Abstract
SummaryBackground: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies. Methods: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib. Results: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (Cmax and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily. Conclusions: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).
Highlights
Genomic instability is a common feature of many types of solid tumors [1], and is widely acknowledged as a key driver of carcinogenesis and acquired drug resistance [2]
Findings from the phase 3 EMBRACA trial demonstrated that treatment with talazoparib 1 mg QD significantly improved progression-free survival (hazard ratio [HR] 0.54 [95% confidence interval (CI)] 0.41 to 0.71; P < 0.001) and patient-reported outcomes compared with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer and a germline BRCA1/2 mutation [19, 20]
This is an ongoing open-label, non-randomized, phase 1 study of the poly(ADP-ribose) polymerase (PARP) inhibitor, talazoparib, in Japanese patients with locally advanced or metastatic solid tumors regardless of mutations in DNA damage repair (DDR)-related genes who are resistant to standard therapies or for whom no standard therapy is available (ClinicalTrials.gov NCT03343054)
Summary
Genomic instability is a common feature of many types of solid tumors [1], and is widely acknowledged as a key driver of carcinogenesis and acquired drug resistance [2]. The halfmaximal inhibitory concentration of talazoparib (4–11 nM) is similar to that of other PARP inhibitors currently under investigation or approved in Japan [12, 13], talazoparib has a PARP-trapping potential that is approximately 100 times greater [12]. Talazoparib (oral 1 mg, once daily [QD]) is approved in the US, EU, and other countries as monotherapy for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with a germline BRCA1/2 mutation [15, 16], and is under investigation in other tumor types [17, 18]. Findings from the phase 3 EMBRACA trial demonstrated that treatment with talazoparib 1 mg QD significantly improved progression-free survival (hazard ratio [HR] 0.54 [95% confidence interval (CI)] 0.41 to 0.71; P < 0.001) and patient-reported outcomes compared with chemotherapy in patients with HER2-negative advanced breast cancer and a germline BRCA1/2 mutation [19, 20]
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