Findings from a phase II study suggest that the combination of the oral PARP inhibitor olaparib and the oral angiogenesis inhibitor cediranib is significantly more active against recurrent, platinum chemotherapy–sensitive ovarian cancer than olaparib alone.

Findings from a phase II study suggest that the combination of the oral PARP inhibitor olaparib and the oral angiogenesis inhibitor cediranib is significantly more active against recurrent, platinum chemotherapy–sensitive ovarian cancer than olaparib alone.

“The significant activity that we saw with the combination suggests that this could potentially be an effective alternative to standard chemotherapy,” said Joyce Liu, MD, MPH, the study's lead author and a medical oncologist at Dana-Farber Cancer Institute in Boston, MA. She presented the results on May 31 at the American Society of Clinical Oncology's annual meeting in Chicago, IL.

Even when chemotherapy is initially effective, Liu explained, ovarian tumors usually develop resistance to it. Consequently, researchers have been exploring alternate regimens using targeted drugs. Because preclinical studies showed that olaparib and cediranib each enhanced the activity of the other—and because a phase I study showed that the combination was well tolerated—Liu and her colleagues launched this study, the first to explore the synergy of a PARP inhibitor and an antiangiogenic agent in ovarian cancer.

The researchers enrolled 90 women with recurrent, platinum-sensitive, high-grade serous or BRCA mutation–related ovarian cancer, randomly assigning them to receive olaparib alone or olaparib plus cediranib. The women had not previously received PARP or angiogenesis inhibitors.

Response rates were markedly higher in the combination arm than in the olaparib-alone arm (80% compared with 48%). Five patients in the combination arm and two in the olaparib-alone arm experienced complete remission. Liu also reported that progression-free survival (PFS) was significantly longer in patients who received the combination compared with the single agent—17.7 months versus 9.0 months. Earlier trials of standard platinum-based chemotherapies have demonstrated PFS times of 8 to 13 months, Liu said.

In addition, Liu noted, “prior studies have suggested that women with BRCA mutations may have increased sensitivity to PARP inhibitors.” Indeed, BRCA mutation carriers who received the olaparib–cediranib combination had a median PFS of 19.4 months compared with 16.5 months in the olaparib-only group.

Surprisingly, the difference was even more marked among women without BRCA mutations and those whose mutation status was unknown: 16.5 months vs. 5.7 months. “That was unexpected, but it does need to be confirmed with further analysis,” remarked Liu. She noted that prior trials have suggested that PARP inhibitors are most effective in women with either platinum-sensitive disease or BRCA mutations.

Patients who received the combination experienced more side effects, particularly high blood pressure, fatigue, and diarrhea. However, side effects were tolerable with dose modifications and aggressive symptom management, Liu said.

“The degree of activity of the cediranib–olaparib combination supports additional clinical evaluation in ovarian cancer,” said Liu, and two phase III trials—one in platinum-sensitive and one in platinum-resistant disease—are being planned.