PARP Inhibition at the Forefront of Ovarian Cancer Treatment Paradigm

Michael Birrer, MD, PhD

PARP inhibition is quickly becoming a major element of the overall ovarian cancer treatment landscape, as several of these agents are continuing to advance through clinical development.

During a discussion at the 34th Annual Chemotherapy Foundation Symposium™, Michael Birrer, MD, PhD, director of Medical Gynecologic Oncology at Massachusetts General Hospital, said that he expects that the FDA will soon approve both niraparib and rucaparib, joining the recent approval of olaparib (Lynparza) in ovarian cancer. The primary focus now, says Birrer, is to optimize the clinical use of these treatments.

"We need to find the best patient population to treat, and we need to define whether we use these drugs in maintenance treatment, or early or late [in sequencing]," he said.

Olaparib was approved in 2014 for women with BRCA-positive advanced ovarian cancer following treatment with ≥3 prior lines of chemotherapy. The approval was based on a phase II study in which olaparib had an objective response rate (ORR) of 34% in 137 heavily pretreated patients with BRCA-positive ovarian cancer. The ongoing phase III SOLO trials are examining olaparib as maintenance therapy or an alternative to chemotherapy in patients with recurrent disease.

In August 2016, the FDA granted a priority review to rucaparib for patients with BRCA-positive advanced ovarian cancer who have received ≥2 prior lines of chemotherapy, based on data from 106 patients across 2 trials, including the ARIEL2 study. In a pooled analysis of data from the studies, the ORR was 54% with rucaparib. A final decision is scheduled by February 23, 2017.

An application was recently submitted to the FDA for niraparib as a maintenance treatment for women with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. The application is based on the phase III NOVA trial, in which niraparib reduced the risk of progression or death by 73% compared with placebo for patients with germline BRCA-positive, platinum-sensitive, recurrent ovarian cancer. The phase III PRIMA trial is examining niraparib as a frontline maintenance treatment in patients with advanced ovarian cancer and homologous recombination deficiency (HRD).

Expanding on HRD, a target for PARP inhibitors, Birrer said that HRD testing may increase the therapeutic opportunities for these agents. Researchers are evaluating HRD assays in many ongoing trials. “The optimal [HRD] assay is not yet defined. It’s evolving fast. We hope that it will be predictive of a PARP inhibitor clinical benefit,” said Birrer.

Summarizing the available data for olaparib, niraparib, and rucaparib, Birrer said, “They all inhibit PARP 1 and PARP 2. There are some slight differences in potency, but I’m not so sure that is clinically relevant. The most extensively studied has been olaparib, but there are no direct comparisons yet [among the agents].”

Birrer said combinations have become the focus for further enhancing the benefit of PARP inhibitors in ovarian cancer. A phase II trial examined olaparib in combination with the VEGF inhibitor cediranib in patients with platinum-sensitive recurrent ovarian, peritoneal, or fallopian tube cancer who have received at least 1 prior platinum based-regimen.

The median progression-free survival with the combination was 17.7 months compared with 9.0 months with olaparib alone (HR, 0.42; 95% CI, 0.23-0.76; P = .005). Birrer noted that there were some significant grade 2-4 toxicities in the combination arm, including hypertension (75%), diarrhea (69%), and fatigue (54%). Two ongoing phase III trials, NRG GY004 and NRG GY005, are further examining the combination in ovarian cancer.

Another PARP/VEGF combination being explored is niraparib and bevacizumab, which is being compared to monotherapy with either agent in the phase III AVANOVA trial. Birrer said the study is now open in Europe and will open in the United States soon.