PARP Inhibitors Advance in Ovarian Cancer

Michael Birrer, MD, PhD

With olaparib approved and niraparib and rucaparib advancing through clinical development, PARP inhibition is becoming a valuable option in the ovarian cancer armamentarium.

In a discussion at the 2016 CFS,^™Michael Birrer, MD, PhD, director of Medical Gynecologic Oncology at Massachusetts General Hospital, said he anticipates that the FDA will approve niraparib and rucaparib in ovarian cancer in the next 6 months to a year.

The focus now, according to Birrer, is on optimizing the 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].”

Olaparib was approved in 2014 for women withBRCA-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 withBRCA-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 withBRCA-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 germlineBRCA-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.