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Expert Discusses Biomarkers for PARP Inhibitors in Ovarian Cancer

Allie Strickler @Alliejayes
Published: Monday, Feb 20, 2017

Dr. Elizabeth Swisher

Elizabeth Swisher, MD

The phase II ARIEL2 study assessed the ability of tumor genomic loss of heterozygosity (LOH), quantified with a next-generation sequencing assay, to predict response to the PARP inhibitor rucaparib (Rubraca) in patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma.

In December 2016, the FDA granted an accelerated approval to rucaparib as a treatment for patients with BRCA-positive advanced ovarian cancer who have received at least 2 prior lines of chemotherapy, based in part on data from the ARIEL2 trial.

The ARIEL2 findings showed that, in patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas who were treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type, LOH low carcinomas.

In an interview with OncLive, lead ARIEL2 author Elizabeth Swisher, MD, professor in Gynecologic Oncology and adjunct professor in Medical Genetics, University of Washington School of Medicine, discussed biomarkers for PARP inhibitors and the evolving role of these agents in ovarian cancer.

OncLive: What was the rationale for conducting this study?

Swisher: We wanted to test predictors of PARP inhibitor response, particularly in women who did not have germline BRCA mutations. It was pretty well accepted that women who had BRCA1/2 mutations and had cancer had good responses to PARP inhibitors, but we knew some women with ovarian cancer, who didn’t have germline mutations, responded, too. We wanted to figure out which patients those were. And when we looked at PARP inhibitor trials that had already been conducted, they hadn’t collected biopsies. So we finally decided to just put a trial together where we could try to answer that question.

So we capped the number of women who had known, inherited BRCA1/2 mutations, so that we would have enough women that didn’t have mutations, and we could answer our question of interest. If you just allow open enrollment, a lot of women with BRCA mutations then gravitate toward PARP inhibitor studies, and you get an overrepresentation of those patients. So we wanted them as a comparison group, but we wanted to limit that group and enroll a lot of women who didn’t have mutations, which hadn’t been as extensively studied before in PARP inhibitor trials.

Then we obtained pretreatment biopsies on everybody, and that allowed us to look at markers of interest that might predict PARP inhibitor sensitivity.

What were the most noteworthy findings that you’d like community oncologists to take away from the study?

Using an LOH predictor of HRD does differentiate women with ovarian cancer into women who are more and less likely to respond. That’s the first takeaway.

The second takeaway is that women with somatic or tumor mutations in BRCA1/2 respond just as well as women with germline mutations.

And the third finding, which is maybe a little unexpected in my mind, was that having a tumor with BRCA1 methylation, or RAD51C methylation, also correlated with patients who were going to respond to the PARP inhibitor, but that’s not a clinically available test right now, so that’s something that, going forward, we’ll have to determine if we need to incorporate it into a testing strategy.

Why was that last finding unexpected to you?

It was unexpected to me because our group, and also TCGA, have shown that there’s about an equal number of ovarian cancers that have BRCA1 methylation compared with mutation, and yet, when you look at survival, women with BRCA1 mutations have a better survival than women with BRCA1 methylation. That’s probably related to the DNA repair defects, and inability to repair chemotherapy damage as well, for women with BRCA1 mutations.

So, since BRCA1 methylated ovarian cancers didn’t have the same advantage in overall survival, I predicted that methylation didn’t have as big of a functional impact as mutation, and therefore, they would not be sensitive to PARP inhibitors. However, that turned out not to be the case.

Also of interest in the methylation story was, because we got these pretreatment biopsies, we also obtained older tissues and archival samples, usually from the time of diagnosis. In one-third of the cases that were methylated at the time of diagnosis, they were not methylated any longer when we did our pretreatment biopsy. So, it seems to be something that the tumor can kind of downregulate during the course of exposure to chemotherapy. Therefore, if you were going to use methylation as a predictor, you would really need to do it based on a pretreatment biopsy and not an older sample.

Are there any next steps planned following these results?

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