PARP inhibitors are now approved in the United States for the treatment of patients with ovarian cancer, specifically approved for those with defective BRCA
genes. This is because if you have a defective BRCA
gene, you can’t perform homologous recombination.
Our overarching question was, “Does amplification of EMSY
—which was previously thought to be a surrogate for BRCA2
dysfunction—surpass homologous recombination?” This suggests that these particular tumors—which make up 10% of ovarian cancers—may have another mechanism to be sensitive to PARP inhibition.
PARP inhibitors went from discovery to the clinic quickly. The first study, which was done about 5 or 6 years ago, showed that patients with BRCA
mutations were quite sensitive to PARP inhibitors. This led to a plethora of studies that have been conducted and are ongoing now.
Basically, in the United States, there are 2 PARP inhibitors that are FDA approved for the treatment of patients with recurrent ovarian cancer. These are olaparib (Lynparza) that was approved a few years ago, and rucaparib (Rubraca), which was approved in December 2016.
Again, both approvals are specifically for treating cancers that have defective BRCA
genes. Olaparib was approved only for women who had inherited a BRCA
mutation, which can be detected by a blood test. Rucaparib is for women who have an inherited or germline mutation in BRCA1/2
or have a specific mutation that would develop inside their tumor called a somatic mutation, both of which can be tested through companion diagnostics.
How does the recent approval of rucaparib affect the field of ovarian cancer research?
This is the paradigm of how we can target defects in DNA repair, and certainly olaparib was a major advance to get that approved. Rucaparib has done a couple of things based on how those studied were designed. First, it moved the FDA approval up to an earlier setting in a disease course. Olaparib was approved only after you've had 3 prior courses of treatment for ovarian cancer and rucaparib was approved after having only 2 prior courses of treatment.
More importantly, the olaparib studies that led to the FDA approval were done in women who had an inherited or germline mutation, whereas the rucaparib studies examined the somatic mutations. The rucaparib approval is for both germline and somatic mutations.
What rucaparib was doing, and what we are trying to do with these EMSY
studies, is trying to expand the arena for which PARP inhibitors can be applied to the treatment of patients with ovarian cancer. By adding somatic mutations, we have now picked up another 6% to 10% of ovarian tumors that can now receive this FDA-approved therapy. The inherited mutations are present in 15% to 20% and the somatic mutations are present in another 5% to 10%, so we are slowly chipping away to find the proper therapies targeted for each specific patient with ovarian cancer.
Has any recent research emerged regarding the use of immunotherapy in the treatment of ovarian cancer?
There have been some studies and there are a number of ongoing studies. The single-agent results of immunotherapy in ovarian cancer have not been as dramatic as they have been in some other tumor types, such as specific types of endometrial cancer, colon cancer, and lung cancer. I don't think single-agent immunotherapy is going to be as promising as it is in other tumors, but now we're trying to augment the treatment by adding 2 and even 3 agents to immunotherapy. The combination would be traditional chemotherapy, other targeted agents or therapeutics, and through that combination there is a reasonable amount of promise for immunotherapy in ovarian cancer.
What do you think is the biggest challenge in the field of ovarian cancer?
The biggest challenge now and, unfortunately for the past 20 years, has been how to overcome platinum resistance in ovarian cancer. Most ovarian cancers are exquisitely sensitive to standard treatments, which include aggressive surgeries followed by combination chemotherapy of which a platinum-containing regimen is a critical part.
Primarily, due to the sensitivity of most ovarian cancer cells to platinum chemotherapy, the tumors fortunately have a dramatic response. Unfortunately, well over half of the tumors and half of the patients will have recurrent disease. Often, we can retreat them with platinum-based therapy or similar drugs, but they are ultimately destined to become resistant to platinum agents. We have been trying to combine agents for a long time but, with some of the more targeted therapeutics, there is a better promise that we can attack platinum-resistant disease.
Jelinic P, Eccles LA, Tseng A, et al. The EMSY threonine 207 phospho-site is required for EMSYdriven suppression of DNA damage repair [published online January 13, 2017]. Oncotarget. doi: 10.18632/oncotarget.14637.