Dr Jhaveri on the Evolution of Endocrine Therapy in ER+ Metastatic 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 rationale behind the ongoing clinical development of elacestrant (Orserdu) and other endocrine therapies in patients with estrogen receptor (ER)–positive metastatic breast cancer, which she presented on at the 41st Annual CFS® Meeting.

The goal of developing endocrine therapy for patients with ER-positive disease is to broaden the treatment paradigm by identifying agents with optimal therapeutic windows, Jhaveri says. In January 2023, the FDA approved the oral selective estrogen receptor degrader (SERD) elacestrant for patients with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer following at least 1 line of endocrine therapy. Prior to the approval of elacestrant, fulvestrant (Faslodex), tamoxifen, and aromatase inhibitors (AIs) were standard therapies for patients with ER-positive, HER2-negative disease, Jhaveri explains. However, ESR1mutations can develop during treatment with AIs or fulvestrant in the metastatic setting, Jhaveri notes. Additionally, although fulvestrant is effective when administered after AIs in patients with metastatic disease, its efficacy when administered after CDK4/6 inhibitors is modest, with a median progression-free survival of approximately 2 months, according to Jhaveri. Furthermore, the efficacy of fulvestrant is dose dependent; the agent is administered via intramuscular injection and thus not orally bioavailable; and it has limited activity in patients with select ESR1 mutations, such as ESR1 Y537S mutations, Jhaveri emphasizes.

The challenges associated with fulvestrant formed the rationale for developing additional breast cancer agents that could overcome the issues of existing therapies through tolerable safety profiles and wide therapeutic windows, Jhaveri says. Elacestrant was the first of these investigational agents to receive FDA approval, and other agents are in late-phase development, including other oral SERDs; novel selective estrogen receptor modulators, such as lasofoxifene (Fablyn); proteolysis-targeting chimeras; and complete ER antagonists, Jhaveri concludes.

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