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Individualizing TROP-2–Directed ADC Therapy in Metastatic Triple-Negative Breast Cancer

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Released: September 28, 2026

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In this commentary, experts review the evolving role of TROP-2–directed antibody–drug conjugates (ADCs) in metastatic triple-negative breast cancer, with emphasis on first-line treatment selection, sequencing after progression, and management of agent-specific toxicities. The discussion examines phase III data from KEYNOTE-355, ASCENT-04/KEYNOTE-D19, ASCENT-03, TROPION-Breast02, and ASCENT, including progression-free survival, overall survival, response rates, and PFS2, while highlighting important differences in trial design that limit cross-trial comparisons. The experts also address how PD-L1 and germline BRCA1/2 status, prior therapy, disease characteristics, toxicity profiles, supportive care needs, and treatment schedules inform ADC selection and sequencing. Practical considerations related to managing neutropenia, diarrhea, stomatitis, ocular toxicity, and ILD/pneumonitis are reviewed alongside strategies to support timely treatment, toxicity monitoring, biomarker testing, and equitable access to ADC therapy and clinical trials.

Javier Cortes
Javier Cortes, MD, PhD
Ana C. Garrido-Castro
Ana C. Garrido-Castro, MD
TROP2 ADCs in mTNBC

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Individualizing TROP-2–Directed ADC Therapy in Metastatic TNBC
Ana C. Garrido-Castro, MD:

For decades, chemotherapy remained the cornerstone of treatment for metastatic triple-negative breast cancer (TNBC), with survival improvements trailing those observed in other breast cancer subtypes. However, the treatment landscape shifted in 2026 with the introduction of first-line indications for 2 TROP-2–directed antibody–drug conjugates (ADCs) in defined patient populations: datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan (SG). The question is no longer whether it is appropriate to use a TROP-2–directed ADC but rather which agent is optimal, when to incorporate it in the disease course, and how to best manage therapy to optimize treatment duration.

TROP-2 is commonly expressed in TNBC, but TROP-2 testing is not required as a companion diagnostic for SG or Dato-DXd, and no predefined immunohistochemical expression threshold governs eligibility for either approved agent. For SG, the ASCENT biomarker analysis showed clinical activity across high, medium, and low TROP-2 expression subgroups, although the low-expression subgroup was small and the magnitude of benefit was greater with higher TROP-2 expression. For Dato-DXd, current TNBC approval and trial eligibility are not based on TROP-2 testing, and data on antitumor activity by TROP-2 expression are lacking. Treatment selection instead depends on disease setting, PD-L1 status, germline BRCA1/2 status, prior therapy, comorbidities, anticipated toxicities, and access.

Selecting First-line Therapy: PD-L1 Status Guides Treatment Selection
Ana C. Garrido-Castro, MD:

For adults with previously untreated locally advanced unresectable or metastatic TNBC, PD-L1 status is a key determinant for the first-line treatment approach.

For patients with a PD-L1 combined positive score (CPS) of 10 or higher, pembrolizumab plus chemotherapy set the benchmark in KEYNOTE-355, a phase III trial in previously untreated locally recurrent inoperable or metastatic TNBC. In the CPS ≥10 population, the final KEYNOTE-355 analysis showed median PFS of 9.7 vs 5.6 months with pembrolizumab plus chemotherapy vs placebo plus chemotherapy (HR: 0.66; 95% CI: 0.50-0.88) and median overall survival (OS) of 23.0 vs 16.1 months (HR: 0.73; 95% CI: 0.55-0.95; P = .0185). ASCENT-04/KEYNOTE-D19, a phase III trial of 443 patients with previously untreated PD-L1–positive (CPS ≥10) advanced unresectable or metastatic TNBC, then compared SG plus pembrolizumab with chemotherapy plus pembrolizumab. Median PFS by blinded independent central review was 11.2 vs 7.8 months (HR: 0.65; 95% CI: 0.51-0.84; P <.001). OS data remain immature, and patients in the control arm were permitted to cross over to SG at progression.

For patients who are not candidates for PD-1/PD-L1 inhibitor therapy, 2 phase III trials evaluated a first-line TROP-2–directed ADC compared with chemotherapy. In ASCENT-03, patients were eligible if their tumors had PD-L1 CPS <10, or if CPS was ≥10 and they had received prior PD-1/PD-L1 inhibitor therapy in the neoadjuvant setting or had a comorbidity precluding PD-1/PD-L1 inhibitor treatment. TROPION-Breast02 enrolled patients with PD-L1–negative tumors and patients with PD-L1-positive tumors who were ineligible for PD-1/PD-L1 inhibitor therapy because of prior neoadjuvant PD-1/PD-L1 inhibitor exposure, a precluding comorbidity, or lack of PD-1/PD-L1 inhibitor availability in their country. In ASCENT-03, 558 patients were randomly assigned to SG or chemotherapy (paclitaxel, nab-paclitaxel, or carboplatin/gemcitabine), with median PFS of 9.7 vs 6.9 months (HR: 0.62; 95% CI: 0.50-0.77; P <.001). In TROPION-Breast02, 644 patients were randomly assigned to Dato-DXd or investigator’s choice of single-agent chemotherapy (paclitaxel, nab-paclitaxel, or [if prior taxane and disease-free interval ≤12 months] carboplatin, capecitabine or eribulin). Median PFS was 10.8 vs 5.6 months (HR: 0.57; 99% CI: 0.44-0.73; P <.0001), and median OS was 23.7 vs 18.7 months (HR: 0.79; 95.01% CI: 0.64-0.98; P = .029).

However, these trials are not directly comparable, as they differed in eligibility criteria, comparator chemotherapy options, crossover design, and endpoints. ASCENT-03 permitted protocol-specified crossover to SG after progression, and mature OS results have not yet been reported. In contrast, TROPION-Breast02 did not include protocol-defined crossover, although patients could receive subsequent standard-of-care therapy after progression, and the trial was powered for dual primary endpoints of PFS and OS. The differences in objective response rates (ORRs) underscore the limitations of cross-trial comparisons: 48% with SG vs 46% with chemotherapy in ASCENT-03 and 63% with Dato-DXd vs 29% with chemotherapy in TROPION-Breast02. In ASCENT-03, the protocol allowed doublet chemotherapy with carboplatin plus gemcitabine, which was received by 44% of patients in the control arm and may have contributed to the higher response rate observed with the comparator.

For patients with germline BRCA1/2–mutated, PD-L1–negative disease, a PARP inhibitor remains a first-line option. SG is FDA approved as monotherapy for first-line treatment of 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 or pembrolizumab and berahyaluronidase alfa-pmph, for first-line treatment of adults with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. Dato-DXd is FDA approved for adults with unresectable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.

Sequencing After Progression
Javier Cortes, MD, PhD:

For patients whose disease progresses on or after an immune checkpoint inhibitor plus chemotherapy and who have not received a prior TROP-2–directed ADC, SG is a guideline-supported subsequent-line option, with treatment selection also informed by germline BRCA1/2 status, HER2 expression, and prior therapy. The phase III ASCENT trial established later-line efficacy for SG in patients with unresectable locally advanced or metastatic TNBC who had received at least 2 prior systemic therapies, including at least 1 for metastatic disease. Among the 468 patients without baseline brain metastases, median PFS was 5.6 vs 1.7 months with SG vs single-agent chemotherapy of physician's choice (HR: 0.41; 95% CI: 0.32-0.52; P <.001), and median OS was 12.1 vs 6.7 months (HR: 0.48; 95% CI: 0.38-0.59; P <.001).

As ADCs move earlier in the disease course, a recurring question is whether overall survival benefit with treatment in the first-line setting is influenced by subsequent therapy. PFS after next line of treatment (PFS2) evaluates outcomes across both the initial and the subsequent line of therapy. In TROPION-Breast02, median PFS2 was 15.6 months with Dato-DXd vs 11.8 months with investigator's choice of chemotherapy (HR: 0.61; 95% CI: 0.50-0.74). PFS2 also favored SG in ASCENT-03, with a median of 18.2 vs 14.0 months with chemotherapy (HR: 0.70; 95% CI: 0.55-0.90). In ASCENT-04, median PFS2 was not reached with SG plus pembrolizumab vs 21.0 months with chemotherapy plus pembrolizumab (HR: 0.67; 95% CI: 0.48-0.95) despite protocol-permitted crossover to SG.

In germline BRCA1/2-mutated disease, both PARP inhibitors and TROP-2–directed ADCs are supported treatment options, but no head-to-head trial has established the optimal sequencing of these approaches. Sequencing is guided by prior therapy, disease tempo, marrow and organ reserve, prior toxicities, and clinical trial availability. After progression on an ADC, described resistance mechanisms include payload- and target-related mechanisms, providing a biologic rationale for considering an ADC with a different payload or target. However, these observations remain hypothesis generating rather than practice directing, and clinical trial referral should be considered when appropriate. Sacituzumab tirumotecan, another TROP-2–directed ADC, is investigational in the United States and approved only in China for adults with unresectable locally advanced or metastatic TNBC after ≥2 prior systemic therapies, including ≥1 for advanced/metastatic disease.

Anticipating and Managing Agent-Specific Toxicity
Javier Cortes, MD, PhD:

In the absence of a head-to-head comparison, selection between the 2 approved first-line TROP-2–directed ADCs is informed largely by toxicity profile, supportive care requirements, and treatment schedule. Their differing molecular constructs are associated with distinct toxicity profiles, making these differences mechanistically plausible rather than arbitrary.

SG carries a boxed warning for severe neutropenia and severe diarrhea, consistent with its SN-38 payload. In ASCENT-03, neutropenia occurred in 67% of patients (43% grade ≥3) and diarrhea in 54% (9% grade ≥3). Primary granulocyte colony-stimulating factor (G-CSF) prophylaxis is recommended for, at least, patients at increased risk of febrile neutropenia, alongside blood count monitoring before each dose and treatment holds for low neutrophil counts. Diarrhea is managed proactively, with atropine for early-onset diarrhea and loperamide and/or other antidiarrheals for late-onset diarrhea. PRIMED, an open-label, single-arm phase II study in 50 patients with HER2-negative advanced breast cancer receiving SG, evaluated primary prophylaxis with G-CSF (0.5 MU/kg/day subcutaneously on Days 3, 4, 10, and 11) and loperamide (2 mg twice daily or 4 mg once daily on Days 2, 3, 4, 9, 10, and 11) during the first 2 cycles, with continuation thereafter at the treating physician’s discretion. During the first 2 cycles, grade ≥3 neutropenia occurred in 16% of patients, no febrile neutropenia was reported, and grade ≥2 diarrhea occurred in 16%, including grade 3 diarrhea in 4%.

Dato-DXd has a distinct toxicity profile characterized primarily by mucosal, ocular, and pulmonary adverse events. In TROPION-Breast02, treatment-related oral mucositis/stomatitis occurred in 60% of patients (24% grade 1, 27% grade 2, and 8% grade 3), and treatment-related ocular surface events occurred in 47% (24% grade 1, 16% grade 2, and 7% grade ≥3), including dry eye in 24% of patients (1% grade ≥3). A steroid-containing mouthwash is recommended 4 times daily and as needed for prophylaxis of oral mucositis/stomatitis, and patients should hold ice chips or ice water in the mouth throughout the Dato-DXd infusion. Patients should use preservative-free lubricating eye drops at least 4 times daily and as needed and avoid contact lenses unless directed by an eye care professional. Ophthalmic examination (including visual acuity testing, slit lamp examination with fluorescein staining, intraocular pressure, and fundoscopy) is advised at treatment initiation and end of treatment and as clinically indicated; visual acuity testing and slit-lamp examination should be performed every 3 cycles during treatment. Interstitial lung disease (ILD) or pneumonitis, reported in approximately 3% of patients in the pooled prescribing information safety population with breast cancer, requires vigilant monitoring, and treatment should be permanently discontinued for grade ≥2 ILD/pneumonitis.

Treatment schedule is also an important consideration when selecting therapy. Dato-DXd is given once every 21 days, whereas SG is given on Days 1 and 8 of a 21-day cycle. Proactive toxicity management is important, not only for quality of life, but also for maintaining treatment exposure, as early prevention and management of adverse events can reduce dose interruptions, dose reductions, and treatment discontinuation.

Access, Equity, and Practice Readiness
Javier Cortes, MD, PhD:

Expanding ADC use raises questions about delivery and selection. TNBC disproportionately affects Black and younger women, and Black women have approximately 40% higher breast cancer mortality despite a slightly lower overall incidence of breast cancer. Gaps in authorization, biomarker testing, and access to centers equipped to deliver ADC therapy may further widen disparities in care and outcomes.

Practical barriers can also affect timely and sustained access to ADC therapy. Prior authorization requirements and financial toxicity may delay treatment initiation, and infusion capacity can be constrained by treatment schedules, including the Day 1 and Day 8 dosing of SG. Safe administration also depends on clinical infrastructure that may not be uniformly available, including timely laboratory monitoring, access to growth factor support, ophthalmologic evaluation when indicated, and imaging for suspected ILD.

Fortunately, several strategies can help close these gaps. Patient and financial navigation reduces delays and early discontinuation. Community and academic partnerships extend ADC delivery and monitoring closer to home. Equitable access to germline BRCA1/2 and PD-L1 testing helps preserve biomarker-driven treatment options for all eligible patients, and structured referral and navigation pathways may improve clinical trial access for populations that remain underrepresented, including diverse and rural patients. Follow-up can be tailored through electronic patient-reported symptom tracking, telehealth visits during early treatment cycles, and patient education adapted to language and health literacy needs. Symptom tracking is particularly useful in the first cycles of ADC therapy, when several clinically important toxicities may first emerge and when prompt recognition of side effects can facilitate timely intervention. As ADC use expands, establishing the necessary infusion, laboratory, supportive care, and toxicity monitoring infrastructure will be essential to ensure that eligible patients can initiate treatment promptly and continue therapy safely.

Your Thoughts
How are you selecting and sequencing TROP-2–directed ADCs for your patients with metastatic TNBC, and which supportive care strategies have been most effective in maintaining therapy? Answer the polling question and join the conversation by posting a comment in the discussion section below.

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For a patient with previously untreated metastatic TNBC who is not a candidate for PD-1/PD-L1 inhibitor therapy, which consideration most often drives your choice between SG and Dato-DXd?

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