Expert Discusses Biomarkers for PARP Inhibitors in Ovarian Cancer

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?

The next steps are already underway. We enrolled a second cohort in ARIEL2, that we called Part 2. Because the HRD predictor performed well in ARIEL1, we now have another issue that we want to address. These patients weren’t heavily pretreated; they had only 1 or 2 previous regimens of chemotherapy before. So in women who have had more treatments for their recurrent ovarian cancer, we wanted to see how they would respond to PARP inhibitors. So we enrolled another couple hundred patients in Part 2, and those data aren’t out yet, but I think it’s going to be interesting to see how this does in a more resistant patient population.

The LOH predictor was also refined in ARIEL2. We had decided where to set our cutoff based on TCGA data, which included patients treated with platinum, so we set a predetermined cutoff of how we would define our LOH biomarker for ARIEL2. The intent of ARIEL2 was always to refine that biomarker, because now, we have patients getting PARP inhibitors and, we wanted to see if we could make it a little better by fudging where we set the cutoff.

Then, that revised biomarker is being tested in the ARIEL3 population, which is the phase III maintenance trial after platinum, in which patients with recurrent ovarian cancer get platinum chemotherapy, and then they’re randomized 2:1 to maintenance rucaparib versus placebo, and then again, that LOH-HRD test is used, but it’s the one that’s been refined in ARIEL2. That’s a registration study, and we’ll be able to determine how that biomarker works within that population and whether or not it adds information about who to treat at that point.

Can you talk about the general role of PARP inhibitors, and what you see for these agents going forward in this space?

I think the role for PARP inhibitors is very exciting in ovarian cancer. Of all tumors, it may be ovarian cancer for which they’re almost best designed, because ovarian cancer has a very high rate of DNA repair deficiency, more than many other solid tumors. They’re kind of cut out for ovarian cancer.

Going forward, we’re going to increasingly use PARP inhibitors earlier in the course of treatment, as they’re not as effective later on. They should be used upfront, or at least at first recurrence.

We’re also going to be increasingly combining PARP inhibitors with other biologic drugs, other chemotherapy agents, or even immunotherapy agents. There’s a trial with a combination of a PARP inhibitor and PD-1 inhibitor, and I think those types of combinations, where we can harness DNA repair and immunotherapy together, are pretty exciting.

Combinations may also extend who is eligible for a PARP inhibitor, because you can imagine a combination where a cancer that wouldn’t respond to a PARP inhibitor alone, but the combination sensitizes the cancer to the PARP inhibitor by creating some DNA repair alterations that then sensitize the cancer to the PARP inhibitor. So we may be able to expand the number of patients who can benefit from PARP inhibitors with strategic combinations.

What impact has the FDA approval of the PARP inhibitor rucaparib had on this treatment landscape?

Olaparib (Lynparza) had been approved for just germline mutation carriers who had recurrent ovarian cancer—and it was used further down in the treatment; patients had to have failed previous treatments before. For rucaparib, patients only had to have failed 2 previous treatments, and it included individuals with somatic mutations.

Ovarian cancer hasn’t been a cancer where we’ve had a lot of actionable mutations, where we’ve done a lot of tumor sequencing. That’s been common in melanoma, colon cancer, and lung cancer, where you sequence the tumor and use a targeted drug. But in ovarian cancer, we have few actionable mutations.

About 6% or so of ovarian cancers have somatic BRCA1/2 mutations, so those patients do just as well as germline mutation patients. So rucaparib was approved for somatic BRCA mutations, in addition to germline BRCA mutations. I think that’s created the first real incentive in the United States to sequence ovarian cancers for an actionable mutation for a targeted drug. It expands what we have available in the United States for PARP inhibitors, but I think in the bigger picture, it has created a buzz in the gynecologic oncology world. We have to start sequencing these cancers if we’re going to identify these somatic mutations, for which these patients have a good drug that’s approved. That will probably be a paradigm shift for us.

Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18: 75-87. Lancet Oncol. 2017;18(1):75-87. doi:10.1016/S1470-2045(16)30559-9.