DS8201-A-U303 (DESTINY-Breast04): A Phase 3, multicenter, randomized, open-label, active-controlled trial of DS-8201a, an anti-HER2-antibody drug conjugate (ADC), versus treatment of physician’s choice for HER2-low, unresectable and/or metastatic breast cancer subjects


This is a randomized, 2-arm, Phase 3, open-label, multicenter study to compare the safety and efficacy of trastuzumab deruxtecan versus the physician's choice (2:1) in HER2-low, unresectable and/or metastatic breast cancer participants. The sponsor proposes to define a new HER2-low population in this trial including tumors with IHC 1+ and IHC 2+/ISH- HER2 expression.


Accepting new patients

Primary Study Objective(s)

The primary objective of this study is to compare the progression-free survival (PFS) benefit of DS-8201a to physician’s choice in HER2-low, hormone receptor (HR)-positive breast cancer, based on blinded independent central review (BICR)

Core eligibility

Note: This is only a partial list of eligibility criteria.

Including patients who:

  • Are at least 18 years old
  • Have pathologically documented breast cancer that:
    • Is unresectable or metastatic
    • Has low-HER2 expression defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested)
    • Is HR-positive or HR-negative
    • Has progressed on, and would no longer benefit from, endocrine therapy
    • Has been treated with 1 to 2 prior lines of chemotherapy/adjuvant in the metastatic setting
    • 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)
  • Have documented radiologic progression (during or after most recent treatment)
  • Have adequate archival tumor samples available or are wiling to provide fresh biopsies prior to randomization for:
    • Assessment of HER2 status
    • Assessment of post-treatment status
  • Have at least one protocol-defined measurable lesion
  • Have protocol-defined adequate cardiac, bone marrow, renal, hepatic and blood clotting functions
  • Agree, if of reproductive/childbearing potential, to follow instructions for method(s) of contraception and agrees to avoid preserving ova or sperm for at least four-and one-half months after treatment (or longer, per locally approved labels)

Excluding patients who:

  • Are ineligible for all options in the physician's choice arm
  • Have breast cancer ever assessed with high-HER2 expression
  • Have previously been treated with any anti-HER2 therapy, including an antibody drug conjugate
  • Have uncontrolled or significant cardiovascular disease
  • Have spinal cord compression or clinically active central nervous system metastases
  • Have a 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
  • Have any medical history or condition that per protocol or in the opinion of the investigator is inappropriate for the study

Accepting new patients


Learn more at


Principal Investigator(s)

Cynthia Lynch
Eugene Ahn
Damien Hansra