RLY-5836 + ribociclib + fulvestrant

This is a **combination therapy** consisting of three drugs: **RLY-5836**, **ribociclib**, and **fulvestrant**, studied for the treatment of advanced or metastatic breast cancer harboring PIK3CA mutations, particularly in the hormone receptor-positive (HR+), HER2-negative setting. **RLY-5836** is an investigational, orally bioavailable, allosteric, pan-mutant, and isoform-selective inhibitor of phosphoinositide 3-kinase alpha (PI3Kα), designed to selectively inhibit mutant forms of PI3Kα, targeting the PI3K/AKT/mTOR pathway involved in oncogenic signaling. **Ribociclib** is a small molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), and **fulvestrant** is a selective estrogen receptor degrader (SERD) that antagonizes and degrades the estrogen receptor. This combination is being studied to achieve multiline pathway inhibition for HR+ breast cancers, especially those progressing on previous therapies. The study involving this combination was part of a Phase 1 trial for advanced breast cancer, with RLY-5836 clinical development later deprioritized in favor of a sibling compound.[2][3][5]