BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments 
are not based on molecular stratification. We hypothesized that metastatic, 
castration-resistant prostate cancers with DNA-repair defects would respond to 
poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with 
olaparib.
METHODS: We conducted a phase 2 trial in which patients with metastatic, 
castration-resistant prostate cancer were treated with olaparib tablets at a 
dose of 400 mg twice a day. The primary end point was the response rate, defined 
either as an objective response according to Response Evaluation Criteria in 
Solid Tumors, version 1.1, or as a reduction of at least 50% in the 
prostate-specific antigen level or a confirmed reduction in the circulating 
tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells 
per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome 
analysis, and digital polymerase-chain-reaction testing were performed on 
samples from mandated tumor biopsies.
RESULTS: Overall, 50 patients were enrolled; all had received prior treatment 
with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) 
had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a 
response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving 
the study treatment for more than 6 months. Next-generation sequencing 
identified homozygous deletions, deleterious mutations, or both in DNA-repair 
genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 
patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a 
response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic 
somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. 
The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients 
[20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse 
events, findings that are consistent with previous studies of olaparib.
CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose 
prostate cancers were no longer responding to standard treatments and who had 
defects in DNA-repair genes led to a high response rate. (Funded by Cancer 
Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research 
UK number, CRUK/11/029.).