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**NUV-422 + fulvestrant** is a combination therapy under clinical investigation for the treatment of hormone receptor–positive (HR+), HER2-negative advanced breast cancer that is resistant to prior hormonal therapy and CDK4/6 inhibitor treatment. NUV-422 is a selective, oral small molecule inhibitor of cyclin-dependent kinases CDK2, CDK4, and CDK6, with limited activity against CDK1. Fulvestrant is a selective estrogen receptor degrader (SERD) used to block and degrade the estrogen receptor in breast cancer cells. The rationale for this combination is to simultaneously inhibit cell cycle progression (by blocking multiple CDKs) and suppress estrogen-driven signaling to overcome resistance to existing therapies. The combination is being developed by Nuvation Bio and includes oral administration of NUV-422 and intramuscular fulvestrant, tested in phase 1/2 studies focused on safety and efficacy in patients with advanced breast cancer who have previously received endocrine therapy and a CDK4/6 inhibitor[3][5].
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