Preclinical and Clinical Trial Results Using Talazoparib and Low-Dose Chemotherapy

Purpose: On the basis of preclinical data, we hypothesized that low doses of chemotherapy (10% of therapeutic doses) with full dose of a PARP inhibitor could have improved efficacy and tolerability. Patients and Methods: In this phase I dose-escalation study, patients with BRCA-normal advanced malignancies were assigned to either talazoparib/temozolomide or talazoparib/irinotecan. Talazoparib was dose-escalated from 500 mcg to 1 mg daily before dose escalation of temozolomide/irinotecan. The starting dose of temozolomide was 25 mg/m2/day orally on days 1 to 5 and irinotecan was 25 mg/m2/day intravenously on days 1 and 15. The primary objectives of this trial were safety and tolerability, dose-limiting were enrolled in talazoparib + temozolomide and 22 in talazoparib + irinotecan. DLTs were hematologic in both arms, but all hematologic adverse events resolved with either treatment inter-ruption and/or dose reductions of talazoparib. The MTDs were talazoparib 1 mg + temozolomide 37.5 mg/m2 and talazoparib 1 mg + irinotecan 37.5 mg/m2. There were four partial responses in the talazoparib + temozolomide arm and five in the talazoparib + irinotecan arm for a response rate of 23% (9/40). The pharmaco-kinetic profiles of talazoparib + temozolomide/irinotecan were similar to that of talazoparib monotherapy. Responses were seen independent of homologous recombination (HR) status and HR deficiency score. Conclusions: These results show that talazoparib with low-dose temozolomide or irinotecan is reasonably well tolerated and demonstrates clinical activity in a wide range of cancers. Random-ized trials of talazoparib with or without low-dose chemotherapy are ongoing in small cell lung cancer and ovarian cancer.

Automated summary

This study aimed to investigate the efficacy and tolerability of low-dose chemotherapy in combination with a PARP inhibitor. The results showed that talazoparib with low-dose temozolomide or irinotecan demonstrated clinical activity in various types of cancers. Randomized trials are currently ongoing to further evaluate the combination therapy in small cell lung cancer and ovarian cancer.