ESMO E-Learning: PARP Inhibitors: Past, Present and Future

In this E-Learning module, the authors provide an essential background on poly(ADP-Ribose) Polymerase (PARP) protein family, in particular PARP-1 and PARP-2 which participate in DNA single strand break repair and are key enzymes in the base excision repair mechanism.

The authors compare different PARP inhibitors in terms of relative PARP-trapping capacity, single agent dose, side effects, clinical benefit and status of regulatory approvals.  

They detail about the concept of synthetic lethality, homologous recombination deficiency (HRD) test development approach, methods used to determine sensitivity to PARP inhibitors, and provide an overview of diagnostic tests in clinical trials.  

In the next sections, the authors discuss the data from pivotal clinical trials with PARP inhibitors in the management of ovarian, breast, prostate, pancreatic cancers by coupling the clinical data with information on HRD testing status. Subsequently, they elaborate emerging area on extending the clinical benefit beyond BRCA1/2 mutated cancers.

The authors state that not all patients will respond, and that drug resistance is nearly inevitable. Therefore, it is needed to build on PARP inhibitor monotherapy efficacy. There are clear opportunities in different tumours and molecular subtypes beyond current monotherapy-approved indications.

The authors emphasise that concurrent chemotherapy combinations are challenging. Rational combinations will widen the breadth of application of PARP inhibitors. However, combination efficacy needs to be balanced against synergistic toxicities.

This E-Learning module is an excellent educational opportunity to comprehend the successful story of clinical development of PARP inhibitors, their application in the oncology practice and to learn about evolving strategies in terms of therapeutic targeting, thus moving the field of PARP inhibition forward.