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

• Published in: Clinical cancer research Vol. 29; no. 1; pp. 40 - 49
• Main Authors: Wainberg, Zev A, Singh, Arun S, Konecny, Gottfried E, McCann, Kelly E, Hecht, J Randolph, Goldman, Jonathan, Chmielowski, Bartosz, Finn, Richard S, O'Brien, Neil, Von Euw, Erika, Price, Megan M, Martinez, Diego, Yonemoto, Lisa, Brennan, Meghan, Glaspy, John A, Slamon, Dennis J
• Format: Journal Article
• Language: English
• Published: United States 04.01.2023
• Subjects: Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Female; Humans; Irinotecan - administration & dosage; Neoplasms - drug therapy; Temozolomide - administration & dosage
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-22-1553

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. 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 toxicities (DLT), and maximum tolerated dose (MTD). Of 40 patients enrolled, 18 (mean: 7 prior therapies) 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 interruption 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 pharmacokinetic 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. 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. Randomized trials of talazoparib with or without low-dose chemotherapy are ongoing in small cell lung cancer and ovarian cancer.