A Comprehensive Monograph on Talazoparib (Talzenna®): From Molecular Mechanism to Clinical Practice

I. Executive Summary

Talazoparib, marketed under the brand name Talzenna®, is a highly potent, orally bioavailable small molecule inhibitor of the poly (ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2. Its therapeutic effect is rooted in the principle of synthetic lethality, a mechanism particularly effective in tumors harboring deficiencies in the homologous recombination repair (HRR) pathway, most notably those with germline mutations in the BRCA1 or BRCA2 genes. Talazoparib is distinguished from other agents in its class by a dual mechanism of action that combines catalytic inhibition of the PARP enzyme with exceptionally potent "PARP trapping," a process that sequesters the enzyme on DNA, forming a cytotoxic complex that is profoundly disruptive to DNA replication. This high trapping efficiency is believed to be a key driver of its clinical activity.

Talazoparib has secured regulatory approval for two primary indications based on robust clinical evidence from pivotal Phase 3 trials. First, as a monotherapy for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative locally advanced or metastatic breast cancer, an approval supported by the EMBRACA trial. This study demonstrated a significant improvement in progression-free survival (PFS) for Talazoparib compared to standard chemotherapy. Second, it is approved in combination with the androgen receptor inhibitor enzalutamide for the treatment of adult patients with HRR gene-mutated metastatic castration-resistant prostate cancer (mCRPC). This indication was established by the TALAPRO-2 trial, which showed a marked improvement in radiographic progression-free survival (rPFS) and a clinically meaningful benefit in overall survival (OS).