Levine Weighs in on Complex PARP Inhibitor Landscape in Ovarian Cancer

Douglas A. Levine, MD

Douglas A. Levine, MD

The explosion of PARP inhibitors for the treatment of ovarian cancer continues to expand, offering additional therapeutic options for patients.

The PARP inhibitors rucaparib (Rubraca), olaparib (Lynparza), and niraparib (Zejula), have all achieved impressive results among patients with ovarian cancer. For example, a posthoc analysis of the phase III ENGOT-OV16/NOVA trial presented at the 2017 ASCO Annual Meeting showed that ovarian cancer patients with or without germlineBRCAmutations who had a partial response to previous platinum-based therapy had superior progression-free survival (PFS) after treatment with niraparib.

At the time of unblinding, 45% of patients in the niraparib group who were BRCA-positive had a PFS event versus 72% in the placebo group (HR, 0.24; 95% CI, 0.131-0.441). In the non—BRCA-positive cohort, 56% of patients had a PFS event versus 80% in the placebo group (HR, 0.35; 95% CI, 0.230-0.532).

Douglas Levine, MD, director of the Division of Gynecologic Oncology at Perlmutter Cancer Center, NYU Langone School of Medicine, says that researchers are now exploring PARP-inhibitor combinations, such as with checkpoint inhibitors, to increase clinical activity, particularly inBRCA-negative patients.

Levine sat down withTargeted Oncologyat ASCO to provide his insight on some of the recent data with PARP inhibitors in ovarian cancer, as well as his predictions for the field in the next several years.

TARGETED ONCOLOGY:What is your perspective on the posthoc analysis of niraparib in ovarian cancer?

Levine:The niraparib study showed that in patients who had a partial response, in addition to those who had a complete response, the outcomes are very similar. What that means is that if you have aBRCAmutation, you have a very long progression-free interval of PFS and, if you have homologous recombination deficiency, you also have a fairly good outcome with that drug. One thing that is buried in the data is that outcomes are much less successful when you do not have aBRCAmutation or do not have a homologous recombination defect.

TARGETED ONCOLOGY:Do you believe that these PARP inhibitors are game-changers for this field?

Levine:The PARP inhibitor landscape is getting more complex. It is wonderful that we have all of these great drugs and options for our patients, it is a real breakthrough. It’s an incredibly exciting time and it’s remarkable; however, it is complex and confusing. The real question is when to use the PARP inhibitors and for which types of patients. The label, the indication, and the insurance coverage will drive that to a greater or a lesser extent. One thing we have to think about is that some of the agents are indicated for patients who have a germline and/or somatic mutation, and niraparib has an indication for all comers, yet the effect is much less when you do not have a BRCA mutation or a homologous recombination defect.

Therefore, genetic testing will become very important because that may stratify when you want to use these agents. If you don’t have a mutation, you can only use niraparib in maintenance right now. Whereas if you have a mutation, you can delay that, let the patient be off treatment for a while, and then use the drug when they recur in the setting of a somatic or germline BRCA mutation.

TARGETED ONCOLOGY:Are there any novel combinations with these PARP inhibitors being explored?

Levine:The next step in the evolution of PARP inhibitors is figuring out how to combine them, particularly for the majority of patients who don’t have aBRCAmutation. Some of the most exciting concepts being reported [involve] immune-oncology—checkpoint inhibitors being combined with PARP inhibitors, and there are preclinical data that are impressive. It'll be very exciting to see how the ongoing trials come out with PARP inhibitors combined with various checkpoint inhibitors.

TARGETED ONCOLOGY:We saw long-term data of maintenance olaparib at the 2017 ASCO Annual Meeting. What are your thoughts on those findings?

Levine:The long-term outcomes of olaparib used in the maintenance setting basically confirm prior reports that olaparib is effective in theBRCA-mutation carriers and outcomes are improved. There was a recent study looking at health-related quality of life also showing that, when you control for toxicity in the maintenance setting, the outcomes are also beneficial.

TARGETED ONCOLOGY:What other data are particularly exciting in this space?

Levine:As reported at the 2017 ASCO Annual Meeting, ARIEL4 is a trial in progress. It is a confirmatory trial looking at rucaparib in the [relapsed] treatment setting and we expect it will confirm the ARIEL2 results.

There is also FOLR1 , which is a very exciting drug of folate receptor alpha molecule and folate receptors are expressed on 60% of ovarian cancers. This trial is ongoing and it is targeting women with platinum-resistant ovarian cancer. Due to the design and the expression of the folate receptor, it seems very promising, but time will tell.

TARGETED ONCOLOGY:Looking at some of the recent PARP inhibitor research, what does it indicate about the progress of the ovarian cancer field moving forward?

Levine:The field of ovarian cancer as it relates to PARP inhibition is dramatically changing and is very dynamic. What we are doing several years from now will be completely different than what we are doing now. We are moving PARP inhibitors earlier and earlier in treatment; someday, they may be a part of first-line treatment or first-line maintenance. It is definitely going to change over time. What we are doing today is different than what we will be doing in the future.

We will know how to apply the PARP inhibitors both toBRCAcarriers, and more importantly, how to apply them either alone or likely in combination for those women who do not have aBRCAmutation.

Reference:

Mirza RM, Monk B, Gil-Martin M, et al. Efficacy of niraparib on progression-free survival (PFS) in patients (pts) with recurrent ovarian cancer (OC) with partial response (PR) to the last platinum-based chemotherapy.J Clin Oncol.2017;35 (suppl; abstr 5517).