to use preservative-free lubricating eye drops at least 4 times a day, as needed, and to avoid contact lenses unless directed by an eye care professional. A comprehensive ophthalmic examination, including visual acuity testing, slit-lamp examination with fluorescein staining, intraocular pressure, and fundoscopy, should be performed at treatment initiation, at the end of treatment, and as clinically indicated; visual acuity testing and slit-lamp examination should be repeated every 3 cycles while on treatment. New or worsening pulmonary symptoms should prompt evaluation for ILD/pneumonitis; treatment should be withheld for suspected ILD/pneumonitis, and patients with confirmed grade ≥2 ILD/pneumonitis require permanent discontinuation and prompt systemic corticosteroid treatment.

These practical differences can inform shared decision-making. Baseline gastrointestinal disease or limited marrow reserve may increase the monitoring burden with sacituzumab govitecan, whereas preexisting ocular disease, recurrent mucositis, or pulmonary risk factors may affect the feasibility of Dato-DXd. These considerations are not absolute selection rules, but they can guide supportive care planning, patient counseling, and early toxicity recognition.

How the TROP2 ADC Landscape Continues to Evolve
Sacituzumab tirumotecan is another TROP2-directed ADC in clinical development. In the randomized phase III OptiTROP-Breast01 trial conducted in China, 263 patients with previously treated locally recurrent or metastatic TNBC received sacituzumab tirumotecan or physician's choice of chemotherapy. Median BICR-assessed PFS was 6.7 vs 2.5 months (HR: 0.32; 95% CI: 0.24-0.44; P <.00001), and at the prespecified interim OS analysis, median OS was not reached vs 9.4 months (HR: 0.53; 95% CI: 0.36-0.78; P = .0005). ORR was 45.4% vs 12.0%, and median duration of response was 7.1 vs 3.0 months. As of August 2026, sacituzumab tirumotecan is not FDA- or EMA-approved for breast cancer. In China, however, it is approved for unresectable locally advanced or metastatic TNBC after ≥2 prior systemic therapies, including ≥1 in the advanced/metastatic setting, as well as for unresectable or metastatic HR-positive/HER2-negative breast cancer after prior endocrine therapy and ≥1 line of chemotherapy in the advanced disease setting.

As TROP2 ADC indications move into earlier lines of therapy, treatment decisions will increasingly depend on disease subtype, prior therapies, regulatory status, expected toxicity, supportive care infrastructure, and patient priorities. Familiarity with the pivotal data and agent-specific management requirements will be important as healthcare professionals integrate these therapies while preserving future treatment options.

Your Thoughts
How are you thinking about the current role of TROP2 ADCs in the management of patients with HR-positive/HER2-negative or triple-negative breast cancer? Tell us where you practice and about your ability to access TROP2 ADCs. Access the program page, an online guided infographic resource, and other certified educational activities associated with this discussion.

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