I have talked a lot about our need to take the next step in clinical care, understanding the best sequencing of our drugs. Since we have a number of new drugs to treat advanced prostate cancer we now need to better understand which drugs should be used in which men as well as their proper sequencing.

To do this we need to understand the genetic differences that our cancers have from each other.

Cancer is a genetic disease and what we refer to, as prostate cancer is not one distinct disease, but it is many different diseases. To better sequence the drugs we also need to understand these genetic differences. We know that some drugs will work for certain genetic strains of prostate cancer while in other genetic strains it will not work.

Towards this end, results from a recent phase 2 trial that was published in The New England Journal of Medicine has shown that treatment with olaparib, a poly(adenosine disphosphate

[ADP]-ribose) polymerase (PARP) inhibitor in men with advanced prostate cancer who no longer responded to standard treatments and who also had defects in their DNA-repair genes achieved a high response rate.

The trial enrolled 50 men with metastatic castration-resistant prostate cancer (mCRPC) who had already received and failed chemotherapy with docetaxel. It was noted that 49 and 29 of the men had also received abiraterone or enzalutamide and cabazitaxel, respectively. All of the men in the trial were treated with olaparib 400 mg orally twice daily.

When the genetics of the trial subjects were evaluated the researchers found that of the 16 evaluable men who had homozygous deletions, deleterious mutations, or both in their DNA-repair genes, including BRCA1 and BRCA2, ATM, Fanconi’s anemia genes, and CHEK2, 88% achieved a response to the olaparib treatment.

The researchers also reported that the most common grade 3 or 4 adverse events were anemia and fatigue.

“Our trial marks a significant step forward in the treatment of prostate cancer, showing that olaparib is highly effective at treating men with DNA repair defects in their tumors,” said chief investigator Professor Johann de Bono, head of drug development at The Institute of Cancer Research in England, and The Royal Marsden NHS Foundation Trust……. It also proves the principle that we can detect prostate cancers with specific targetable mutations using genomic sequencing to deliver more precise cancer care by matching treatment to those men most likely to benefit.”

Olaparib is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with deleterious or suspected deleterious germline BRCAmutated in women with advanced ovarian cancer who have been treated with at least 3 prior lines of chemotherapy.

As we move into the era of personalized medicine we will need to develop additional information about the genetic differences that characterize each of our cancers. Applying this information to better understand drug sensitivity is vital for better treatment outcomes and to control the costs associated with using treatments that will not work because of underlying genetics.

Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015; 373:1697-1708.