Justin Chura, MD, explains how gene mutations play a role in ovarian cancer, and remarks on new opportunities in treating ovarian cancer with PARP (poly [ADP-ribose] polymerase) inhibitors.
PUBLISHED December 21, 2017
Maurie Markman, MD: Turning to the question of possible new strategies, as Dr. Chura mentioned, it’s really a remarkable time, as somebody who has been involved in this area for over 30 years, in terms of new opportunities for therapy. One of the most exciting is this class of drugs known as PARP inhibitors. I’d like to talk a little bit about the PARP inhibitors. Justin, what are PARP inhibitors, and how do we believe they work in ovarian cancer?
Justin Chura, MD: Anya actually has a BRCA mutation. So, she has inherited one of the genes that predisposes her as high risk for both breast and ovarian cancer. She’s had the disease of ovarian cancer. We know that the BRCA genes are involved in when cells replicate, and they duplicate their DNA. They have to match up perfectly. That fidelity, if there’s a loss in that, is where the BRCA genes work. They ensure that there’s correct replication. And so, cancer cells, to grow, need to replicate and divide. When they already have a defective gene in the BRCA pathway, they’re a little bit predisposed to not being able to correct the errors and replication. Then, we add in a drug, a PARP inhibitor, which also acts on that same pathway of what’s called homologous recombination. And that drug also acts along that homologous recombination pathway, in a patient with a BRCA mutation, or even now without. We know that it interferes with the cells ability to replicate, and grow, and divide. And so, that’s how we think the PARP inhibitors work.
The first glimmers of hope were mostly found in patients with the BRCA mutations, because they already had a predisposition in which their cells’ lines were not going to be able to replicate in a reliable fashion. And so, we add in this medication that further works along that way. But that’s talking about what we call a genotype, someone’s inherited genes.
We’ve also identified what we call a phenotype. A phenotype is what we see on the surface. What does somebody look like? Our phenotype is whether we’re blonde-haired or brown-haired. We’ve identified a phenotype called HRD (homologous recombination deficiency). And that phenotype, which can be identified through testing of the tumor, can identify another subset of patients that can particularly benefit from PARP inhibitors.
Maurie Markman, MD: You mentioned BRCA mutations and the germline. One of the questions that has come up, obviously meaning that it is present in every cell, from conception onward, is the possibility that those mutations are just going to be in the cancer cell, itself. And the term we use is “somatic.” Does it make a difference, from the perspective of potential benefits of these PARP inhibitors, if it’s only in the cancer versus in the germline?
Justin Chura, MD: It certainly makes a difference for the individual patient and her family when it’s not in the germline. That’s a key thing to remember. When patients have a germline BRCA mutation, we have to think about children, siblings, and really extend that out in terms of who is at risk. When it’s a somatic mutation, and is just in the cancer, itself, those cells are then still exquisitely susceptible to PARP inhibition. And so, I think that having the presence of the mutation when it is just somatic still is a very good marker of what the cancer will respond to, in terms of therapeutic options for the patient.
Maurie Markman, MD: One of the issues that then comes up in the discussion about the patient using PARPs, as you alluded to, is even utilizing PARP inhibitors if an individual does not have a known BRCA mutation. In fact, BRCA mutations are now recommended to be looked at long before we are talking about potential therapies with PARPs. It’s now recommended early on in the course of the illness, really at the time of diagnosis, by a variety of groups. If there’s that family risk of identifying that information for both women and men in that family—children, grandchildren, nieces, and nephews, etc—that information may be available. But even in the presence of a normal BRCA mutation, there could be the absence of a BRCA mutation in terms of the germline that could be in the somatic area. So, that’s a reason to look.
But another question that comes up, and is included in the available data, is that patients with ovarian cancer seem to benefit from these PARP inhibitors, even in the absence of a BRCA mutation. Can you comment on that?
Justin Chura, MD: Absolutely. It’s definitely a complex question, and it leads into how we’re talking about using PARP inhibitors. The first approval, in 2013, was for a PARP inhibitor in patients with a BRCA mutation who had more than 3 lines of therapy. That was approved as a treatment, and those patients had to have the germline BRCA mutation. There have been other approvals for either germline or somatic mutation settings, for treatment in patients with 2 lines of prior therapy. We’ve also studied PARP inhibitors in what we call the maintenance or switch maintenance settings. Here, patients have to be what we consider platinum-sensitive, meaning that they respond to platinum-based therapy. We treat with a platinum-based regimen, whether that’s carboplatin and any of the other chemotherapies which me may combine it with. And assuming that they achieve either a complete response or a partial response, those patients are then eligible for PARP inhibitors, regardless of their BRCA status. We know, from some subgroup analyses, that the patients with the BRCA mutations will have the most profound benefit. But even those without BRCA mutations still experience a clinical benefit, in what we call their progression-free survival. The PARP inhibitor can extend, if you will, the remission, to a degree. And so, in that setting of what we call maintenance or switch maintenance, that’s where PARP inhibitors can play a role, regardless of the BRCA status.