It is common knowledge that men with metastatic castration-resistant prostate cancer (CRPC) don’t all have the same disease. There are many different types or flavors of prostate cancer.

These differences are involved in the genetic structure of the cancer cell its self. Some prostate cancers have mutations in the DNA repair genes (genes whose job is to repair other gene mutations). It has been shown that prostate cancer that have these mutations are more likely to respond to the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. (Currently olaparib is FDA approved for certain types of advanced ovarian cancers.)

In the recently evaluated phase II TOPARP trial, 17 of the 49 evaluable men responded to the investigation drug olaparib. Six of these men had radiologic responses and 11 had biochemical responses, as determined by a reduction in prostate-specific antigen (PSA) levels of greater than 50%. Four of these men had responses that lasted more than 12 months.

Mirroring these results, Joaquin Mateo, MD, a clinical research fellow in the Prostate Targeted Therapy Group and Drug Development Unit at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust in the United Kingdom and colleagues used next-generation sequencing to detect both somatic and germline mutations in genes associated with DNA repair. They found that mutations in these genes were present in tumors from 15 of the 49 men in their study. Of these 15 men 13 responded positively to olaparib. (The results were presented at a press briefing at the American Association for Cancer Research (AACR) Annual Meeting, held April 18 to 22 in Philadelphia)

According to Dr. Mateo, “It is known from previous trials that patients with prostate cancer and germline BRCA2 mutations respond to olaparib but they represent less than 2% of cases.” In addition Mateo said that prior sequencing studies showed that as many as one-fifth to one-third of prostate tumors developed somatic BRCA2 mutations. “Despite being different genes, many of

[these genes] have shown, in preclinical studies, to sensitize tumors to PARP inhibition.”

This leads us to the question, how accurately can we identify men with damage to their DNA repair genes? Without specificity we woud not be able to know which men could benefit from a PARP inhibitor.

According to Mateo, the specificity of the DNA repair gene panel was 94%, meaning that 94% of men without these mutations can be correctly identified as having tumors with wild-type versions. Men without the mutation are not likely to benefit from olaparib, but those who do might gain a significant benefit.

In a trial at seven different UK centers men who had previously been treated and progressed on one or two lines of chemotherapy received 400 mg of olaparib twice daily. Side effects were consistent with previous olaparib studies in other tumor types which included anemia and fatigue were the most common grade 3 or higher adverse events. Thirteen (26%) of the men required a dose reduction.

The researchers have taken the next step and are now testing this prostate cancer stratification strategy in a second part of the TOPARP trial. They are enrolling only those men who have mutations in genes associated with DNA repair.

“We are now conducting a second validation trial that prospectively screens patients for mutations in these genes of interest, which just opened to recruitment in the United Kingdom earlier this month,” said Mateo. By the end of the year, they also expect to open a randomized phase II study of olaparib in earlier-stage prostate cancer patients.

This is a good example of how we will develop personalized treatments for men with prostate cancer. These treatments will eventually be able to be targeted specifically to men who will benefit. This will allow us not to give men treatments that will not benefit them, provide more time for their cancer to progress while also reaping economic savings both to the individual and to society.

Joel T. Nowak, M.A., M.S.W.