Durvalumab Plus Olaparib or Cediranib Active in Gynecologic Cancers

A phase I study combining the programmed death ligand 1 (PD-L1) inhibitor durvalumab with either olaparib or cediranib found that the combinations are reasonably well tolerated and active in recurrent women’s cancers.

“High PD-L1 expression in human ovarian cancer is shown to correlate with a poor prognosis,” wrote study authors led by Jung-Min Lee, MD, of the National Cancer Institute in Bethesda, Maryland. Single-agent immunotherapy has shown limited activity, however, and other data suggest that combining programmed death 1 (PD-1)/PD-L1 therapy with ADP-ribose polymerase inhibition or vascular endothelial growth factor (VEGF) receptor inhibition could improve responses.

The new study was a phase I dose escalation trial of durvalumab paired with olaparib or cediranib, with a goal of finding a recommended phase II dose for the combinations. It included 26 women with recurrent solid tumors; ovarian carcinoma was the most common tumor type, in 19 of 26 women (73%). The results were published online ahead of print in the Journal of Clinical Oncology.

The recommended phase II doses were determined to be durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or cediranib 20 mg, 5 days on/2 days off. The study did not find a dose-limiting toxicity with the olaparib combination. With cediranib, the intermittent schedule was chosen to account for recurrent grade 2 and non–dose-limiting grade 3 and 4 adverse events with a daily schedule; these included lymphopenia, diarrhea, abdominal pain, and others.

The most common treatment-emergent adverse events (TEAE) with olaparib was hematologic toxicity, which occurred at a greater frequency in combination with durvalumab than previously reported with olaparib monotherapy. All patients experienced at least one TEAE of any grade.

The durvalumab-olaparib combination yielded an objective response rate of 17% (two responses out of 12 patients). The authors noted that most patients did have some benefit, though, with a disease control rate of 83%. Of 12 cediranib patients assessed for response, six attained a partial response, and three had stable disease, for a 50% response rate and a 75% disease control rate. Responses were not correlated with PD-L1 expression.

“We demonstrated durvalumab plus olaparib and durvalumab plus intermittent cediranib are tolerable and clinically active combinations in women’s cancers,” the authors concluded, noting that identifying effective predictive biomarkers of response remains an important challenge. “The preliminary activity findings warrant the ongoing single-arm phase II expansions now open to accrual.”