Introduction
Patients with metastatic hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) breast cancer have experienced improved prognosis with the introduction of endocrine therapy in combination with cyclin‐dependent kinase 4/6 (CDK4/6) inhibitors [1, 2, 3]. With the advent of novel antibody‐drug conjugate (ADC) therapies, a new treatment paradigm is emerging in the post‐endocrine therapy setting following chemotherapy. Trastuzumab deruxtecan (T‐DXd), a HER2‐targeted ADC, has demonstrated significant clinical benefit in patients with HER2‐low metastatic breast cancer [4, 5], while sacituzumab govitecan (SG), a trophoblast cell surface antigen 2 (TROP2)–directed ADC, has demonstrated improved clinical outcomes in heavily pretreated patients with HR+/HER2− metastatic breast cancer [6].
TROP2 is widely expressed on the cell surface of various solid tumors [7], including breast cancer [8, 9, 10]. Datopotamab deruxtecan (Dato‐DXd) is an ADC targeting TROP2 that consists of a humanized IgG1 monoclonal antibody coupled to a potent topoisomerase I inhibitor through a cleavable linker designed to remain stable in the circulation [11]. Dato‐DXd has been evaluated in both early‐ and late‐phase clinical trials, including the Phase I TROPION‐PanTumor01 study and the Phase III TROPION‐Breast01 trial [12, 13].
In TROPION‐Breast01, Dato‐DXd significantly improved progression‐free survival and demonstrated a favorable and manageable safety profile compared with investigator's choice chemotherapy in previously treated patients with inoperable or metastatic hormone receptor–positive/HER2‐negative breast cancer. However, clinical data on Dato‐DXd remain limited, particularly in patients with HR+/HER2− disease who have previously been treated with topoisomerase I inhibitor–based ADCs, a population not included in these clinical trials.
To address this unmet need and to provide evidence reflective of routine clinical practice, we conducted a single‐center study to evaluate the clinical performance of Dato‐DXd in patients with hormone receptor–positive/HER2‐negative metastatic breast cancer. Although SG has demonstrated efficacy in HR+/HER2− breast cancer internationally, it has not yet been approved by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan for this patient population during the study period. Therefore, Dato‐DXd represented an important ADC treatment option in this clinical setting, including for patients previously treated with T‐DXd.
Methods
Patient Selection and Enrollment Criteria
This retrospective cohort study included patients with HR+/HER2‐negative metastatic breast cancer (mBC) who received Dato‐DXd at our institution from May to December 2025. Eligible patients met the following criteria [1]: histologically confirmed metastatic breast cancer [2]; treatment with at least 1 cycle of Dato‐DXd [3]; confirmation of HR‐positive and HER2‐negative status based on the most recent tumor biopsy before initiation of Dato‐DXd (HR‐positive defined as estrogen receptor or progesterone receptor expression ≥ 1% by immunohistochemistry (IHC), and HER2‐negative defined as IHC 0, 1+, or 2+ with negative in situ hybridization); and [4] presence of metastatic disease with evaluable lesions and available response assessments. Prior exposure to ADCs was not an exclusion criterion.
At the time of this study, alternative ADCs, including SG, were not available as approved treatment options in Japan for this clinical setting, and there was insufficient evidence to preclude the sequential use of ADCs. Therefore, patients who had previously received ADCs were also eligible for treatment with Dato‐DXd. Clinical and pathological data were retrospectively collected from electronic medical records in our institutional database.
Extracted variables included patient demographics, tumor characteristics, prior treatment history, and laboratory findings. The study protocol was approved by the Institutional Review Board of Saitama Medical University on July 18, 2025 (approval number: 19‐224). Because of the retrospective nature of the study, the requirement for informed consent was waived.
All procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki.
Treatment and Response Assessment
Dato‐DXd 6.0 mg/kg was administered intravenously on Day 1 of a 21‐day cycle. Up to two dose reductions were permitted for Dato‐DXd (4.0 mg/kg intravenously once every 3 weeks and 3.0 mg/kg intravenously once every 3 weeks), but doses could not be re‐escalated per protocol. If toxicity requiring further dose reduction occurred, treatment was discontinued.
Treatment was continued until disease progression, intolerable toxicity, or other reasons requiring discontinuation. Treatment response was assessed by investigators based on radiographic evaluations performed in routine clinical practice, with RECIST version 1.1 criteria used retrospectively for descriptive purposes in patients with assessable disease. The objective response rate (ORR) was defined as the proportion of evaluable patients who achieved a complete response (CR) or partial response (PR) as their best overall response.
The disease control rate (DCR) was defined as the proportion of patients achieving CR, PR, or stable disease (SD) at 12 weeks. The clinical benefit rate (CBR) was defined as the proportion of patients achieving CR, PR, or SD lasting at least 24 weeks. Real‐world progression‐free survival (rwPFS) was defined as the time from initiation of Dato‐DXd to the first documented disease progression, whether clinical or radiographic, or death from any cause.
Time to treatment failure (TTF) was defined as the time from initiation of Dato‐DXd to treatment discontinuation for any reason, with patients remaining on treatment censored at the date of last follow‐up. Overall survival (OS) was defined as the time from initiation of Dato‐DXd to death from any cause or last follow‐up. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Adverse Event Management
For the prevention of oral mucositis, oral hygiene status, including the frequency and method of tooth brushing, was regularly assessed during treatment. When necessary, patients were promptly referred for dental evaluation. At the initiation of Dato‐DXd, preventive measures against oral mucositis, including routine gargling with saline containing azulene sodium sulfonate, were implemented.
If oral mucositis progressed to grade ≥ 2, a topical steroid ointment was recommended. During treatment, oncology pharmacists provided ongoing patient education and monitored adherence to adverse event management protocols. For ocular adverse events, the use of preservative‐free artificial tears (Soft Santear, Santen Pharmaceutical Co.
Ltd.) was recommended as supportive care according to institutional practice. Respiratory symptoms were assessed, peripheral oxygen saturation was measured at every visit, and regular imaging examinations were performed for early detection of interstitial lung disease (ILD).
Statistical Analysis
All statistical analyses were performed using EZR. Baseline characteristics, effectiveness, and safety data were summarized using descriptive statistics. Categorical variables were compared using Fisher's exact test.
Time‐to‐event endpoints, including TTF, rwPFS, and OS, were estimated using the Kaplan–Meier method, with median values and corresponding 95% confidence intervals (CIs) reported. Hazard ratios (HRs) were estimated using Cox proportional hazards regression models. Univariate and multivariate Cox regression analyses were performed to identify prognostic factors.
A two‐sided p value < 0.05 was considered statistically significant.
Results
Patients
Between May and December 2025, a total of 18 patients were included in this study. Baseline clinicopathological characteristics are summarized in Table 1. All patients were female, with a median age of 56 years (range, 48–81).
At diagnosis, 12 patients (66.7%) had Stage II disease, while 3 patients (16.7%) each had Stage III or Stage IV disease. Regarding HER2 expression, four patients (22.2%) had HER2‐zero tumors, whereas 14 patients (77.8%) had HER2‐low disease, including 10 patients (55.6%) with HER2 1+ and four patients (22.2%) with HER2 2+ and negative fluorescence in situ hybridization.
Bone metastases were observed in 12 patients (66.7%). Visceral metastases were present in 14 patients (77.8%), including liver metastases in 14 patients (77.8%), lung metastases in nine patients (50.0%), and brain metastases in five patients (27.8%). The median number of treatment lines for metastatic disease before Dato‐DXd administration was 8 (range, 3–12).
Dato‐DXd was administered as third‐ to eighth‐line therapy in 12 patients (66.7%) and as ninth‐line or later therapy in six patients (33.3%). The median number of prior endocrine therapy lines was 2 (range, 0–5), and the median number of prior chemotherapy lines was 4.5 (range, 1–7). Thirteen patients (72.2%) had received prior T‐DXd treatment.
Previous treatments in the metastatic setting included aromatase inhibitors, selective estrogen receptor modulators or degraders, taxane‐based chemotherapy, capecitabine or other oral fluoropyrimidines, eribulin, CDK4/6 inhibitors, and antiangiogenic therapy.
Efficacy
Up to January 2026, the median follow‐up duration was 5.6 months. At the time of analysis, treatment had been discontinued in 15 patients (83.3%), primarily due to disease progression (n = 14, 77.8%). One patient discontinued treatment because of transfer to another institution to participate in a clinical trial.
Two patients (11.1%) were continuing Dato‐DXd treatment. A total of three deaths (16.7%) were recorded. In the overall population, four patients (22.2%) had SD, and 13 patients (72.2%) experienced PD, resulting in an ORR of 0%, a DCR of 22.2%, and a CBR at 24 weeks of 16.7% (Table 2).
The median rwPFS and OS in the overall cohort were 3.2 months and not reached, respectively (Figure 1). The median TTF was 3.3 months. OS data were immature because of the short follow‐up period and the limited number of events.
In exploratory univariate analyses, a higher number of prior treatment lines (≥ 7) and prior T‐DXd exposure were associated with shorter rwPFS (p = 0.028 and p = 0.021, respectively). In the exploratory multivariate analysis, prior T‐DXd exposure remained associated with shorter rwPFS; however, the association did not reach statistical significance (HR 8.28, 95% CI 0.96–71.26, p = 0.054) (Tables 1, 3). Given the limited sample size and number of events, these findings should be interpreted with caution.
Kaplan–Meier analysis according to prior T‐DXd exposure demonstrated inferior rwPFS among patients previously treated with T‐DXd compared with T‐DXd–naïve patients (2.8 vs. 6.4 months, log‐rank p = 0.008) (Figure 2).
Safety
In our cohort, treatment‐related adverse events (TRAEs) associated with Dato‐DXd were observed in most patients (Table 4). The most frequently reported TRAEs of any grade were alopecia (88.9%), fatigue (77.8%), constipation (61.1%), and stomatitis (55.6%). Other common events included elevations in liver enzymes (aspartate aminotransferase (AST) 55.6%; alanine aminotransferase (ALT) 38.9%), nausea (27.8%), decreased appetite (27.8%), anemia (27.8%), dry eye (16.7%), neutropenia (16.7%), leukopenia (16.7%), keratitis (11.1%), and asthenia (5.6%).
No grade ≥ 3 hematologic toxicities were observed, and grade ≥ 3 non‐hematologic TRAEs were limited to AST and ALT elevations. Five patients required dose reductions due to TRAEs. Importantly, no treatment discontinuations due to TRAEs occurred, no fatal TRAEs were reported, and no cases of ILD were observed in this cohort.
Discussion
This study provides preliminary real‐world evidence specifically evaluating the efficacy and safety of Dato‐DXd in patients with HR‐positive, HER2‐negative metastatic breast cancer. Compared with the TROPION‐Breast01 trial, our cohort included a higher proportion of heavily pretreated patients, with more than half having received seven or more lines of systemic therapy for metastatic or recurrent disease, and 72.2% having prior exposure to T‐DXd. Accordingly, Dato‐DXd monotherapy demonstrated limited clinical activity, with an ORR of 0% and a median rwPFS of 3.2 months.
The absence of objective responses may reflect the heavily pretreated nature and unfavorable baseline clinical characteristics of this real‐world population. Therefore, direct comparison with TROPION‐Breast01 should be interpreted with caution because of substantial differences in patient characteristics and treatment settings. Although these outcomes are worse compared to those reported in the TROPION‐Breast01 trial (ORR 36.4%, median PFS 6.9 months), it is notable that over 70% of our patients had prior T‐DXd exposure, whereas the small subset of T‐DXd–naïve patients had a median rwPFS of 6.4 months.
Given the small sample size and the limited number of patients in the T‐DXd–naïve subgroup, these findings should be considered exploratory and hypothesis‐generating and should be interpreted with caution. The optimal sequencing of T‐DXd, SG, and Dato‐DXd in HR+/HER2− metastatic breast cancer has not yet been established. Available evidence on sequential ADC therapy remains limited, and further studies are needed to determine the optimal treatment sequence [14].
In the present cohort, 13 patients had received prior T‐DXd treatment, and these patients experienced shorter rwPFS with subsequent Dato‐DXd. However, baseline clinicopathological characteristics differed between patients with and without prior T‐DXd exposure, including disease burden, liver metastases, and the number of prior treatment lines. Therefore, the observed difference in rwPFS may have been influenced by these baseline imbalances, and an independent effect of prior T‐DXd exposure cannot be established from the present study.
Cross‐resistance related to the shared deruxtecan payload represents one possible biological hypothesis, along with other potential resistance mechanisms such as altered intracellular trafficking, enhanced lysosomal degradation, upregulation of drug efflux pumps, or activation of alternative survival and DNA repair pathways [15]. Notably, mutations in TOP1, NFE2L2, and KEAP1 have been reported following T‐DXd treatment, which could also play a role in mediating resistance [16]. However, the present study did not include molecular analyses or resistance biomarkers and therefore provides no direct mechanistic evidence for cross‐resistance.
Similarly, shorter PFS has been reported with T‐DXd administered after prior SG in real‐world analyses, suggesting that sequential use of ADCs may be associated with diminished efficacy [17]. Following the recent results of DESTINY‐Breast06 [5], the use of T‐DXd is expected to expand further, resulting in more patients receiving Dato‐DXd beyond T‐DXd. Further accumulation of real‐world data is warranted to clarify the efficacy of subsequent Dato‐DXd and optimal ADC sequencing in this population.
TRAEs associated with Dato‐DXd were generally mild and consistent with previously reported safety profiles [12, 13]. Non‐hematologic toxicities were predominantly low grade, with grade ≥ 3 events limited to AST and ALT elevations. Hematologic toxicities occurred in some patients but were manageable, and dose reductions were required in five cases.
Clinical practice guidelines based on TROPION Breast01 and TROPION PanTumor01 data have already provided recommendations for the prevention, monitoring, and management of common adverse events, including ocular surface events, oral mucositis/stomatitis, and ILD [18]. Routine implementation of these prophylactic and monitoring strategies likely contributed to the relatively low incidence of severe adverse events. Furthermore, the short median progression‐free survival (3.2 months) in this heavily pretreated population may have limited cumulative drug exposure, further reducing the occurrence of high‐grade toxicities.
This study had some limitations. Its retrospective design and single‐institution setting introduce potential biases in data collection and patient selection. The sample size was limited, particularly in key subgroups such as patients previously treated with T‐DXd or those with a small number of prior treatment lines, which may affect the generalizability and statistical power of the findings.
Furthermore, given the limited sample size and number of events, the multivariate Cox regression analysis was underpowered and should be regarded as exploratory rather than confirmatory. In addition, OS data were immature because of the short follow‐up period and limited number of events, precluding meaningful interpretation of OS. Notably, prior ADC exposure was, at the time of this study, limited to T‐DXd due to its approval status by the PMDA, restricting the evaluation of other ADCs in this patient population.
In addition, comparisons between patients with and without prior T‐DXd exposure should be interpreted with caution. As shown in Table S1, several baseline clinicopathological characteristics differed between the T‐DXd–treated and T‐DXd–untreated groups. In particular, HER2 expression status differed significantly, with all patients in the T‐DXd–treated group having HER2‐low disease, whereas the majority of T‐DXd–untreated patients had HER2‐zero tumors.
Furthermore, patients previously treated with T‐DXd tended to have a higher disease burden, including more frequent liver metastases and a greater number of prior treatment lines. Although these differences did not reach statistical significance for most variables, likely due to the small sample size, such imbalances may have confounded the observed efficacy outcomes and limited the ability to draw definitive conclusions regarding the impact of prior T‐DXd exposure on the efficacy of subsequent Dato‐DXd therapy. In addition, radiological assessments were performed as part of routine clinical practice without central review or protocol‐defined imaging schedules.
This reflects the real‐world nature of the study and may introduce variability in rwPFS assessment.
In conclusion, this study provides preliminary real‐world data on the efficacy and safety of Dato‐DXd in heavily pretreated patients with HR‐positive, HER2‐negative metastatic breast cancer. Given the small sample size, these findings should be interpreted with caution. Further accumulation of real‐world data is needed to clarify the efficacy of Dato‐DXd and optimal ADC sequencing.
Author Contributions
Hiroko Shimada: conceptualization, writing – original draft, data curation, investigation, formal analysis. Maki Todo: conceptualization, writing – original draft, validation. Hiroshi Ishiguro: conceptualization, writing – original draft, supervision, project administration, validation.
Emi Mikami: investigation. Wakako Inohana: investigation. Taeko Kurosawa: investigation.
Ayako Nakame: investigation. Ayaka Sakakibara: investigation. Yuki Ichinose: investigation.
Akihiro Fujimoto: investigation. Asami Nukui: investigation. Aya Asano: investigation.
Hideki Yokogawa: investigation. Masahiro Ohara: conceptualization, writing – original draft, writing – review and editing, investigation, formal analysis. Kazuo Matsuura: supervision, project administration.
Takahiro Hasebe: validation, data curation, methodology. Nobuko Fujiuchi: investigation, supervision, project administration. Akihiko Osaki: project administration, supervision, investigation.
Toshiaki Saeki: supervision, project administration, investigation.
Funding
The authors have nothing to report.
Ethics Statement
This study was approved by the Ethics Committee of Saitama Medical University International Medical Center (approval no.: 19‐224; Hidaka, Japan). The requirement for individual informed consent was waived because of the retrospective design of the study. Instead, information about the study was disclosed, and patients were allowed to opt out, in accordance with institutional policy.
Conflicts of Interest
Hiroko Shimada has received lecture fees from Eli Lilly Japan. Hiroshi Ishiguro has received research grants from AstraZeneca, Chugai, Daiichi Sankyo, and Ono Pharmaceutical, and lecture fees from AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Kyowa Kirin, Mitsubishi Tanabe, MSD, Pfizer, and Taiho Pharmaceutical. Ayaka Sakakibara has received lecture fees from AstraZeneca.
Yuki Ichinose has received lecture fees from Daiichi Sankyo, Eisai, and MSD. Aya Asano has received lecture fees from AstraZeneca. Masahiro Ohara has received lecture fees from AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Exact Sciences, Kyowa Kirin, and MSD.
Kazuo Matsuura has received research grants from AstraZeneca, Eisai, and Pfizer, and lecture fees from AstraZeneca, Daiichi Sankyo, Eli Lilly Japan, Exact Sciences, MSD, and Pfizer. Akihiko Osaki has received research grants from AstraZeneca, Chugai, Daiichi Sankyo, Eisai, and Ono Pharmaceutical, and lecture fees from AstraZeneca, Chugai, Eli Lilly Japan, and Gilead. Toshiaki Saeki has received lecture fees from Chugai, Daiichi Sankyo, Gilead, Ono Pharmaceutical, and Taiho Pharmaceutical.
Maki Todo, Emi Mikami, Wakako Inohana, Taeko Kurosawa, Ayako Nakame, Akihiro Fujimoto, Asami Nukui, Hideki Yokogawa, Takahiro Hasebe, and Nobuko Fujiuchi declare no conflicts of interest.
Supporting information