Komal Jhaveri, MD, FACP; and Kevin M. Kalinsky, MD, MS, discuss how emerging oral selective estrogen receptor degraders and proteolysis-targeting chimeras are transforming breast cancer treatment by providing new targeted options for ESR1-mutant tumors, the evolving role of CDK4/6 inhibitor sequencing strategies including molecular progression–based treatment switching, and the integration of antibody-drug conjugates across different breast cancer subtypes from later-line to first-line metastatic settings.
Panelists discuss how oral selective estrogen receptor degraders (SERDs) such as elacestrant are changing treatment for patients experiencing progression on CDK4/6 inhibitors, with current approval for ESR1-mutant tumors and anticipation of additional approvals for other oral SERDs in development.
Panelists discuss how longitudinal surveillance testing could enable treatment interventions based on molecular progression (ESR1 mutations) rather than waiting for radiographic progression, though questions remain about overall survival impact.
Panelists discuss how proteolysis-targeting chimera (PROTAC) agents such as vepdegestrant offer a different mechanism of action compared with oral selective estrogen receptor degrader (SERDs), with promising clinical activity in ESR1-mutant tumors and the need for more data on optimal sequencing strategies.
Panelists discuss how treatment approaches for patients with both ESR1 mutations and PI3K pathway alterations currently rely on single-agent elacestrant for slow-growing disease or doublet therapies for more aggressive cases, with the field rapidly evolving toward targeted combination therapies.
Panelists discuss how the well-tolerated safety profiles of oral selective estrogen receptor degraders (SERDs) and proteolysis-targeting chimeras (PROTACs), despite some low-grade toxicities such as bradycardia and photopsia, make them attractive options, with treatment decisions potentially influenced by specific adverse effect considerations and monitoring requirements.
Panelists discuss how the PATINA trial findings demonstrate significant progression-free survival benefit from adding palbociclib to endocrine and HER2-targeted therapy in patients with estrogen receptor (ER)–positive, HER2-positive disease following induction chemotherapy, though access challenges remain in clinical practice.
Panelists discuss how prior adjuvant CDK4/6 inhibitor exposure complicates metastatic treatment decisions, with limited data supporting rechallenge strategies and the need for more targeted therapies such as CDK2- or CDK4-specific inhibitors.
Panelists discuss how DESTINY-Breast09 data support trastuzumab deruxtecan (T-DXd) plus pertuzumab in frontline HER2-positive disease for select patients with extensive disease or brain metastases while emphasizing individualized treatment decisions to avoid overtreatment.
Panelists discuss how the ASCENT-04 trial findings establish sacituzumab govitecan (SG)plus pembrolizumab as an active standard-of-care combination for triple-negative breast cancer, with considerations needed for patients with prior immunotherapy exposure.
Panelists discuss how treatment decisions between antibody-drug conjugates (ADCs) and continued endocrine-based therapies in HER2-low disease depend on endocrine sensitivity, with ADCs reserved for endocrine-refractory tumors or primary endocrine-resistant cases with short initial response durations.
Panelists discuss how the rapidly evolving breast cancer treatment landscape includes promising developments in oral selective estrogen receptor degraders (SERDs), CDK4/6 inhibitor sequencing strategies, and antibody-drug conjugates (ADCs), with new targeted therapies and bispecifics continuing to emerge.
