Trastuzumab Deruxtecan (DS-8201a) Versus Investigator's Choice for HER2-low Breast Cancer That Has Spread or Cannot be Surgically Removed [DESTINY-Breast04]

This study will compare DS-8201a to physician choice standard treatment. Participants must have HER2-low breast cancer that has been treated before. Participants' cancer: * Cannot be removed by an operation * Has spread to other parts of the body

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Is the age of majority in their country
* Has pathologically documented breast cancer that:

  1. Is unresectable or metastatic
  2. Has low-HER2 expression defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested)
  3. Is HR-positive or HR-negative
  4. Has progressed on, and would no longer benefit from, endocrine therapy
  5. Has been treated with 1 to 2 prior lines of chemotherapy/adjuvant in the recurrent or metastatic setting
  6. Was never previously HER2-positive (ICH 3+ or ISH+) on prior pathology testing (per American Society of Clinical Oncology-College of American Pathologists \[ASCO-CAP\] guidelines)
* Has documented radiologic progression (during or after most recent treatment)
* Has adequate archival tumor samples available or is wiling to provide fresh biopsies prior to randomization for:

  1. assessment of HER2 status
  2. assessment of post-treatment status
* Has at least 1 measurable lesion per Response Evaluation Criteria In Solid Tumors 1.1
* Has protocol-defined adequate cardiac, bone marrow, renal, hepatic and blood clotting functions
* Male and female participants of reproductive/childbearing potential, agrees to follow instructions for method(s) of contraception and agrees to avoid preserving ova or sperm for at least 4.5 months after treatment (or longer, per locally approved labels)

Exclusion Criteria:

* Is ineligible for all options in the physician's choice arm
* Has breast cancer ever assessed with high-HER2 expression
* Has previously been treated with any anti-HER2 therapy, including an antibody drug conjugate
* Has uncontrolled or significant cardiovascular disease
* Has spinal cord compression or clinically active central nervous system metastases
* Has history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
* Has any medical history or condition that per protocol or in the opinion of the investigator is inappropriate for the study

• RESULTModi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5. PMID 35665782
• DERIVEDIyengar AR, Downs EP, Mehta S, Rangarajan N, Woo MS, Sredni ST, Donato RD, Simsek S, Wilson DM, Krieser K, Patzke EB, Kyek N, Anderson C, Wagner T, Hipp J, Nassar A, Barman H. HER2-Ultralow: Prevalence, Characteristics, and Treatment Choices Among Advanced Breast Cancer Patients With Tumors Initially Scored as IHC 0. Breast J. 2026;2026(1):e7212120. doi: 10.1155/tbj/7212120. PMID 42340017
• DERIVEDModi S, Jacot W, Iwata H, Park YH, Vidal Losada M, Li W, Tsurutani J, Ueno NT, Zaman K, Prat A, Papazisis K, Rugo HS, Yamashita T, Harbeck N, Im SA, De Laurentiis M, Pierga JY, Wang X, Gombos A, Tokunaga E, Orbegoso Aguilar C, Yung L, Xiao F, Cheng Y, Cameron D. Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial. Nat Med. 2025 Dec;31(12):4205-4213. doi: 10.1038/s41591-025-03981-4. Epub 2025 Oct 8. PMID 41062831
• DERIVEDUeno NT, Cottone F, Dunton K, Jacot W, Yamashita T, Sohn J, Tokunaga E, Prat A, Tsurutani J, Park YH, Rugo HS, Xu B, Cardoso F, Mitri Z, Mahtani R, Aguilar CO, Xiao F, Harbeck N, Cameron DA, Modi S. Patient-reported outcomes from DESTINY-Breast04: trastuzumab deruxtecan versus physician's choice of chemotherapy in patients with HER2-low mBC. Oncologist. 2025 May 8;30(5):oyaf048. doi: 10.1093/oncolo/oyaf048. PMID 40349139
• DERIVEDYamashita T, Sohn JH, Tokunaga E, Niikura N, Park YH, Lee KS, Chae YS, Xu B, Wang X, Im SA, Li W, Lu YS, Aguilar CO, Nishijima S, Nishiyama Y, Sugihara M, Modi S, Tsurutani J. Trastuzumab deruxtecan versus treatment of physician's choice in previously treated Asian patients with HER2-low unresectable/metastatic breast cancer: subgroup analysis of the DESTINY-Breast04 study. Breast Cancer. 2024 Sep;31(5):858-868. doi: 10.1007/s12282-024-01600-7. Epub 2024 Jun 17.