Dr Hamilton on Treatment Selection After Progression on Frontline CDK4/6 Inhibition in HR+ Breast Cancer

"[There are] a variety of very actionable mutations [we can target in the second-line setting]. It is very clear is that single-agent fulvestrant is just not good enough in a post-CDK4/6 inhibitor world. We [should be thinking] about either using fulvestrant with one of those targeted agents, or perhaps elacestrant."

Erika P. Hamilton, MD, the director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute, discussed how to approach treatment selection for patients with hormone receptor–positive breast cancer following disease progression on a prior CDK4/6 inhibitor in the first-line setting.

The treatment arsenal for second-line estrogen receptor (ER)–positive, HER2-negative breast cancer has become increasingly complex, largely due to the growing clinical utility of mutational profiling in guiding therapeutic selection, Hamilton began. For patients with ESR1 mutations, elacestrant (Orserdu)—a targeted oral selective estrogen receptor degrader—is a viable option, she stated. Alpelisib (Piqray) should be considered for patients harboring PIK3CA mutations, and capivasertib (AZD5363) is available for tumors with PI3K, AKT, or PTEN pathway alterations. These molecularly defined subsets allow for the use of precision therapies that offer superior efficacy over historical endocrine-directed monotherapy, Hamilton asserted.

Data from multiple randomized trials have demonstrated that single-agent fulvestrant (Faslodex) is inadequate in the post-CDK4/6 inhibitor setting, Hamilton reported. As such, treatment strategies for these patients should involve fulvestrant combined with a targeted agent, or substituting fulvestrant with elacestrant for ESR1-mutant tumors, she explained.

For patients without identifiable actionable mutations, treatment rechallenge with CDK4/6 inhibition is emerging as a viable strategy, she noted. Findings from the phase 3 postMONARCH trial (NCT05169567) support the use of abemaciclib (Verzenio) in combination with endocrine therapy in patients who have previously received CDK4/6 inhibition with ribociclib (Kisqali) or palbociclib (Ibrance). This approach has been shown to extend progression-free survival in patients who derived clinical benefit from a first-line CDK4/6 inhibitor, Hamilton stated.

Collectively, these developments underscore the importance of genomic profiling at progression and reinforce the role of combination strategies in the second-line setting for ER-positive disease, Hamilton said. Treatment selection should be guided by prior CDK4/6 inhibitor exposure and mutational status, with a focus on optimizing duration of disease control, she concluded.