Role of PARP Inhibitors in Ovarian Cancer Continues to Evolve

On the evolving role of PARP inhibitors in the treatment of ovarian cancer, Donna McNamara, co-chief of Gynecological Oncology at the John Theurer Cancer Center (JTCC) offers her insight into the topic. The PARP inhibitor Lynparza (olaparib) was approved in December for women with advanced ovarian cancer linked to BRCA mutations, as detected by the BRACAnalysis CDx test.

Ongoing trials at JTCC have been examining PARP inhibitors in ovarian cancer, particularly in patients who have BRCA1/2 mutations. These studies include the SOLO 1 trial, which examined Lynparza as a monotherapy following first-line platinum-based chemotherapy in patients with BRCA-positive ovarian cancer. McNamara discusses the impact of these studies and the outlook going forward for PARP inhibitors in ovarian cancer.

CURE: Can you first discuss the mechanism of action of PARP inhibitors?

Dr McNamara: When we’re talking about PARP inhibitors, we’re talking about DNA repair. We know that the mutations for BRCA1 and BRCA2 cause a disruption in double-stranded DNA repair. The cells are very redundant in terms of trying to keep themselves intact, therefore the PARP inhibitors are in charge of single-stranded DNA repair within the nucleus of the cell. If the PARP protein is disrupted then that causes more double stranded breaks, which can result in cell death.

What are some of the studies being conducted at JTCC with PARP inhibitors in ovarian cancer?

We have a phase 1 trial that was looking at veliparib in breast and ovarian cancer. In breast cancer, it was looking at individuals who had the BRCA1 or the BRCA2 mutations and in ovarian cancer, it was looking both at BRCA-positive as well as BRCA-negative individuals to see if there’s any efficacy for this molecule in either of those diseases.

We don’t have any of the results back right now, but certainly things are looking promising. My understanding, however, is they’re really concentrating more in both diseases in both the BRCA-positives either for BRCA1 or BRCA2 mutations.

The phase 3 study that also closed was our SOLO 1 trial. This is very exciting in ovarian cancer. In diseases such as breast cancer there is maintenance after completion of chemotherapy to try to keep patients in remission. We don’t yet have that for ovarian cancer, but it’s something that we’re desperately looking for.

Although in ovarian cancer only 10 percent to 15 percent of individuals harbor either the BRCA1 or the BRCA2 mutations, these individuals have the unique opportunity of possibly benefitting from PARP inhibitors. These agents seem to be most active in individuals with BRCA1/2 mutations.

The SOLO trial was looking at individuals who have recently completed their adjuvant chemotherapy for ovarian, fallopian tube, or primary peritoneal cancer. If these individuals harbor the BRCA mutation, they had the opportunity of enrolling in the trial and could be randomized either to a placebo or to the PARP inhibitor olaparib. The hope is that the patients that are receiving the olaparib will have an increased progression-free survival or, optimally, overall survival.

What has been observed so far in the PARP inhibitor trials?

We certainly are seeing a clinical benefit to the PARP inhibitors in ovarian cancer, specifically individuals who have platinum-sensitive disease—those individuals who have received their chemotherapy and do not have any signs of disease recurrence at least 6 months after completion of their therapy. In these individuals, we seem to see a benefit if they are positive for either BRCA1 or BRCA2 using the PARP inhibitors such as olaparib, specifically in this instance. The studies with olaparib are showing up to a 65 percent, even 72 percent, clinical benefit and up to a seven-month progression-free survival in this disease.

What are some of the differences between the various PARP inhibitors?

There are some PARP inhibitors that are more ubiquitous and they inhibit both the PARP1 and the PARP2 proteins. There are some that are more specifically targeted, usually toward PARP1. We are finding that the more targeted the agents are, typically the more active that they’re going to be. However, this is still going to come out as we develop stronger inhibitors with different companies over the course of time, and there are several that are certainly in development with several pharmaceutical companies.

Can you discuss the potential for using PARP inhibitors in combination with chemotherapy?

Although we are looking for that magic bullet that is going to automatically get into a cell, a cancer cell and kill it, we are not finding that one agent is going to do the trick. We’re looking at targeting multiple pathways within the cell, hopefully to lead to cell death. We are seeing that the PARP inhibitors do seem to work well in combination with chemotherapy and we’ve been looking at some of the platinum agents like carboplatin, but also with some of the targeted agents like EGFR, PI3-kinase, and others as well. They do seem to be more active if they are combined. This is not just in the ovarian cancers, it’s not just in BRCA1 and BRCA2, but we’re seeing this in different subtypes of cancer, such as lung cancer, where there are trials ongoing looking at the combination of the PARPs with EGFR agents.