Castration-resistant prostate cancer remains as an incurable disease. Exploiting 
DNA damage repair defects via inhibition of poly (ADP-ribose) polymerase (PARP) 
is becoming an attractive therapeutic option. The TOPARP-A clinical trial 
demonstrated that the PARP inhibitor olaparib may be an effective strategy for 
treating prostate cancer. However, several unanswered questions regarding the 
use of olaparib remain: 1) How do we best stratify patients for olaparib 
treatment? 2) Where do we place olaparib in the treatment sequence paradigm? 3) 
Is there cross-resistance between olaparib and currently used therapies? Here, 
we tested putative cross-resistance between current therapies and olaparib in 
treatment-resistant castration-resistant prostate cancer models. 
Docetaxel-resistant cells exhibited robust resistance to olaparib which could be 
attributed to blunted PARP trapping in response to olaparib treatment. 
Upregulated ABCB1 mediates cross-resistance between taxanes and olaparib, which 
can be overcome through decreasing ABCB1 expression or inhibiting ABCB1 using 
elacridar or enzalutamide. We also show that combining olaparib with 
enzalutamide is more effective in olaparib-sensitive cells than either single 
agent. Our results demonstrate that cross-resistance between olaparib and other 
therapies could blunt response to treatment and highlight the need to develop 
strategies to maximize olaparib efficacy.