Reference Detail

Ref Type Journal Article
PMID (28242752)
Authors de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, Kaye S, Sachdev J, Heymach J, Smith DC, Henshaw JW, Herriott A, Patterson M, Curtin NJ, Byers LA, Wainberg ZA
Title Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers.
Journal Cancer discovery
Vol 7
Issue 6
Date 2017 Jun
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Talazoparib Talazoparib 29 21
Drug Name Trade Name Synonyms Drug Classes Drug Description
Talazoparib Talzenna BMN673 PARP Inhibitor (Pan) 17 Talzenna (talazoparib) is an inhibitor of PARP1 and PARP2, which prevents the DNA repair of single strand DNA breaks, thus causing the accumulation of DNA strand breaks, genomic instability and apoptosis, and leads to lethality in homologous recombination repair deficient cells (PMID: 28242752). Talzenna (talazoparib) is FDA approved for use in patients with ERBB2 (HER2)-negative breast cancer harboring deleterious or suspected deleterious germline BRCA mutations (FDA.gov).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRCA2 mutant pancreatic cancer sensitive Talazoparib Phase I Actionable In a Phase I trial, Talazoparib (BMN-673) treatment in pancreatic cancer patients resulted in four patients with a clinical benefit including a partial response in one patient harboring a BRCA2 mutation (PMID: 28242752). 28242752
BRCA1 mutant ovarian cancer predicted - sensitive Talazoparib Phase I Actionable In a Phase I trial, Talazoparib (BMN-673) treatment in ovarian cancer patients harboring germline deleterious BRCA1/2 mutations resulted in an objective response rate of 48%, including one complete response, and a clinical benefit rate of 76% at 24 weeks (PMID: 28242752). 28242752
BRCA1 mutant breast cancer predicted - sensitive Talazoparib Phase I Actionable In a Phase I trial, Talazoparib (BMN-673) treatment in breast cancer patients harboring germline deleterious BRCA1/2 mutations resulted in an objective response rate of 50% (7/14) including one patient with a complete response and six patients with a partial response and a median progression free survival of 34.6 weeks (PMID: 28242752). 28242752
BRCA2 mutant triple-receptor negative breast cancer decreased response Talazoparib Phase I Actionable In a Phase I trial, Talazoparib (BMN-673) treatment in patients with triple-receptor negative breast cancer carrying a BRCA1 and/or BRCA2 mutation resulted in a lower clinical benefit rate (56% vs 89%) compared to treatment in non-triple-receptor negative breast cancer patients carrying a BRCA1/2 mutation (PMID: 28242752). 28242752
BRCA2 mutant ovarian cancer predicted - sensitive Talazoparib Phase I Actionable In a Phase I trial, Talazoparib (BMN-673) treatment in ovarian cancer patients harboring germline deleterious BRCA1/2 mutations resulted in an objective response rate of 48%, including one complete response, and a clinical benefit rate of 76% at 24 weeks (PMID: 28242752). 28242752
BRCA2 mutant breast cancer predicted - sensitive Talazoparib Phase I Actionable In a Phase I trial, Talazoparib (BMN673) treatment in breast cancer patients harboring germline deleterious BRCA1/2 mutations resulted in an objective response rate of 50% (7/14), including one patient with a complete response and six patients with a partial response, and resulted in a median progression free survival of 34.6 weeks (PMID: 28242752). 28242752
BRCA1 mutant triple-receptor negative breast cancer decreased response Talazoparib Phase I Actionable In a Phase I trial, Talazoparib (BMN-673) treatment in patients with triple-receptor negative breast cancer carrying a BRCA1 and/or BRCA2 mutation resulted in a lower clinical benefit rate (56% vs 89%) compared to treatment in non-triple-receptor negative breast cancer patients carrying a BRCA1/2 mutation (PMID: 28242752). 28242752
Unknown unknown Ewing sarcoma not applicable Talazoparib Phase I Actionable In a Phase I trial, Talazoparib (BMN-673) treatment in patients with Ewing sarcoma did not result in any objective responses, however, resulted in a clinical benefit rate of 23% (PMID: 28242752). 28242752
Unknown unknown lung small cell carcinoma not applicable Talazoparib Phase I Actionable In a Phase I trial, Talazoparib (BMN-673) treatment in patients with lung small cell carcinoma resulted in an objective response rate of 9% (2/23), including two patients with a partial response, and four patients with stable disease for at least 16 weeks (PMID: 28242752). 28242752