CDK4/6 Inhibitor Selection in HR+ Metastatic Breast Cancer (Full Video)
Key Points
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CDK4/6 inhibitor plus endocrine therapy is standard of care for patients with hormone receptor (HR)-positive metastatic breast cancer.
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Ribociclib is the preferred CDK4/6 inhibitor based on the more robust survival data shown in the MONALEESA-2 trial.
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Dose reductions or swapping to another CDK4/6 inhibitor can help manage toxicities and keep patients on therapy.
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Oral selective estrogen receptor degraders (SERDs) represent a novel class that may affect the treatment paradigm across breast cancer settings.
CDK4/6 Inhibitor Plus Endocrine Therapy in HR+ Advanced Breast Cancer
Cohosts of the OncologyBrothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Center, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, hosted a panel discussion on HR-positive metastatic breast cancer at the 2025 San Antonio Breast Cancer Symposium. They were joined by four breast cancer experts: Laura Huppert, MD, of UCSF Health; Komal Jhaveri, MD, FACP, of Memorial Sloan Kettering Cancer Center; Heather McArthur, MD, of UT Southwestern; and Hope Rugo, MD, of City of Hope.
CDK4/6 Inhibitor Selection in Metastatic Breast Cancer
The standard of care in HR-positive metastatic breast cancer is endocrine therapy plus a CDK4/6 inhibitor, such as ribociclib, abemaciclib, or palbociclib. In the MONALEESA-2 trial, ribociclib showed statistically significant improved overall survival (OS) for HR-positive advanced breast cancer in the first and second line. In the MONARCH 2 trial, abemaciclib demonstrated numerically improved OS in the first line. Palbociclib saw less use after the advent of ribociclib and abemaciclib, but has recently shown promise in combinations such as the INAVO120 trial regimen.
Based on the available data, the doctors agreed that ribociclib is generally the preferred CDK4/6 inhibitor for eligible patients with HR-positive metastatic breast cancer. An alternative agent may be warranted in patients who are older, have underlying liver dysfunction, or have a high QT interval at baseline. The INAVO120 regimen may also be preferred for patients who meet the study criteria.
CDK4/6 Inhibitor Side Effects in Advanced Breast Cancer
Ribociclib is associated with neutropenia and, less commonly, liver enzyme elevations and QTc interval prolongation. Comparatively, abemaciclib is associated with less neutropenia, but a high rate of diarrhea, and palbociclib is associated with lower toxicity in general. The diarrhea associated with abemaciclib can be a limiting factor, especially in the metastatic setting where treatment is optimizing for quality of life, said Dr. Rugo.
For patients starting ribociclib, liver function tests (LFTs) should be monitored monthly, and doses can be held to let LFT abnormalities resolve. Steroids may also be used to help manage high-grade events. Additionally, the QT interval should be checked at baseline and after 2 weeks. QT prolongation is more likely in patients receiving additional medications that also affect the heart.
Given that data in breast cancer consistently showed CDK4/6 inhibitors can maintain efficacy despite dose reductions, most patients should start at the full recommended dose for each agent and reduce the dose from there to manage toxicities, said Dr. McArthur. If toxicities with one agent become unmanageable, swapping to another CDK4/6 inhibitor is worth consideration based on various trials like postMONARCH and MAINTAIN.
CDK4/6 Inhibitors and SERDs in HR+ Metastatic Breast Cancer
The panel also discussed the role that oral SERDs may play in HR-positive metastatic breast cancer as research on the class continues to evolve. SERDs have shown “very exciting” early data in high-risk early breast cancer, and could reinvent the endocrine therapy backbone that has been largely unchanged for many years, said Dr.Jhaveri.Data for SERDs will continue to mature, and ongoing studies are investigating the optimal sequences or combinations for SERDs and CDK4/6 inhibitors, Dr. Jhaveri said.
Overall, breast cancer has seen many approvals and positive data in the past few years, and it’s an exciting time for breast cancer treatment. Although t CDK4/6 inhibitors are moving into the adjuvant setting in high-risk patients, the next challenge may be selecting therapies for first-line HR-positive metastatic breast cancer therapy, said Dr. McArthur.