PARP inhibitors: clinical development, emerging differences, and the current therapeutic issues

Abstract

Following years in development, poly-adenosyl-ribose polymerase (PARP) inhibitors continue to advance the treatment of ovarian and breast cancers, particularly in patients with pathogenic BRCA mutations. Differences in clinical trial design have contributed to distinct indications for each of the PARP inhibitors. Toxicity patterns are also emerging that suggest agents differ in their normal tissue tolerance - beyond what might be expected by dose variations and/or exposure to prior treatment. PARP inhibitor resistance is an increasingly relevant issue as the drugs move to the forefront of advanced ovarian/breast cancer treatment, and is an active area of ongoing research. This review examines the PARP inhibitor clinical trials that have led to approved indications in ovarian and breast cancers, PARP inhibitor targets and pharmacological differences between the PARP inhibitors, emerging mechanisms of resistance, and key clinical questions for future development.

Keywords: BRCA; breast cancer; homologous recombination deficiency; ovarian cancer; poly-adenosyl-ribose polymerase inhibition; poly-adenosyl-ribose polymerase inhibitor resistance; poly-adenosyl-ribose polymerase inhibitors.

Figure 1

Correlation of platinum sensitivity with response to olaparib (AZD2281) in BRCA-mutated ovarian cancer, taken from the presentation by Fong et al.^[14] in the ASCO 2008 Annual Meeting. Longer complete and partial responses (CR/PR light green), and stable disease (SD, dark green), were seen in platinum-sensitive ovarian cancer, but also in some platinum-resistant and a brief signal in platinum- refractory ovarian cancer

Figure 2

PARP inhibitor targets