Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved trastuzumab deruxtecan in combination with pertuzumab and datopotamab deruxtecan for new first-line indications in patients with metastatic breast cancer, according to a September 16 announcement from Daiichi Sankyo.
Trastuzumab deruxtecan plus pertuzumab was approved for adults with HER2-positive unresectable or recurrent breast cancer. In contrast, datopotamab deruxtecan was approved for adults with hormone receptor-negative, HER2-negative unresectable or recurrent breast cancer, commonly referred to as triple-negative breast cancer (TNBC). Both are DXd antibody-drug conjugates developed by Daiichi Sankyo.
The approvals are supported by two Phase 3 studies: DESTINY-Breast09, which evaluated trastuzumab deruxtecan plus pertuzumab in first-line HER2-positive metastatic breast cancer, and TROPION-Breast02, which evaluated datopotamab deruxtecan in previously untreated advanced TNBC in patients for whom immunotherapy was not an option.
Yuki Abe, PhD, Senior Executive Officer, Head of R&D Division in Japan and Head of Research at Daiichi Sankyo, said:
“These two approvals represent significant advances for the treatment of metastatic breast cancer.”
Daiichi Sankyo noted that trastuzumab deruxtecan plus pertuzumab represents a new first-line treatment option after more than a decade in which taxane, trastuzumab and pertuzumab have been a key standard for HER2-positive metastatic disease. The company also highlighted datopotamab deruxtecan as a TROP2-directed therapy that has demonstrated an overall survival benefit in first-line metastatic TNBC.
DESTINY-Breast09 Supports Trastuzumab Deruxtecan Approval
The trastuzumab deruxtecan approval was based on results from the global, randomized, open-label Phase 3 DESTINY-Breast09 trial (NCT04784715), which enrolled 1,157 patients with HER2-positive metastatic breast cancer.
Patients were randomized to trastuzumab deruxtecan plus pertuzumab, trastuzumab deruxtecan plus placebo, or the standard regimen of a taxane, trastuzumab, and pertuzumab.
In the comparison reported to date, trastuzumab deruxtecan plus pertuzumab reduced the risk of disease progression or death by 44% compared with taxane, trastuzumab and pertuzumab, with a hazard ratio of 0.56 (95% CI, 0.44–0.71; P<0.00001).
Median progression-free survival was:
- 40.7 months with trastuzumab deruxtecan plus pertuzumab
- 26.9 months with taxane, trastuzumab and pertuzumab.
The confirmed overall response rate was 85.1% with trastuzumab deruxtecan plus pertuzumab compared with 78.6% in the control arm, while median duration of response was 39.2 months versus 26.4 months, respectively.
The DESTINY-Breast09 findings were presented at the 2025 ASCO Annual Meeting and subsequently published in The New England Journal of Medicine. Read the DESTINY-Breast09 publication in NEJM.
The safety profile was consistent with previous experience with trastuzumab deruxtecan, with no new safety signals identified. In the Japanese patients included in the approval dataset, interstitial lung disease was reported in 33.3% of those receiving trastuzumab deruxtecan plus pertuzumab.
DESTINY-Breast09: The Trial Changing the Future of HER2-Positive Breast Cancer
TROPION-Breast02 Supports Datopotamab Deruxtecan Approval
The approval of datopotamab deruxtecan was based on the Phase 3 TROPION-Breast02 trial (NCT05374512), which enrolled 644 patients with previously untreated, locally recurrent, inoperable or metastatic TNBC for whom PD-1/PD-L1 inhibitor therapy was not an option.
Patients were randomized to datopotamab deruxtecan or investigator’s choice of chemotherapy.
Datopotamab deruxtecan produced a statistically significant 5-month improvement in median overall survival, with median OS of 23.7 months compared with 18.7 months with chemotherapy (HR 0.79; 95% CI, 0.64–0.98; P=0.029).
The treatment also reduced the risk of disease progression or death by 43% compared with chemotherapy. Median progression-free survival was 10.8 months versus 5.6 months, respectively (HR 0.57; P<0.0001).
The results were presented at the 2025 ESMO Congress and have since been published in Annals of Oncology. Read the TROPION-Breast02 publication.
The safety profile of datopotamab deruxtecan was consistent with previous studies. The most frequently reported adverse reactions in the approval dataset included stomatitis, nausea, alopecia, dry eye, and constipation. No interstitial lung disease cases were observed among the 17 Japanese patients treated with datopotamab deruxtecan in TROPION-Breast02.
Both trastuzumab deruxtecan and datopotamab deruxtecan carry warnings for interstitial lung disease in Japan, including the risk of serious and potentially fatal events, and patients are recommended to undergo appropriate monitoring before and during treatment.
TROPION-Breast02: Datopotamab Deruxtecan Preserves Quality of Life in First-Line Metastatic TNBC
Expanding First-Line Options Across Breast Cancer Subtypes
HER2-positive breast cancer and TNBC are among the more aggressive breast cancer subtypes. The new Japanese approvals expand the use of antibody-drug conjugates earlier in the metastatic treatment pathway and provide additional first-line options across two biologically distinct forms of breast cancer.
Daiichi Sankyo and AstraZeneca jointly develop and commercialize trastuzumab deruxtecan and datopotamab deruxtecan globally, while Daiichi Sankyo retains exclusive rights to both medicines in Japan.
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