Expert Highlights PARP Inhibitor Advancements in Ovarian Cancer, Points to Future Combos

David O'Malley, MD

The role of PARP inhibitors in the treatment landscape of ovarian cancer continues to advance the field, but in the maintenance setting, there is a debate over which agent is the most optimal.

The recent additions of olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca) in the ovarian cancer paradigm have led to more practice-changing treatment options for patients who progress on earlier lines of therapy. Olaparib and niraparib have an additional FDA indication in the maintenance setting, with rucaparib showing efficacy in this setting, as well. Rucaparib has been submitted to the FDA for approval in the maintenance setting and was granted a priority review designation in December 2017, explains David O'Malley, MD.

In the randomized phase III ARIEL3 study, rucaparib increased progression-free survival (PFS) in the maintenance setting for patients with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The median PFS with rucaparib was 16.6 months (95% CI, 13.4-22.9) compared with 5.4 months for placebo (95% CI, 3.4-6.7). Similar PFS benefits were observed in patients with BRCA wild-type tumors and those with homologous recombination deficiency (HRD) or low to high loss of heterozygosity.

For patients with germline or somatic BRCA mutations, there was a 77% reduction in the risk of progression or death with rucaparib versus placebo (HR, 0.23; 95% CI, 0.16-0.34; P <.0001). In the HRD group, risk reduction with rucaparib was 68% (HR, 0.32; P <.0001).

OncLive: Please provide an overview of your presentation at the meeting. You were part of a debate on maintenance therapy, correct?

Can you discuss the current role of PARP inhibitors and where you see them headed in the future?

In an interview with OncLive at the 2018 Society of Gynecologic Oncology Annual Winter Meeting, O'Malley, a professor in the Department of Obstetrics and Gynecology at The Ohio State University Comprehensive Cancer Center, discussed the excitement surrounding PARP inhibitors for patients with ovarian cancer.O'Malley: The debate I was involved in is looking at maintenance therapy in patients with platinum-sensitive ovarian cancer. We each took one of the agents, which had been tested in clinical trials. We have rucaparib, olaparib, and niraparib. I was given the responsibility of discussing rucaparib.The current role of PARP inhibitors are in a couple of different patient populations. One of those populations are BRCA mutations, either in the germline or in the somatic of the tumor. Both of those have indications. Olaparib has an indication in 3 or more prior lines of therapy in those with germline mutations, while rucaparib has indications of more than 2 lines of prior therapy in both somatic and germline.

How do you determine which agent to give a patient? Are there any biomarkers?

Can you discuss the combination of niraparib and bevacizumab (Avastin)?

There are now 2 drugs that are approved in the platinum-sensitive maintenance setting. Those are olaparib and niraparib. Rucaparib has been submitted to the FDA, but we have not yet heard if it will receive approval. In this population of patients, many of the trials concentrated on BRCA mutations as well as HRD status. Both current drugs are approved in all-comers, no matter what their somatic or germline status is.Trying to determine which drug to give was the format of the debate. Currently, there are 2 drugs that are approved and we think there will be a third drug. Looking at those drugs and trying to figure out what to use is not yet possible. I do not think those drugs will ever be compared. They all seem to have similar efficacy, and a lot of this comes down to balancing toxicity, dosing schedules, convenience, and other factors.Right now, we can say that there are multiple trials ongoing at the phase III level, both in upfront first-line therapy, as well as in the recurrent and platinum-sensitive settings. These drugs are difficult to combine with other classic cytotoxic therapies, especially the alkylating agents, such as platinum-based therapies.

Can you discuss olaparib and durvalumab (Imfinzi) in combination?

Overall, how are PARP inhibitors tolerated?

When we are looking at combining these drugs, we are looking at other biologic therapies. They seem to be much better tolerated in the combination. We have seen some interesting results. For example, there was a phase III trial investigating the combination of cediranib and olaparib. That was the NRG-GYN 005 trial. Yet, we do not have the results on this and we are hoping to enroll patients in those trials. Since there are so many clinical trials out there, we hope to have any eligible patient treated on a clinical trial.PARP inhibitors are being looked at in multiple levels to include antivascular, checkpoint inhibitors, and all 3 together. There are currently trials that are being designed. We have approximately 14 clinical trials, which are utilizing PARP inhibitors in the upfront and recurrent settings in the United States and worldwide. We are considering every possible conceivable combination, mostly in the maintenance phase, determining how the checkpoint inhibitors are placed, as well as the antivascular therapies in the treatment phase.The toxicity is somewhat of a challenging question. When you are taking agents daily, particularly oral agents, patients find that very convenient. The problem of taking the agent is you have therapy every day. We have looked at adverse events such as fatigue, gastrointestinal related, and hematologic related, which can limit the quality of life in patients. However, we have looked at patient-reported outcomes and if we can keep the disease from coming back in the maintenance phase in platinum-sensitive disease, those patients do better.

When you look at comparison treatment from placebo versus PARP inhibitors, there is not much difference when treating these patients. There are clearly side effects that we need to balance and we need to look at patient-reported outcomes as we move forward in trying to ascertain the best place to use these drugs. Overall, they are well tolerated but there are some side effects that can impact a patient's quality of life, specifically, the fatigue and gastrointestinal side effects.

Ledermann J, Oza AM, Lorusso D, et al. ARIEL3: a phase 3, randomised, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma (OC). Ann Oncol. 2017;28 (suppl_5) doi:10.1093/annonc/mdx440.034.

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