Quest Continues to Extend Reach of Immunotherapy, PARP Inhibitors in Ovarian Cancer

Matthew Powell, MD

Single-agent immunotherapy has elicited minimal responses in patients with ovarian cancer, but the preclinical rationale for combinations with chemotherapy, antivascular therapy, and PARP inhibitors is strong and worthy of further pursuit, said Matthew Powell, MD.

“There are now 4 large randomized trials that involve not only combinations of checkpoint inhibitors and chemotherapy, but also PARP inhibitors and/or antivascular agents, said Powell. “The [rationale] has been demonstrated in preclinical and animal models; now, we have real-life data showing that these combinations make sense.”

In addition, PARP inhibitors have demonstrated strong single-agent activity, both as later-line treatments and maintenance therapy—and frontline maintenance for select agents—in patients with BRCA1/2 mutations. The activity of these agents has also been noted in patients with homologous recombination deficiency (HRD) and wild-type tumors, added Powell.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer and Soft Tissue Sarcoma, Powell, associate professor, Obstetrics and Gynecology, and chief, Division of Gynecologic Oncology, Washington University School of Medicine in St. Louis, discussed the trials that are generating excitement for combination immunotherapy as well as the impact of PARP inhibitors in the treatment of patients with ovarian cancer.

OncLive: Could you discuss the enthusiasm for immunotherapy in advanced ovarian cancer?

Powell: Initially, we had a lot of excitement for immunotherapy. Across oncology, checkpoint inhibitors were the latest and greatest thing. Unfortunately, in ovarian cancer, single-agent immunotherapy has been disappointing, with response rates around 9% to 10%. These responses have not been durable either. Microsatellite instability—high status, which we know is a marker of response for patients receiving checkpoint inhibitors, is rare in ovarian cancer. We don't have a biomarker signal that's driving things yet.

However, we do know that combination therapy looks quite exciting. Combinations with PARP inhibitors and antiangiogenic agents seem to have a lot of promise. These combinations look good, and right now we’re combining them with chemotherapy and moving them to the upfront setting.

Could you discuss the preclinical rationale for these combinations?

The NSGO-AVANOVA2/ENGOT-OV24 study, which was presented at the 2019 ASCO Annual Meeting and looked at niraparib (Zejula) versus niraparib plus bevacizumab (Avastin), showed an exciting doubling in progression-free survival (PFS). This is a nonchemotherapy regimen that was used in platinum-sensitive ovarian cancer. These data were quite impressive and almost unexpected.

We know PARP inhibitors can impede the cancer cell's ability to repair itself. When there's an inability to repair itself, there are more neoantigens that are created. These neoantigens are, hopefully, what's allowing the immune system to interact with the cancer. When we use checkpoint inhibition, we’re giving the immune system permission to attack the cancer and there we can see increased benefit.

How else could we move away from chemotherapy?

To expand on the combinations between antivascular therapy and PARP inhibitors, we saw similar results from the initial study of olaparib (Lynparza) and cediranib in patients with germline mutations. The combination seemed to have much more of a benefit in patients who had wild-type tumors; these patients didn’t have a BRCA mutation. That was really exciting to see. [These strategies] are designed with the hope of prolonging survival on maintenance strategies that have less toxicity and aren't leading to damaged bone marrow, hair loss, and all the other adverse events (AEs) there are with standard chemotherapy.

How are PARP inhibitors impacting the landscape?

We know that at least half of high-grade ovarian cancers have a deficiency in part of the repair process, which we call HRD. Capitalizing on that deficiency is where PARP inhibitors come in. It has been very exciting to move PARP inhibitors up from fourth- and fifth-line therapy to earlier on in the disease course. Now we have upfront data from the SOLO-1 study showing a striking benefit when olaparib is given as maintenance therapy after carboplatin and paclitaxel in patients with a germline or somatic BRCA1/2 mutation. That has really enhanced our enthusiasm for using PARP inhibition in different [settings].

There are also data behind olaparib, rucaparib (Rubraca), and niraparib. The 2 olaparib trials, ARIEL3, and the NOVA studies, all looked [at patients with platinum-sensitive recurrence] and showed very nice hazard ratios in the 0.2 to 0.3 range for patients with a germline or somatic mutation. There is a little less activity if patients do not have HRD, but it’s still there—even if patients had wild-type cancers.

Regarding the AEs of these drugs, they are generally well tolerated. There are strategies for minimizing some of the AEs with dose holds and occasionally dose reductions to try to allow for patients to be on these medications for a long time.

How do you differentiate between available PARP inhibitors?

It's really difficult; they are all about the same in terms of efficacy. There were differences in the trials, so it's hard to do cross-trial comparisons. We don't have any head-to-head trials. All of these trials were done with a placebo control. Therefore, we use their toxicity profiles to help guide us. There are slight differences among the drugs as far as how they affect platelets and their dosing schedule. There is one PARP inhibitor that is given once a day, whereas the other 2 are given twice a day. Some have a little bit more of an influence on elevating creatinine. These factors may drive our choices, but there's no clear and convincing winner. We individualize them to the patient.

What are the important data to be aware of regarding PARP inhibitors?

We looked at the differences in PFS [with these inhibitors]. The hazard ratio, in a patient with a BRCA1/2 mutation, is around 0.3, which translates to a 70% reduction in the risk of recurrence. Patients with HRD have about a 60% reduction or 50% reduction in the risk of recurrence [with these agents]. BRCA1/2 wild-type patients have a benefit, but it's a little more modest with a hazard ratio of around 0.6.

It’s clear that we have a much better understanding of the biology of ovarian cancer. We also understand that biomarkers are important. Some of those biomarkers are the grade of the cancer and the molecular subtype, whether it’s the gene mutation or the HRD signature.