Dr Tarantino on the Evolving Role of THP in HER2+ Metastatic Breast Cancer

"I do feel in the second line, there's going to be several options, but the CLEOPATRA regimen is one of these options in the second line if patients are treated with T-DXd [in the] first line."

Paolo Tarantino, MD, a research fellow at Dana-Farber Cancer Institute, provided clinical perspective on the evolving role of trastuzumab (Herceptin) plus pertuzumab (Perjeta), and a taxane (THP) in HER2-positive metastatic breast cancer following the readout of data from the phase 3 DESTINY-Breast09 trial (NCT04784715).

In the current landscape, treatment decisions are becoming increasingly individualized, and first-line regimens may been become moore based on disease biology, prior exposures, and patient-specific considerations, rather than uniform algorithmic pathways. THP has long been the standard of care in the first-line setting, based on data from the phase 3 CLEOPATRA trial (NCT00567190).

DESTINY-Breast09 compared fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) with or without pertuzumab vs THP. Although data presented at the 2025 ASCO Annual Meeting showed that T-DXd plus pertuzumab demonstrated improved progression-free survival (PFS) vs THP, Tarantino noted that in the absence of mature overall survival (OS) data, the CLEOPATRA regimen remains a clinically appropriate option for select patients, particularly those with less aggressive disease or greater concern for early toxicity. Notably, data for T-DXd monotherapy have not yet been reported.

Treatment selection in the first-line setting may also be influenced by hormone receptor (HR) status. For patients with HR-positive/HER2-positive disease, Tarantino highlighted findings from the phase 3 PATINA trial (NCT02947685), which evaluated maintenance endocrine therapy plus trastuzumab, pertuzumab, and the CDK4/6 inhibitor palbociclib (Ibrance). In contrast, for HR-negative/HER2-positive disease, T-DXd plus pertuzumab may be favored in the first-line setting due to its enhanced activity in more aggressive disease biology.

In the second-line setting, uncertainty remains regarding optimal sequencing if a T-DXd–based regimen is used in the first line. Tarantino noted that a taxane-based regimen combined with trastuzumab and potentially pertuzumab remains a viable option. Given that chemotherapy retains cytotoxic efficacy even in cases of HER2 downregulation post–T-DXd exposure, this approach may offer continued disease control.

Tarantino emphasized that the CLEOPATRA regimen should not be considered obsolete but instead repositioned within a more tailored treatment paradigm. As sequencing strategies evolve and new data emerge, particularly regarding OS and real-world outcomes, the integration of CLEOPATRA-based regimens will continue to depend on individualized treatment goals and disease characteristics.