The crash was reported at 5:35 p.m. on Westlake Boulevard just north of Mulholland Highway, said California Highway Patrol Officer Edgar Figueroa.
A witness reported the motorcyclist was unconscious when deputies from the Los Hills Sheriff's Station began performing CPR on him. He was pronounced dead at the scene.
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The rider was described as a man in his mid-30s, Figueroa said.
The CHP issued a SigAlert closing all lanes of Westlake Boulevard in both directions.
An investigation was underway.