We know that prostate cancer is a heterogeneous disease, but most of our treatments are not based on the different molecular stratification exhibited by the disease. One of the differences we do recognize in the cancer is that some of the tumors have genetic DNA-repair defects. There has been evidence that in those cancers exhibiting these types of defects, a possible treatment is poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibition with the investigation treatment olaparib.

Researchers conducted a phase 2 trial in which men with metastatic, castration-resistant prostate cancer (mCRPC) were treated with olaparib tablets at a dose of 400 mg twice a day.

The trial enrolled 50 men; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 men who could be evaluated had a positive response with 12 men receiving the study treatment for more than 6 months.

The identified genetic defects in the tumors included; homozygous deletions, deleterious mutations, or both in DNA-repair genes, including BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK.

These findings are consistent with previous studies of olaparib.

Treatment with the PARP inhibitor olaparib in men whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. The two next steps would be to commence a phase III trial as well as evaluating the potential for PARP inhibitors like olaparib in even earlier stages of the cancer when these genetic defects might also appear.

 

N Engl J Med 2015; 373:1697-1708October 29, 2015DOI: 10.1056/NEJMoa1506859; Joaquin Mateo, M.D., etal.