Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers

Abstract

Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation–associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day. Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation–associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620–9. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539

Unravelling the biology of SCLC: implications for therapy

“…The results of initial in vitro studies indicated that SCLC cell lines are sensitive to PARP inhibitors, and provided preclinical validation that PARP inhibition enhances the anticancer activity of chemotherapy (and perhaps other DNA-damaging therapies) by downregulating key DNA-repair mechanisms 76 . These preclinical data supported the inclusion of a cohort of patients with SCLC in a phase I study of monotherapy with the PARP inhibitor talazoparib; the reported ORR was 9% and the clinical benefit rate at ≥16 weeks was 26% 81 . Indeed, clinical trials of a number of PARP inhibitors, in a range of treatment settings, are ongoing in patients with SCLC (TABLE 1).…”

Targeting DNA damage in SCLC

“…In a subsequent expansion cohort a clinical benefit rate (partial response (PR) + stable disease (SD) > 6 weeks) of 26% (6/23) was demonstrated for talazoparib monotherapy among patients with platinum sensitive ED SCLC. Talazoparib was well tolerated with 4% grade III-IV toxicities, most commonly haematological suppression [59].…”

PARP inhibitors: Clinical utility and possibilities of overcoming resistance

“…A recent phase I dose escalation trial in several tumor types, including ovarian, breast, prostate, small cell lung, found that talazoparib as a single agent had a significant clinical benefit in all tumor types. In ovarian, the maximum tolerated dose (1 mg/day) resulted in a clinical benefit rate of 76% in BRCA-mutant cancers [27]. Reported toxicities include alopecia, neutropenia, thromobocytopenia, anemia, fatigue, and nausea [27].…”

“…In ovarian, the maximum tolerated dose (1 mg/day) resulted in a clinical benefit rate of 76% in BRCA-mutant cancers [27]. Reported toxicities include alopecia, neutropenia, thromobocytopenia, anemia, fatigue, and nausea [27]. Based on clinicaltrials.gov, there are currently 12 trials actively recruiting patients that are utilizing talazoparib as a single agent or in combination (Table 2).…”