Dr Jhaveri on the Use of CDK4/6 Inhibitors Plus Endocrine Therapy in Breast Cancer

Komal Jhaveri, MD, FACP, section head, Endocrine Therapy Research Program, clinical director, Early Drug Development Service, Patricia and James Cayne Chair for Junior Faculty, Memorial Sloan Kettering Cancer Center, discusses the current state of the frontline treatment paradigm, as well as ongoing developments, for patients with estrogen receptor (ER)–positive metastatic breast cancer.

First-line therapeutic approaches have transformed over the years for patients with ER-positive metastatic breast cancer in large part because of the incorporation of CDK4/6 inhibitors alongside endocrine therapy, Jhaveri begins. These treatments have demonstrated a significant overall survival benefit, she explains, adding that with ribociclib (Kisqali), survival rates have exceeded 5 years, irrespective of menopausal status, marking a revolution in patient treatment. However, a subset of patients either exhibit primary endocrine resistance or develop acquired resistance to these agents, which results in continued tumor growth, according to Jhaveri. This underscores the need to determine effective treatment strategies for patients whose tumors progress after first-line therapy, Jhaveri emphasizes.

Investigators’ primary focus has been on identifying the optimal sequence of therapies following disease progression on CDK4/6 inhibitors, she continues. Substantial research has been conducted, and ongoing trials aim to address these challenges, she notes. Breakthroughs have resulted from a deeper understanding of the genomic landscape in patients with resistant disease, Jhaveri states. This involves identifying germline BRCA mutations and investigating other genomic alterations that could guide treatment decisions, such as utilizing PARP inhibitors to target specific genetic profiles, she says.

Recent FDA approvals reflect these advancements, Jhaveri explains. For example, the oral selective estrogen receptor degrader elacestrant (Orserdu) has been FDA approved for patients with ER-positive, HER2-negative advanced or metastatic breast cancer harboring ESR1 mutations since January 2023, Jhaveri expands. Additionally, in November 2023, the AKT inhibitor capivasertib (Truqap), in combination with fulvestrant (Faslodex), received FDA approval for patients with hormone receptor (HR)–positive, HER2-negative breast cancer harboring PIK3CA,AKT1, or PTEN mutations. Moreover, alpelisib (Piqray) is now used in combination with fulvestrant for patients with HR-positive, HER2-negative breast cancer with PIK3CA mutations.

Currently, clinical decisions are increasingly informed by biomarker testing, enabling more personalized treatment strategies, Jhaveri emphasizes. This approach ensures that subsequent therapies are tailored to the molecular characteristics of the tumor, optimizing patient outcomes, she concludes.