An all-oral combination of the investigational agents olaparib and cediranib nearly doubled progression-free survival in platinum-sensitive recurrent ovarian cancer in a National Cancer Institute (NCI)-sponsored randomized phase II trial reported at the 2014 ASCO Annual Meeting.¹ The toxicity profile of the combination was acceptable.

“This is the first study to explore the activity of the combination of a PARP inhibitor and antiangiogenesis drug in ovarian cancer, and we found that the combination is more active than olaparib alone. The progression-free survival compares favorably with standard-of-care chemotherapy. And we saw activity in both carriers and noncarriers of BRCA [mutations],” said lead investigator Joyce F. Liu, MD, MPH, a medical oncologist at Dana-Farber Cancer Center, Boston.

Still Investigational

“This combination is not yet ready for clinical practice, as neither of these drugs is currently [U.S. Food and Drug Administration]-approved for ovarian or for any other cancer. We also need additional clinical studies to confirm the findings and see how this combination compares to standard treatment,” Dr. Liu said.

Olaparib is an oral PARP inhibitor that blocks DNA repair, and cediranib is an oral angiogenesis inhibitor that blocks vascular endothelial growth factor (VEGF) receptor. Clinical trials were mounted based on preclinical evidence of synergy in ovarian cancer between PARP inhibitors and antiangiogenesis drugs, Dr. Liu explained. This is the first time this combination has been explored in a clinical trial, she added.

The randomized, open-label phase II study was conducted from October 2011 to June 2013 in 90 patients with platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer treated at nine different cancer centers. All patients enrolled in the trial had experienced disease recurrence at least 6 months after their last platinum-based therapy. They had high-grade serous, endometrioid, or other histologic subtypes with known germline BRCA mutation. Median age was 58.

The combination of olaparib plus cediranib significantly improved progression-free survival vs olaparib alone. Median progression-free survival was 17.7 months for the combination vs 9 months for olaparib alone, representing an 8.7-month improvement (P = .005). To put this into context, studies with standard chemotherapy in platinum-sensitive patients show progression-free survival between 8 and 13 months.

Stratified by BRCA Status

Dr. Liu said that previous studies have suggested that women with BRCA mutations may be more sensitive to PARP inhibition, so they stratified patients according to BRCA status. In patients with BRCA mutations, a trend was observed toward increased activity for the combination, but the progression-free survival difference was much more robust for the combination in noncarriers and patients with unknown BRCA status.

Median progression-free survival in BRCA mutation carriers was 19.4 months for the combination vs 16.5 months for olaparib alone (nonsignificant); in noncarriers or those of unknown BRCA status, median progression-free survival was 16.7 months for the combination vs 5.7 months for olaparib alone (P = .008).

“This was a post hoc exploratory analysis of a phase II trial showing the difference in activity was most pronounced in non-BRCA mutation carriers. This was an unexpected finding and needs to be confirmed,” she noted.

Toxicity was higher with the combination. The most common adverse events related to the combination were hypertension, diarrhea, and fatigue. Dr. Liu said these toxicities were manageable with aggressive symptom management and dose reductions.

Further Study

“Results support additional clinical evaluation of this combination in ovarian cancer,” she stated. Two phase III trials are being planned for platinum-sensitive and platinum-resistant ovarian cancer by one of NCI’s new National Cancer Trial Network Groups (NRG Oncology Group), the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group. ■

Disclosure: The study authors reported no potential conflicts of interest.

Reference

1. Liu J, Barry WT, Birrer M, et al: A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. ASCO Annual Meeting. Abstract LBA5500. Presented May 31, 2014.