Sequencing and Treatment Approaches for ADCs in HR+ Metastatic Breast Cancer

Three antibody-drug conjugates (ADCs) are now approved for use in hormone receptor-positive (HR+), HER2-negative metastatic breast cancer, each with a distinct molecular architecture. With these choices, the dilemma of sequencing to maximize efficacy and minimize adverse events becomes a challenge for oncologists. In a presentation at the 2026 Miami Breast Cancer Conference, Komal Jhaveri, MD, FACP, FASCO, Breast Medicine Service, Early Drug Development Service, and Endocrine Therapy Research Program at Memorial Sloan Kettering Cancer Center and associate professor at Weill Cornell Medical College, discussed these agents and potential approaches.¹

The ADC Landscape in HR+ Breast Cancer

Trastuzumab deruxtecan (T-DXd; Enhertu) is an anti-HER2 ADC consisting of a humanized HER2-directed antibody conjugated to a potent topoisomerase I inhibitor payload via a cleavable linker, with a drug-to-antibody ratio of approximately 8:1. Its clinical utility in HER2-negative disease rests on the observation that approximately 85% of HR+ tumors express low or ultralow levels of HER2 (IHC 1+, IHC 2+/ISH−, or IHC >0 to <1+), enabling meaningful target engagement even below the threshold of HER2 positivity.

Sacituzumab govitecan (SG; Trodelvy) is an anti-TROP2 ADC that employs a humanized IgG1κ antibody, a pH-sensitive hydrolyzable linker, and an SN-38 payload delivered at a drug-to-antibody ratio of 7.6:1. Because TROP2 is expressed across virtually all breast cancer subtypes, SG does not require biomarker selection and is applicable to nearly 100% of patients.

Datopotamab deruxtecan (Dato-DXd; Datroway) is likewise a TROP2-directed ADC but uses an exatecan-derived DXd payload coupled via a tetrapeptide-based cleavable linker at a drug-to-antibody ratio of approximately 4:1, conferring a distinct toxicity profile compared with SG.

T-DXd in HER2-Low and HER2-Ultralow Disease: DESTINY-Breast04 and DESTINY-Breast06

The DESTINY-Breast04 (NCT03734029) trial established T-DXd as a practice-changing therapy for patients with HER2-low metastatic breast cancer who had received prior chemotherapy in the metastatic setting.² Among the HR+ cohort (n = 494), T-DXd produced a median progression-free survival (PFS) of 9.6 months compared with 4.2 months for treatment of physician’s choice (TPC). The median overall survival (OS) was 23.9 months with T-DXd vs 17.5 to 17.6 months with TPC in the updated analysis. Notably, 70% of enrolled patients had received a prior CDK4/6 inhibitor, 67% had 3 or more prior lines of endocrine therapy, and approximately 60% had received 1 prior line of chemotherapy, underscoring the heavily pretreated nature of this population.

Building on this, the DESTINY-Breast06 (NCT04494425) trial examined T-DXd in chemotherapy-naive patients with HR+, HER2-low or HER2-ultralow metastatic breast cancer who had progressed on endocrine therapy plus CDK4/6i.³ Among 866 randomized patients, T-DXd improved median PFS from 8.1 months with TPC to 13.2 months in the HER2-low and intention-to-treat (ITT) populations (HR, 0.62–0.64; P <.001). In the HER2-ultralow exploratory cohort (n = 152), T-DXd yielded a median PFS of 13.2 months vs 8.3 months for TPC (HR, 0.78). Confirmed objective response rates (ORR) were 56.5% vs 32.2% in the HER2-low population and 61.8% vs 26.3% in the HER2-ultralow group. At the first interim OS analysis (approximately 40% maturity), no statistically significant OS benefit was demonstrated, though a favorable trend was observed across all populations. Crucially, T-DXd preserved global health status and quality of life while delaying deterioration in physical functioning, role functioning, pain, and fatigue relative to TPC, albeit with higher rates of gastrointestinal adverse effects. The most important safety concern remained drug-related interstitial lung disease/pneumonitis, which occurred in 11.3% of patients overall (grade 3, 0.7%; grade 5, 0.7%).

Subgroup analyses from DESTINY-Breast06 demonstrated that the PFS benefit of T-DXd was preserved regardless of time to progression on first-line endocrine therapy plus CDK4/6i, disease burden, visceral involvement, and primary vs secondary endocrine resistance. Among patients with primary endocrine resistance (time to progression less than 6 months on first-line endocrine therapy plus CDK4/6i), median PFS was 14.0 months with T-DXd vs 6.5 months with TPC (HR, 0.38). Comparable benefit was observed in patients with lower disease burden, where median PFS with T-DXd ranged from 15.0 to 23.3 months. Based on this evidence, T-DXd is now recognized by both the National Comprehensive Cancer Network (NCCN) and ESMO Living Guidelines as a preferred treatment option for eligible patients with HER2-low or HER2-ultralow HR+ MBC.

Sacituzumab Govitecan: TROPiCS-02 and ASCENT-07

SG was approved for HR+/HER2-negative metastatic breast cancer based on the TROPiCS-02 trial (NCT03901339), which randomized 543 patients with endocrine-resistant disease who had received 2 to 4 prior lines of chemotherapy (98% prior CDK4/6i; median 3 prior lines of therapy) to SG or chemotherapy. SG demonstrated a statistically significant improvement in median PFS (5.5 vs 4.0 months; HR, 0.66; 95% CI, 0.53-0.83; P =.0003) and OS (14.5 vs 11.2 months; HR, 0.79; 95% CI, 0.65-0.95; nominal P =.0133).⁴ SG is currently standard of care for patients with HR+/HER2-negative metastatic breast cancer following prior endocrine therapy and chemotherapy.

ASCENT-07 (NCT05840211) evaluated whether SG could be moved earlier in the treatment course, specifically as first chemotherapy in patients with HR+/HER2-negative metastatic breast cancer following at least 2 prior lines of endocrine-based therapy. Among 690 randomized patients (approximately 80% visceral disease, 70% liver metastases, more than 90% prior endocrine therapy plus CDK4/6i), SG did not achieve its primary end point of a statistically significant improvement in PFS by blinded independent central review (median 8.3 vs 8.3 months; HR, 0.85; 95% CI, 0.69-1.05; P =.130).⁵ The ITT analysis showed a numerical improvement (median 8.4 vs 6.4 months; HR, 0.78; nominal P =.008). Notably, an early OS trend favored SG (HR, 0.72; 95% CI, 0.54-0.97; nominal P =.029), and 61% of chemotherapy-arm patients received an ADC as subsequent therapy, potentially diluting the OS signal. Treatment discontinuation due to adverse events was lower with SG than chemotherapy (3% vs 7%). Overall, SG remains the standard of care in its approved post-chemotherapy indication, and the ASCENT-07 data do not support a shift to first-line chemotherapy use.

Dato-DXd: TROPION-Breast01

Dato-DXd was evaluated in the TROPION-Breast01 trial (NCT05104866) against investigator's choice chemotherapy in patients with HR+/HER2-negative metastatic breast cancer following at least 1 prior endocrine therapy and CDK4/6i.⁶ Among 732 randomized patients, Dato-DXd significantly extended median PFS (6.9 vs 4.5 months; HR, 0.64; 95% CI, 0.53-0.76). The PFS benefit was consistent across subgroups defined by duration of prior CDK4/6i use (whether less than or more than 12 months) and was also observed in patients with baseline brain metastases, where median PFS was 5.6 vs 4.4 months (HR, 0.73). In the PFS2 analysis, Dato-DXd showed a meaningful advantage over chemotherapy (median 11.7 vs 10.4 months; HR, 0.76; 95% CI, 0.63-0.93). However, OS was not improved (median 18.6 vs 18.3 months; HR, 1.01; 95% CI, 0.83-1.22). When OS was adjusted for subsequent ADC treatment—received by a substantial proportion of patients—the HR improved to 0.86 (95% CI, 0.70-1.06), suggesting dilution of the OS signal by postprogression ADC crossover.

The safety profile of Dato-DXd was distinguished from SG principally by significantly lower rates of grade 3 or higher neutropenia (1% vs 31%) and a notably higher rate of stomatitis (any grade 50% vs 13%). Patient-reported quality of life outcomes were generally maintained with Dato-DXd relative to chemotherapy, with Dato-DXd delaying confirmed deterioration in pain and physical functioning.

ADC Sequencing: Evidence, Challenges, and Emerging Trials

As ADCs become embedded across multiple lines of therapy, questions of optimal sequencing have become clinically urgent. A retrospective analysis of 68 patients treated with 2 or more sequential ADCs found that cross-resistance at first restaging on the second ADC occurred in 59.4% of cases and was more frequent when the second ADC shared the same antibody target as the first (78.5% vs 53.1%). Median PFS with the first ADC was 7.55 months, falling to only 2.53 months with the second. This finding underscores that sequencing 2 ADCs targeting the same antigen is biologically unfavorable. ⁷

Conversely, phase 2 data from a study of enfortumab vedotin (an anti-Nectin-4 ADC with a monomethyl auristatin E [MMAE] payload) in patients who had received prior SG showed a median PFS of 3.48 months in SG-pretreated patients vs 3.52 months in SG-naive patients, suggesting that switching to an ADC with a different target and payload can largely circumvent prior ADC resistance.⁸ Prospective investigation into the optimal sequencing of T-DXd and Dato-DXd is being conducted through the TBCRC 064 (TRADE DXd; NCT06533826) trial, which randomizes patients to T-DXd or Dato-DXd as ADC1, with mandated crossover to the complementary agent at progression. The TBCRC 067 ENCORE registry (NCT06774027) is similarly capturing prospective and retrospective efficacy and safety data for T-DXd and SG sequences, including patient-reported outcomes and translational biospecimens.

On the horizon, the DYNASTY-Breast02 trial (NCT06018337) is evaluating DB-1303/BNT323 (a HER2-directed ADC) vs chemotherapy in 532 patients with endocrine-resistant HR+/HER2-low metastatic, with primary completion expected in May 2026. The TroFuse-010 trial (NCT06312176) is assessing sacituzumab tirumotecan (Sac-TMT) plus or minus pembrolizumab vs TPC in 1200 patients with HR+, HER2-negative metastatic breast cancer after at least 1 prior line of endocrine-based therapy including CDK4/6i, with results anticipated in 2027. These trials are poised to further expand the ADC options available to patients and will have important implications for sequencing decisions.

Treatment Roadmap and Conclusions

Jhaveri concluded that the current treatment roadmap for HR+/HER2-negative metastatic breast cancer integrates ADCs as core components of the postendocrine therapy continuum. Following 1 to 3 lines of sequential endocrine-based and targeted therapy, patients with HER2-low tumors are eligible for T-DXd, which may now be considered even prior to chemotherapy in the context of the DESTINY-Breast06 label. For patients with HER2-ultralow disease, T-DXd also represents an emerging option. SG is the standard of care after prior endocrine therapy and chemotherapy, based on TROPiCS-02 data. Dato-DXd provides an additional chemotherapy-alternative option, with a differentiated toxicity profile that may favor its use in patients at higher risk for hematologic complications. Beyond these ADCs, biomarker-driven strategies—including PARP inhibitors for germline or somatic BRCA1/2 or PALB2 mutations, PI3K inhibitors for PIK3CA mutations, and selpercatinib (Retevmo) for RET alterations—continue to inform individualized treatment selection.

In summary, the advent of multiple approved ADCs for HR+/HER2-negative metastatic breast cancer represents one of the most consequential advances in the management of this disease in recent years. Optimizing their use requires careful attention to HER2 expression status, prior therapy history, toxicity profiles, and the growing body of evidence on cross-resistance and post-ADC outcomes. Ongoing prospective sequencing studies and next-generation ADC trials will continue to refine treatment algorithms, with the ultimate goal of extending meaningful, high-quality survival for patients with this common and challenging malignancy.

REFERENCES

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