A phase 1 evaluation of the safety and tolerability of niraparib in combination with everolimus in advanced ovarian and breast cancers.

Objectives: Phase 1 trial to determine the safety and tolerability of everolimus and niraparib in patients with advanced ovarian and breast malignancies.

Results: Fourteen heavily pretreated patients were enrolled (12 high-grade serous ovarian cancer, 1 clear cell ovarian cancer, and 1 triple negative breast cancer). All patients were PARP naïve and received comprehensive genomic profiling prior to enrollment. Two DLTs were experienced in cohort 2 (niraparib 200 mg daily and everolimus 5 mg 3 days per week) with one patient experiencing prolonged thrombocytopenia and the other experiencing severe hypertension. Four additional patients were enrolled after dose de-escalation with one patient again experiencing severe hypertension leading to conclusion of the study. The most frequent grade 3 or greater adverse events were thrombocytopenia, hypertension, anemia, fatigue, neutropenia, and elevated alkaline phosphatase. Two patients had a PR and five patients had SD. ORR was 18% and the CBR was 45% in 11 evaluable patients. Median PFS was 6 months, and median OS is approximately 18 months with three patients still alive at the data cutoff.

Conclusions: The combination of everolimus and niraparib demonstrated significant toxicity at lower doses and is not feasible due to rapid onset and severe hypertension. This limitation possibly blunted the efficacy of the combination as PFS was modest, but OS was surprisingly robust due to three patients with ovarian cancer remaining alive with platinum refractory disease. Further investigation of multiagent blockade of the PI3K pathway combined with PARP is warranted.