PARP Inhibitors' Impact on Advanced Ovarian Cancer
Insights From: Oliver Dorigo, MD, PhD, Stanford University Medical Center; Whitney Graybill, MD, MS, Medical University of South Carolina; Matthew Powell, MD, Washington University School of Medicine
Oliver Dorigo, MD, PhD: PARP inhibitors are certainly one of the most exciting development in the treatment of ovarian cancer patients. We have, over the last 7 or 8 years, conducted several studies with a variety of PARP inhibitors that have all shown they do make a valuable difference for patients. We have tested various PARP inhibitors in the treatment setting and in the maintenance setting, and we are now combining PARP inhibitors in clinical trials with other drugs.
There are 3 PARP inhibitors currently approved for ovarian cancer patients, namely niraparib, olaparib, and rucaparib. Rucaparib and olaparib can be used in patients who have germline, and in the case of rucaparib, somatic, mutations or BRCA1 or BRCA2 for treatment. Olaparib and niraparib also have indications for maintenance therapy in those patients who have successful treatment of platinum-sensitive ovarian cancer recurrences.
We have seen in a variety of studies that maintenance therapy with PARP inhibition in this group of patients with platinum-sensitive recurrent disease provides a very meaningful increase in progression-free survival. Certain patients have very long-term survivals that last more than 5 or 6 years, for example, on olaparib. And those are observations that, to all of us in the field who treat patients with ovarian cancer, are extremely exciting. We likely are going to see outcomes here that we’ve never seen before.
Whitney S. Graybill, MD, MS: PARP enzymes work by helping to repair single-stranded breaks in DNA. PARP inhibitors block the ability of PARP to repair these single-stranded breaks. And in patients who have BRCA1 or BRCA2 mutations or are HR deficient, PARP enzymes are important for the repair of single-stranded breaks in DNA. So, PARP inhibitors don’t allow PARP to repair the single-stranded breaks, which then during the replication process become double-stranded breaks. Cells that have mutated BRCA1 or BRCA2, or are HR deficient, are then unable to repair these double-stranded breaks. With replication and going to a more error-prone mechanism of repair, these double-stranded breaks ultimately lead to cell death.
Another mechanism by which PARP inhibitors can cause cell death is by PARP trapping. A PARP inhibitor can bind PARP on damaged DNA and prevent replication of the DNA. It actually acts as a poison, also known as PARP poison.
Matthew Powell, MD: There are 3 PARP inhibitors currently FDA approved and 2 of them have a similar indication on the label now, and one, being unique, is rucaparib. Rucaparib is still just indicated for the treatment of disease in patients who have had 2 prior lines of chemotherapy. These are patients who have a germline and/or a somatic mutation. So, the tumor itself carries a BRCA1 or BRCA2 gene mutation. Now, additional data are obviously coming out that may expand their labels. But at the current time, that information is in front of the FDA.
As far as when we look at olaparib and niraparib, as well as a treatment indication that olaparib has for fourth-line therapy, they both have a maintenance indication. Olaparib and niraparib have a maintenance indication after 2 prior platinum-based chemotherapies. If patients had a partial or a complete response to their platinum therapy, they can be considered for maintenance therapy, and those indications were borne out in trials that looked at an active PARP inhibitor versus placebo. That maintenance indication is for all-comers at this point. So, regardless of BRCA status or HRD status, patients can receive a maintenance drug with that biomarker of responding to platinum twice.