olaparib + onalespib

Olaparib + onalespib is an investigational combination therapy consisting of two small molecule inhibitors with distinct mechanisms of action. Olaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor that impairs DNA repair by inhibiting PARP enzymes involved in single-strand break repair. Onalespib is a second-generation non-ansamycin heat shock protein 90 (HSP90) inhibitor that disrupts the function of HSP90 client proteins, many of which are involved in homologous recombination repair (HRR). The rationale for combining these agents is to overcome resistance to PARP inhibitors by further disrupting HRR through HSP90 inhibition. Preclinical studies and phase 1 clinical trials have shown that this combination can be safely administered and demonstrates preliminary anti-tumor activity—particularly in BRCA-mutated ovarian cancer models with acquired PARPi resistance and tumors harboring RB-pathway alterations[1][2][8]. The combination has been studied primarily in advanced solid tumors including ovarian cancer.