Trastuzumab deruxtecan (T-DXd) with or without Endocrine Therapy: What Final TALENT Results Reveal?
Trastuzumab deruxtecan (ENHERTU) is a HER2-directed ADC co-developed by AstraZeneca and Daiichi Sankyo, with established efficacy in HER2-positive and HER2-low metastatic breast cancer. Its role in HR+, HER2-low early-stage breast cancer was evaluated in the Phase II investigator-initiated TALENT trial (NCT04553770), which investigated neoadjuvant T-DXd alone, in combination with anastrozole, or followed by docetaxel plus cyclophosphamide chemotherapy. Final results presented at the ESMO Congress 2026 showed low pathological complete response (pCR) rates of 7%, 3% and 9%, respectively, while pCR/near-pCR rates (residual cancer burden [RCB] 0/1) were 16–17% across the three arms.
As of October 2026, ENHERTU’s approved breast cancer indications include first-line treatment of unresectable or metastatic HER2-positive disease in combination with pertuzumab, as well as certain HER2-low/ultralow metastatic settings. In May 2026, the FDA also approved T-DXd-based treatment for HER2-positive early-stage breast cancer; these approvals do not extend to the HER2-low population studied in TALENT. The final TALENT results therefore represent important clinical evidence, but further evidence is needed to establish a role for neoadjuvant T-DXd in HR-positive, HER2-low early breast cancer.
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Phase II TALENT Study: Final Results | ||||
|
Category |
Parameter |
Arm A: T-DXd alone |
Arm B: T-DXd + anastrozole |
Arm C: T-DXd followed by chemotherapy |
|
Efficacy |
pCR) rate |
7% |
3% |
9% |
|
pCR + near-pCR (RCB 0/1) rate |
16% |
17% |
17% | |
|
ORR |
62% |
66% |
72% | |
|
Safety |
Most common AEs |
Nausea, fatigue | ||
|
Grade 2 treatment-related ILD cases |
NA |
1 case |
2 cases | |
|
Treatment discontinuations due to TRAEs |
2 patients |
3 patients |
5 patients | |
|
Deaths |
1 |
Not reported |
Not reported | |
|
T-DXd: trastuzumab deruxtecan; pCR: pathological complete response; RCB: residual cancer burden; ORR: objective response rate; AE: adverse event; TRAE: treatment-related adverse event; ILD: interstitial lung disease | ||||
Conclusion
Breast cancer remains the most common cancer in women in the United States, accounting for 306,791 cases in 2025, with HER2-low disease more prevalent in HR-positive breast cancer, accounting for over 65% of cases. Landmark advances such as trastuzumab (HERCEPTIN) and pertuzumab (PERJETA) established the backbone of modern neoadjuvant and first-line regimens, with subcutaneous formulations further improving convenience and access. Further, approval of trastuzumab deruxtecan (ENHERTU) has intensified the competitive HER2 landscape, accelerating the shift toward ADC-based regimens as potential next-generation standards of care. However, final results from the Phase II TALENT trial showed low pCR rates (3–9%) with neoadjuvant T-DXd-based regimens in HR-positive, HER2-low early-stage breast cancer, despite ORR of 62–72%. These findings highlight the challenge of translating tumor shrinkage into pCR and indicate that the role of T-DXd in this early-stage setting remains to be established.