talazoparib

Overview

Talazoparib is a potent PARP1/PARP2 inhibitor with among the highest PARP-trapping activity of the PARPi class. It is FDA-approved for adult patients with deleterious or suspected deleterious germline BRCA1/2-mutated HER2-negative locally advanced or metastatic breast cancer. Like other PARPi, its mechanism exploits synthetic lethality with homologous-recombination (HR) deficiency. See also olaparib, rucaparib, niraparib, and veliparib for related class members.

Evidence in the corpus

• Talazoparib is named alongside olaparib, rucaparib, niraparib, and veliparib as a class member of PARP inhibitors whose efficacy in BRCA1/2-wild-type mCRPC may be extended by targeting the USP10-TRMT10A axis; high TRMT10A expression tracks with PARPi resistance across the class in prostate cancer cell lines PMID:28068672.

Resistance mechanisms

• High expression of TRMT10A (a BRCA1-recruitment scaffold phosphorylated by ATM at Ser28) is associated with higher olaparib IC50 in PCa cell lines, placing TRMT10A-mediated HR upregulation as a resistance mechanism applicable across the PARPi class including talazoparib; USP10 inhibition with spautin-1 degrades TRMT10A and restores PARPi sensitivity PMID:28068672.

Cancer types (linked)

• PRAD — mCRPC context for PARP inhibitor class discussion; TRMT10A/USP10 axis identified as resistance determinant.

Sources

• PMID:28068672 — Yang et al., TRMT10A/USP10 axis in mCRPC; talazoparib named as PARPi class member.

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