AZD7648 potentiated the efficacy of olaparib in BRCA-deficient OC-PDXs, but did not sensitize BRCA-proficient OC-PDXs to olaparib, despite an equivalent inhibition of DNA-PK, suggesting the need of a pre-existing olaparib activity to benefit from the addition of AZD7648. This work suggests that AZD7648, an inhibitor of DNA-PK, dosed in combination with PLD or olaparib is an exciting therapeutic option that could benefit ovarian cancer patients and should be explored in clinical trials.