RLY-5836 + palbociclib + fulvestrant

RLY-5836 + palbociclib + fulvestrant is an investigational **triple combination therapy** for the treatment of **advanced or metastatic hormone receptor-positive, HER2-negative breast cancer** harboring a PIK3CA mutation. It combines: - **RLY-5836**, a small molecule, allosteric, pan-mutant, isoform-selective inhibitor of phosphoinositide 3-kinase alpha (PI3Kα) designed to selectively inhibit mutant PI3Kα activity, which is commonly mutated in certain cancers[4][5]. - **Palbociclib**, a small molecule cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, acting to halt cell cycle progression in tumor cells. - **Fulvestrant**, a selective estrogen receptor degrader (SERD) that leads to degradation of the estrogen receptor and downregulation of estrogen signaling. The combination aims to block oncogenic signaling via the PI3K pathway, inhibit cell cycle progression, and ablate hormone-driven tumor growth. The development of RLY-5836 as a single agent and in combinations was led by Relay Therapeutics. As of 2025, clinical development for RLY-5836 was **suspended** in breast cancer and solid tumors, with sibling compound RLY-2608 prioritized in the pipeline instead[4][5].