The FDA granted a first-line label expansion for AstraZeneca and Daiichi Sankyo’s Enhertu, clearing the antibody-drug conjugate for use in adults with unresectable or metastatic HER2-positive breast cancer. The decision follows trial data presented at ASCO and positions Enhertu as a new standard option earlier in the disease course. Roche simultaneously won expanded FDA clearances for two HER2 companion diagnostics — the Pathway 4B5 antibody and the Ventana HER2 Dual ISH probe — enabling clinicians to identify Enhertu-eligible patients across the full spectrum of HER2 expression. AstraZeneca and Daiichi Sankyo will likely adjust trial designs and market strategy to accelerate uptake while pathology labs integrate the broadened assay claims. The Roche approvals allow pathology teams to pair IHC and ISH testing to capture HER2-positive patients who may benefit from the new Enhertu combination with pertuzumab. Companion diagnostics identify protein expression and gene amplification; using both assays improves patient selection across HER2-low to HER2-ultralow categories. Clinically, the move could shift first-line regimen selection for HER2-positive metastatic disease and require payers and health systems to update treatment algorithms and diagnostic pathways. Laboratories should expect demand for dual-assay HER2 testing to increase as oncologists align prescribing with the new label language.