All pumped up about PARPs

A report in this week’s issue of the New England Journal of Medicine (which is never shy about promoting itself) provides more early, and interesting, evidence of the future potential of so-called PARP inhibitors in cancer therapy.

PARP stands for “poly(ADP-ribose) polymerase”, and there are a wide variety of PARPs. These are enzymes that are involved in the continuous repair of breaks in DNA. Basically, by inhibiting the activity of PARPs in cancer cells one can stop the repair of breaks in the DNA of the cancer cells and therefore theoretically stop the replication of the cancer cells. (I hope that’s a simple enough explanation.) Research on PARPs has been going on for a while now, and we are just seeing the first data about PARP inhibitors coming out of the clinical research labs.

The paper by Fong et al. in the New England Journal of Medicine is based on use of a drug known as olaparib or AZD2281 (and is available in full on line). Another drug, BSI-201, has also shown interesting results. However, the majority of the data available so far is in patients with specific types of breast cancer or ovarian cancer.

The data reported by Fong et al included just 3 patients with prostate cancer out of the 60 patients studied. And “durable objective antitumor activity was observed only in confirmed carriers of a BRAC1 or BRAC2 mutation” and one other patient with a high probability of being a BRAC carrier. It is not entirely clear from the paper exactly how many of the three prostate cancer patients were carriers of a BRAC gene: it was definitively at least one, but it may not have been all three.

The currently available data suggest that:

  • PARP inhibitors are an exciting new type of drug that hold potential in treatment of many types of cancer.
  • Specific PARP inhibitors may work better in certain patients with certain cancer because of genetic variations (just as olaparib appears to only have activity in BRAC gene carriers).
  • It is probable that PARP inhibitors will work best when used in combination with other agents (as shown by a study in so-called “triple negative” breast cancer patients presented at the ASCO annual meeting this year, in which BSI-201 was combined with standard chemotherapy, and increased survival  from 5.7 months with chemotherapy alone to 9.2 months when the BSI-201 was added).
  • PARP inhibitors seem to have a very good safety profile. In the above-mentioned breast cancer trial, when used in combination with chemotherapy, BSI-201 seemed to have no increased impact on the side effects of the chemotherapy, and the side effects reported in the olaparib trial also appear to be relatively few and of low grade.

The “New” Prostate Cancer InfoLink looks forward to data from trials of PARP inhibitors in prostate cancer patients specifically. It may well be that early trials of this type will explore treatment of prostate cancer patients who are carriers of the BRAC1 and BRAC2 gene. The BRAC genes are particularly prevalent in people of Ashkenazi Jewish ethnicity. The prevalence of BRAC genes in the general population is much less well established, but it is relatively low (certainly less than 5 percent of the population as a whole carries these genes).

What is certain is that it will be a while yet before we can know whether either olaparib or BSI-201 are effective in prostate cancer — but there azre lots more PARP inhibitors in the pipeline, and a good chance that at least one of them will have some degree of activity in selected prostate cancer patients.

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