PARP Inhibition: A Necessity of Treatment in Recurrent Ovarian Cancer

Debra Richardson, MD

PARP inhibitors have become an integral treatment strategy for women with BRCA-mutated high-grade serous ovarian and endometrioid cancer, as both a later-line therapy and as a maintenance therapy following platinum-based chemotherapy, said Debra Richardson, MD, FACOG, FACS.

“Many women who have platinum-sensitive recurrent ovarian cancer are not being offered maintenance therapy, but it’s clear that [this approach] improves progression-free survival and seems to help maintain quality of life (QoL),” said Richardson. “It's very important that we get the word out there for those women suffering from recurrent ovarian cancer.”

Given that all 3 PARP inhibitors—niraparib (Zejula), olaparib (Lynparza), and rucaparib (Rubraca)—have shown similar hazard ratios in women with platinum-sensitive disease, the decision of which to prescribe is often based on toxicity, dosing schedule, and provider coverage, said Richardson. Furthermore, BRCA status and platinum-sensitivity confer a greater likelihood of response to these agents.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer, Richardson, associate professor, Section of Gynecologic Oncology, Oklahoma TSET Phase I Program, Stephenson Cancer Center, Oklahoma University Medicine, discussed the current indications for PARP inhibitors in the recurrent setting and ongoing work being done to broaden their utility in the field.

OncLive: Could you discuss the utility of PARP inhibitors in the recurrent setting?

Richardson: There are 3 FDA-approved PARP inhibitors for the treatment of patients with recurrent ovarian cancer, and also for maintenance therapy. These agents include rucaparib, niraparib, and olaparib and have been shown to be beneficial in both patients with [germline and somatic] BRCA mutations as well as in those with wild-type disease in the maintenance setting. In the treatment setting, the indication is limited to patients with BRCA-mutated disease.

Are BRCA mutations and platinum sensitivity the best indicators of response to PARP inhibitors?

Those are the best [indicators]. By far, BRCA mutations, whether germline or somatic, seem to be equivalent [in terms of response to PARP inhibition]. All [of the pivotal] trials done were generally limited to patients with high-grade serous and high-grade endometrioid ovarian cancer. However, even patients who do not have a BRCA mutation or homologous recombination deficiency (HRD) can benefit from PARP inhibitors. This has been a little bit confounding.

Are there certain patient characteristics that would indicate response to one PARP inhibitor over another?

There are no differences between the PARP inhibitors that we know of. They've never been compared in a head-to-head trial. They all have similar hazard ratios.

Does the decision between PARP inhibitors come down to toxicity and dosing?

I would say it comes down to toxicity, dosing schedule, and potentially patient insurance and what will be most affordable for them.

Should HRD be considered a biomarker of response?

There is an FDA-approved companion diagnostic for rucaparib, which is FoundationFocus™ CDxBRCA, based on the ARIEL2 trial. However, in the maintenance setting, you don't need to use that information. Any patient with high-grade serous or endometrioid ovarian cancer who has a platinum-sensitive recurrence and had a complete response or partial response to their most recent platinum-based treatment [is eligible for PARP inhibition]. With regard to treatment, I usually limit these agents to my patients with a known BRCA mutation, whether germline or somatic, if they have not already had a PARP inhibitor.

Could you discuss ongoing work with biomarkers of response?

It's unclear why some patients who we wouldn’t expect to respond, do respond to PARP inhibitors. That being said, if we think about who was included in the trials, these are platinum-sensitive patients. Platinum-sensitivity itself may be a biomarker. Patients have high-grade serous and high-grade endometrioid disease, so there may be something more at play than just HRD.

With the read out of one frontline maintenance trial and more to come, will PARP inhibitors still play a role in the treatment setting?

I'm hoping to put my patients who have already been exposed to PARP inhibitors on trials. Are there things that can re-sensitize patients to PARP inhibitors? We need to know more about what leads to PARP resistance and whether we can identify that. This is where liquid biopsies may become more important—especially in a patient with a known BRCA mutation who doesn’t respond to treatment. Do we need to look for reversion mutations? Are there other mechanisms of resistance that have developed, and how do we identify those? Are there agents we can combine with PARP inhibitors to help overcome that resistance? Those are all unanswered questions.

What is the biggest challenge in the space, and what are the steps being taken to address it?

The fact that we cannot cure recurrent ovarian cancer [is a challenge]. I would love to find a cure. We want to try and help our patients live as long as possible with as good a QoL as we can provide. We want to turn ovarian cancer into a chronic disease and reduce toxicity while we do so.

If a patient recurs on frontline maintenance therapy with olaparib, what is your approach?

The patient would have to have a BRCA mutation and have had a platinum-sensitive recurrence. In that case, I would look for a clinical trial for them. If I didn't have one, I'd probably turn to platinum-based doublet chemotherapy with bevacizumab (Avastin) based on data from the OCEANS and GOG-213 trials.

Where does veliparib stand in development?

Veliparib is currently being evaluated in the phase III trial GOG-3005/Velia trial; data from that trial should be presented at the 2019 ESMO Congress. In the study, patients received veliparib with chemotherapy and veliparib maintenance. There was a small phase I/II trial with veliparib in recurrent ovarian cancer, but I'm not aware of veliparib being developed further in that space.

What research is most important to focus on moving forward?

If I had that answer, that would be the holy grail. Combination therapies [will be an important focus], it will potentially include immunotherapy with an antiangiogenic agent, or some combination of a PARP inhibitor with an antiangiogenic agent. Some combination of biologic agents and immunotherapy is probably the most promising approach that I'm aware of.