As part of our coverage of the 2017 Society of Gynecologic Oncology annual meeting, being held March 12th to March 15th in National Harbor, Maryland, we are speaking with Dr. Elizabeth Swisher, MD, a professor in the department of obstetrics and gynecology at the University of Washington whose research focuses on the genetics and prevention of gynecological cancers. Dr. Swisher and her colleagues presented data from the ARIEL2 trial of rucaparib in patients with relapsed, primary platinum-sensitive, high-grade ovarian carcinoma who have germline or somatic BRCA mutations (abstract 1, abstract 7).
—Interviewed by Anna Azvolinsky, PhD
OncoTherapy Network: First, what is the biology of BRCA-mutated ovarian cancer? Are there clinical differences between ovarian cancers with BRCA somatic versus germline mutations?
Dr. Swisher: That’s a good question. So, the BRCA-mutated ovarian cancers have deficiencies in homologous recombination, which is a very important DNA repair pathway. And so that makes those cancers specifically vulnerable to drugs that cause [DNA] damage that needs to be repaired by homologous recombination which includes platinum [chemotherapy] and drugs we’ve used previously. And now it creates a particular vulnerability to a new class of drugs called PARP inhibitors. In terms of
germline and somatic mutations at the outcomes level, we don’t see any difference between the two. They both cause the same sensitivity to the same therapeutics. The only difference on the clinical level is that germline mutations are from an inherited predisposition and therefore, have implications for family members whereas somatic mutations are random events that are occurring in the cancer and don’t have any implications for family members.
OncoTherapy Network: Okay. Can you talk about rucaparib? What is the drug and what does it target?
Dr. Swisher: Rucaparib is one of the PARP inhibitors and that is a class of drugs that inhibits the PARP enzyme and the PARP enzyme is important in DNA repair and actually a number of DNA repair pathways. So, cancers that have deficiencies in homologous recombination are specifically more sensitive to PARP inhibitors because they rely on alternate DNA repair strategies that the PARP enzyme is vital to.
OncoTherapy Network: What were the results of this portion of the phase II rucaparib ARIEL2 study that were presented at the meeting? Can you talk about some of the specifics?
Dr. Swisher: ARIEL2 demonstrated that rucaparib is highly active in cancers that have germline and somatic BRCA mutations in ovarian cancers that are recurrent, and it also showed that other ovarian cancers without BRCA mutations, that there is a subset that are also sensitive [to this drug]. And that we can look at various predictors to identify whether or not these cancers will be sensitive to PARP inhibitors, specifically, in ARIEL2, the first thing we evaluated was an LOH [loss of heterozygosity] test that looks at genomic alterations, allelic imbalances that can be downstream effect of homologous recombination deficiency. And if cancers have high LOH, but no BRCA mutation then they have a higher response rate than cancers that have low LOH, but no BRCA mutation. And of course the cancer cases with the BRCA mutations have the highest response rates of all.
OncoTherapy Network: You presented data on the state of the promoters of the BRCA1 gene as well as another recombination and DNA repair gene, RAD51C, and how these promoters influence patients’ responses to rucaparib. Can you tell us about those details?
Dr. Swisher: So, cancers sometimes have hypermethylation of the promoter region of tumor suppressor genes and that is an alternate form of downregulating the gene. So methylation can downregulate the gene similarly to a mutation that causes a defect in the gene in the cancer. About 15% of ovarian cancers have mutations in BRCA1 and it turns out that about 10% of the cancers now also have methylation of the gene and it's a different 10%, so a mutation and methylation never occur in the same cancer. The cancer seems to pick one pathway or the other to downregulate the gene. And having downregulation of BRCA1 or another gene in that same pathway, RAD51C, also creates the same sensitivity to rucaparib as a mutation in the gene does. And this is really a new finding in terms of we can now possibly use methylation as a predictor to identify patients who are likely to have a good response [to this drug].
OncoTherapy Network: And just lastly, are there follow-up studies that are now ongoing or planned in this patient population with rucaparib?
Dr. Swisher: Yes, definitely. I think there are two areas. One is that the ARIEL2 samples are really unique amongst all clinical trial samples right now in that they are the only group of cancers where pretreatment biopsies were done; the patients had measurable disease so we could see whether they were responding and they were treated with a single drug, a PARP inhibitor and not a combination of drugs. And that allows us to really look at those cancers and figure out what are the predictors, the alterations of the cancer that are making the cancer respond to a PARP inhibitor while other cancers are resistant. So, the LOH analysis that we presented, the methylation and mutation analyses that we presented, this is really the first wave. We plan to use these samples to dig more deeply into whether we can further improve the predictors, can we come up with a more refined set of predictors that will really help us use precision medicine to pick which patients are going to respond and which are not going to respond so we can bring that benefit to the patient.
And the second thing is the follow-up study. ARIEL 3 is a phase III, randomized, placebo-controlled study—it’s a registration study where rucaparib is being used as maintenance therapy following response to platinum in patients with recurrent ovarian cancer. So, in that study, we will apply what we learned from ARIEL2 in terms of predictors. We refined the LOH cut-off from ARIEL2 to maximize our ability to separate responders from nonresponders and then we are going to apply that to the patients in ARIEL3 and see if that would be a good way to select patients for maintenance therapy.
OncoTherapy Network: Thank you so much for joining us today, Dr. Swisher.
Dr. Swisher: Thank you for having me.