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Zovegalisib + atirmociclib + fulvestrant is an investigational triplet combination regimen being evaluated for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer harboring PIK3CA (PI3Kα) mutations. The regimen consists of three active agents: zovegalisib (RLY-2608), a mutant-selective, allosteric PI3Kα inhibitor developed by Relay Therapeutics; atirmociclib (PF-07220060), a selective CDK4 inhibitor developed by Pfizer; and fulvestrant, a standard-of-care selective estrogen receptor degrader (SERD). By selectively targeting mutant PI3Kα and CDK4 while sparing wild-type PI3Kα and CDK6, the combination aims to maximize antitumor efficacy and overcome endocrine resistance while minimizing toxicities such as hyperglycemia and neutropenia. In the Phase 1/2 ReDiscover trial, the triplet demonstrated encouraging clinical activity and a manageable safety profile in heavily pretreated patients.
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