Japan Approves T-DXd, Dato-DXd in Select First-Line Metastatic Breast Cancer Indications

Japan's Ministry of Health, Labour and Welfare has approved trastuzumab deruxtecan (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) for the first-line treatment of adult patients with HER2-positive unresectable or recurrent breast cancer; and datopotamab deruxtecan (Dato-DXd; Datroway) for the first-line treatment of adult patients with unresectable or recurrent triple-negative breast cancer (TNBC) who are not candidates for PD-1/PD-L1 inhibitor therapy.¹

The HER2-positive approval is based on data from the phase 3 DESTINY-Breast09 trial (NCT04784715), in which T-DXd plus pertuzumab reduced the risk of disease progression or death by 44% vs a taxane, trastuzumab (Herceptin), and pertuzumab (THP; HR, 0.56; 95% CI, 0.44-0.71; P < .00001).^1,2 The median progression-free survival (PFS) was 40.7 months for the T-DXd–based regimen vs 26.9 months for THP.

The TNBC approval is supported by findings from the phase 3 TROPION-Breast02 trial (NCT05374512), where Dato-DXd extended median overall survival (OS) to 23.7 months vs 18.7 months with investigator's choice of chemotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .029).^1,3

"[T-DXd] in combination with pertuzumab is the first new treatment regimen in more than a decade for patients with metastatic HER2-positive disease, and [Dato-DXd] is the only TROP2-directed medicine to demonstrate an OS benefit for patients with metastatic TNBC in the first-line setting," Yuki Abe, PhD, senior executive officer and head of the Research and Development Division in Japan at Daiichi Sankyo, stated in a news release.¹

In December 2025, the FDA approved fam-trastuzumab deruxtecan-nxki in combination with pertuzumab for the frontline treatment in adult patients with unresectable or metastatic HER2-positive (immunohistochemistry 3+ or in situ hybridization–positive) breast cancer, as determined by an FDA-approved test.⁴ In May 2026, datopotamab deruxtecan-dlnk was approved by the FDA for the treatment of adult patients with unresectable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.⁵ These decisions were also backed by data from DESTINY-Breast09 and TROPION-Breast02, respectively.^4,5

How was DESTINY-Breast09 conducted, and what additional data were reported?

DESTINY-Breast09 was a global, randomized, open-label phase 3 trial that enrolled patients with HER2-positive advanced or metastatic breast cancer who had received no prior chemotherapy or HER2-directed therapy for metastatic disease.²

Patients were randomly assigned 1:1:1 to receive T-DXd plus pertuzumab, T-DXd plus placebo, or THP. PFS by blinded independent central review (BICR) served as the primary end point.

At the prespecified interim analysis, data were reported for the T-DXd–plus–pertuzumab arm (n = 383) and the THP arm (n = 387), while the T-DXd monotherapy arm remained blinded.

Beyond the PFS benefit, T-DXd plus pertuzumab generated a confirmed objective response rate of 85.1% vs 78.6% with THP, including complete response rates of 15.1% and 8.5%, respectively. The median duration of response was 39.2 months with the T-DXd–based regimen vs 26.4 months with THP.

What was the design of TROPION-Breast02? What other supporting data were reported?

TROPION-Breast02 was a randomized, open-label, international phase 3 trial in patients with previously untreated, locally recurrent inoperable or metastatic TNBS for whom immunotherapy was not an option.³

Patients were randomly assigned 1:1 to receive Dato-DXd at 6 mg/kg intravenously every 3 weeks (n = 323) or to the investigator’s choice of chemotherapy (n = 321), with stratification by geographic region, disease-free interval, and PD-L1 status.

The trial's dual primary end points were PFS by BICR and OS.

Dato-DXd produced a median PFS of 10.8 months (95% CI, 8.6-13.0) vs 5.6 months (95% CI, 5.0-7.0) with chemotherapy, reflecting a 43% reduction in the risk of progression or death (HR, 0.57; 99% CI, 0.44-0.73; P < .0001).

What safety data were reported across the 2 trials?

In DESTINY-Breast09, grade 3 or higher adverse effects (AEs) occurred in 63.5% of patients treated with T-DXd plus pertuzumab vs 62.3% with THP; the most common with the T-DXd regimen were neutropenia, hypokalemia, and anemia.² Adjudicated drug-related interstitial lung disease or pneumonitis was reported in 12.1% of patients receiving T-DXd plus pertuzumab, including 2 grade 5 events, vs 1.0% of those receiving THP. Investigators reported that safety was consistent with the known profiles of the individual agents.

In TROPION-Breast02, grade 3 or higher treatment-related AEs were reported in 33% of patients treated with Dato-DXd vs 29% with chemotherapy, and treatment-related AEs led to discontinuation in 4% and 7% of patients, respectively.³ There were no treatment-related deaths in either arm, and the safety profile was consistent with prior reports for Dato-DXd.

References

1. Enhertu and Datroway approved in Japan for two new first-line indications for patients with metastatic breast cancer. News release. Daiichi Sankyo. September 16, 2026. Accessed September 16, 2026. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202609/20260916_E.pdf
2. Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan plus pertuzumab for HER2-positive metastatic breast cancer. N Engl J Med. 2025;394(6):551-562. doi:10.1056/NEJMoa2508668
3. Dent R, Shao Z, Schmid P, et al; TROPION-Breast02 investigators. Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial. Ann Oncol. 2026;37(8):1066-1080. doi:10.1016/j.annonc.2026.03.008
4. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. FDA. December 15, 2025. Accessed September 16, 2026. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-pertuzumab-unresectable-or-metastatic-her2-positive
5. Datroway approved in the U.S. as first TROP2 directed antibody drug conjugate for first-line treatment of patients with metastatic triple negative breast cancer who are not PD-1/PD-L1 inhibitor candidates. News release. Daiichi Sankyo. May 22, 2026. Accessed September 16, 2026. https://daiichisankyo.us/web/dsi/press-releases/-/article/datroway-approved-in-the-us-as-first-trop2-directed-antibody-drug-conjugate-for-first-line-treatment-of-patients-with-metastatic-triple-negative-breast-cancer-who-are-not-pd-1pd-l1-inhibitor-candidates