Elacestrant is an oral selective estrogen receptor degrader (SERD) approved for patients with ER-positive, HER2-negative advanced or metastatic breast cancer harboring ESR1 mutations following endocrine therapy. The Phase I/II ELEVATE study is evaluating elacestrant in combination with targeted therapies, including CDK4/6, PI3K, AKT, and mTOR inhibitors, to overcome mechanisms of endocrine resistance in ER+/HER2− advanced breast cancer. Preliminary results from the Phase Ib elacestrant (258–345 mg) plus capivasertib (320–400 mg) cohorts (n=31) identified a recommended Phase II dose (RP2D) of elacestrant 345 mg plus capivasertib 320 mg BID (4 days on/3 days off) in cohort 2 (n=9). The combination demonstrated encouraging clinical activity, particularly in patients with co-existing ESR1 and PIK3CA mutations, supporting the continued development of elacestrant based combination strategies aimed at addressing resistance pathways and improving outcomes in endocrine-resistant disease.

The safety profile of elacestrant plus capivasertib in the ELEVATE study was consistent with the known safety profiles of each targeted therapy and standard-of-care endocrine therapy.

KOL insights

“The combination of elacestrant plus capivasertib is designed to address an unmet need for patients with ER+/HER2- PI3K-pathway altered metastatic breast cancer, particularly when co-existing ESR1 and PIK3CA mutations are present.” –Expert Opinion

“Building on the data we saw last year at SABCS, we continue to be encouraged by elacestrant’s potential clinical benefit observed across numerous combinations with different agents targeting ER+/HER2- metastatic breast cancer.”–Expert Opinion

Conclusion

Breast cancer is the most common cancer among women in the United States. In 2025, there are an estimated ~693,000 incident cases of breast cancer in the 7MM. The United States accounts for approximately ~44% of the 7MM prevalent HR+ breast cancer population.

In the evolving ER+/HER2− metastatic breast cancer treatment landscape, CDK4/6 inhibitor-based endocrine therapy remains the established standard of care, while oral SERDs and targeted therapies including AKT and PI3K inhibitors are being explored to address endocrine resistance following disease progression. Preliminary Phase I/II ELEVATE data suggest that elacestrant plus capivasertib may represent a promising combination approach, particularly in patients with co-existing ESR1 and PIK3CA mutations, supporting the rationale for dual targeting of the estrogen receptor and AKT pathways. As competition intensifies among next-generation SERDs, SERD based combinations, and PI3K/AKT pathway-targeted therapies, larger studies will be needed to further define the clinical utility and positioning of this combination within the post-CDK4/6 treatment paradigm.