Lyndsay J. Willmott, MD
The ovarian cancer treatment paradigm underwent another transformation near the end of 2016 with the FDA approval of the PARP inhibitor rucaparib (Rubraca) for patients with BRCA
-positive advanced ovarian cancer who have received at least 2 prior lines of chemotherapy.
The field shifted again when niraparib (Zejula), another PARP inhibitor, was approved in March 2016 as a maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
The two agents joined the PARP inhibitor olaparib (Lynparza), which was approved in December 2014 for the treatment of women with BRCA
-positive advanced disease following treatment with 3 or more prior lines of chemotherapy.
“These drugs allow us to harness [homologous repair deficiency] and give us a chance to kind of use the tumor against itself,” said Lyndsay J. Willmott, MD. “It is kind of a brilliant concept. It makes patients excited that they can actually say ‘I can use this to my advantage’ and, overall, the tolerability is good.”
Next steps, researchers say, involve moving these novel agents into earlier lines of treatment to maximize patient outcomes.
Willmott, a gynecologic oncologist with Arizona Oncology, highlighted the FDA-approved PARP inhibitors and how these approvals have impacted clinical practice and patient outcomes and quality of life in an interview during the 2017 OncLive®
State of the Science Summit on Ovarian Cancer.OncLive: Please provide an overview of your discussion on PARP inhibitors. Willmott
: When you’re talking about PARP inhibitors, the most important thing I think about is the mechanism of action of the drug. The idea about PARP inhibitors is that they’re kind of taking advantage of errors that can happen in patients with ovarian cancer. Essentially, it is using the tumor biology to your advantage. These include some of these repair proteins that allow us to fix DNA damage and they are actually the most perfect repair proteins. Therefore, when we lose these perfect repair proteins, we have to rely on other proteins to make up the difference. BRCA1/2
and a whole group of other proteins are responsible for what we call homologous repair. We could have mutations in those proteins that can occur in our germline—which are the cells that make up our whole body—or on the tumor itself, which we call somatic. Then, we have to rely on other types of DNA repair. That can include things like nonhomologous end joining. There are a slew of proteins responsible for that, but one of the most important ones are PARP.
The idea is that if we can inhibit these other forms of DNA repair and take the PARP enzyme and make it no longer effective, then this can lead to accumulation of double-stranded breaks. These homologous repair proteins, such as BRCA, normally would fix these. If we don’t have BRCA available, then the cells can’t repair those double-stranded breaks and then they die. That’s the idea behind PARP inhibition.
There have been a number of trials designed to look at PARP inhibitors, and they have been looked at in both the general population—patients who have been previously exposed to chemotherapies—as well as in more modern trials, with the ideas of looking at these treatments as upfront treatment and maintenance. We have also kind of tried to break down to see if patients with BRCA
mutations are more likely to benefit from the drug versus the general population.
The first PARP inhibitor that was on the market was olaparib. There have been multiple trials involving this drug, but essentially the current FDA approval is for patients who have received greater than or equal to 3 prior regimens in the setting of a BRCA
mutation. This drug has its own companion diagnostic, which is looking at germline mutations.
The second drug, called rucaparib, also recently received FDA approval just in December 2016. That was a slightly different indication, as it’s for patients who received at least 2 prior regimens, again for BRCA
mutations. However, this approval also includes patients with somatic mutations. The companion diagnostic for rucaparib actually looks at the tumor and evaluates it for BRCA
mutations. If patients have such mutations, then they're eligible.