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

Abstract

ObjectivesPhase 1 trial to determine the safety and tolerability of everolimus and niraparib in patients with advanced ovarian and breast malignancies.ResultsFourteen 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.ConclusionsThe 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.

Case report: Response to everolimus in a patient with platinum resistant, high grade serous ovarian carcinoma with biallelic TSC2 inactivation

“…Furthermore, a phase 1 trial to determine the safety and tolerability of everolimus in combination with PARP inhibitor (PARPi) niraparib in patients with advanced ovarian or breast cancer was previously reported. This study demonstrated that the combination of everolimus and niraparib was associated with significant toxicity, even at lower doses of both agents, and was therefore not feasible; no TSC2 mutations were identified in any of the patients in that study ( 15 ).…”