The FDA has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab for first-line treatment of unresectable or metastatic HER2-positive breast cancer. Supported by Phase 3 DESTINY-Breast09 results, the regimen significantly improved progression-free survival and objective response rates compared with standard THP therapy, establishing a new frontline treatment option for HER2-positive disease.

This article reviews recent pivotal HER2+ breast cancer trials, highlighting oral TKIs, antibody-drug conjugates, and chemotherapy-sparing strategies. Key studies—including HER2CLIMB-05, DESTINY-Breast11, DESTINY-Breast09, and PHILA—demonstrate improved progression-free survival, higher pathologic complete responses, and durable disease control. These findings support innovative, biology-driven therapies that may reshape first-line and maintenance treatment paradigms in both early and metastatic HER2+ disease.

TUKYSA combo improves PFS in first-line HER2+ metastatic breast cancer maintenance, the first update to treatment paradigm since 2012.

Two years of Verzenio plus endocrine therapy shows OS benefit in high-risk HR+, HER2- early breast cancer at seven-year follow-up.

FDA grants Priority Review for Enhertu plus pertuzumab in first-line HER2+ metastatic breast cancer, with decision expected April 2025.

Verzenio plus endocrine therapy offers statistically significant OS improvements over endocrine therapy alone in high-risk patients.

ctDNA genotyping reveals ESR1, PIK3CA mutations and CCND1, FGFR1 amplifications predict worse outcomes with palbociclib in HR+/HER2- ABC.

T-DXd plus pertuzumab nearly doubled progression-free survival compared to standard THP for first-line metastatic HER2+ breast cancer.