Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

Abstract

Genetic complexity and DNA damage repair defects are common in different cancer types and can induce tumor-specific vulnerabilities. Poly(ADP-ribose) polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality and have emerged as promising anticancer therapies, especially in tumors harboring deleterious germline or somatic breast cancer susceptibility gene (BRCA ) mutations. However, the utility of PARP inhibitors could be expanded beyond germline BRCA1/2 mutated cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. US Food and Drug Administration (FDA)-approved PARP inhibitors include olaparib, rucaparib, and niraparib, while veliparib is in the late stage of clinical development. Talazoparib inhibits PARP catalytic activity, trapping PARP1/2 on damaged DNA, and it has been approved by the US FDA for the treatment of metastatic germline BRCA1/2 mutated breast cancers in October 2018. The talazoparib side effect profile more closely resembles traditional chemotherapeutics rather than other clinically approved PARP inhibitors. In this review, we discuss the scientific evidence that has emerged from both experimental and clinical studies in the development of talazoparib. Future directions will include optimizing combination therapy with chemotherapy, immunotherapies and targeted therapies, and in developing and validating biomarkers for patient selection and stratification, particularly in malignancies with 'BRCAness'. Key PointsPARP inhibitors are a family of enzymes that play a role in DNA repair.

Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells

“…7Di-ii). However, this combination was less selective for the ATM-KO cells, consistent with reports of enhanced systemic toxicity with talazoparib treatment [43]. Notably, at doses with similar single-agent efficacy, and therefore likely trapping ability, the impacts of combining AZD6738 with talazoparib versus olaparib on growth inhibition are equivalent in ATM-KO cells ( Supplementary Fig.…”

DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage

“…The accumulation of DSBs during S-phase by PARP inhibitor treatment, in combination with impaired HR, results in a potent anticancer activity while healthy cells are not affected. Promising clinical results demonstrating this concept ultimately led to the approval of four different PARP inhibitors (olaparib, niraparib, rucaparib and talazoparib) for treatment of breast, ovarian and pancreatic cancer [109].…”

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

“…Since 2014, three PARPi have been approved by FDA and EMA for use in OvC-olaparib, rucaparib, and niraparib [144]. Another PARPi-veliparib and talazoparib-are showing promising clinical results and facing FDA and EMA approvals in the treatment of OvC shortly [193][194][195].…”

“…Olaparib-approved by FDA and EMA for use in OvC therapy [144] Rucaparib-approved by FDA and EMA for use in OvC therapy [144] Niraparib-approved by FDA and EMA for use in OvC therapy [144] Veliparib-advanced clinical trials in combination with carboplatin and paclitaxel. Veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer PFS than carboplatin plus paclitaxel induction therapy alone [193,194] Talazoparib-ongoing advanced clinical trials [194,195] Cell cycle checkpoints…”