A decade of clinical development of PARP inhibitors in perspective

Abstract

Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/ BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors.

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

“…In conclusion, basic research into DNA damage repair biochemistry led to the identification of PARP, the inhibition of which, almost 40 years later, is showing great promise in the treatment of BRCA-deficient ovarian, breast, prostate and pancreatic cancer patients [87][88][89]. Work from our lab and others discussed here has shown that PARP inhibitors may also have potential in treating patients with ATM-deficient tumours.…”

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

“…Over the years, nicotinamide and 3-aminobenzamide, representing the first generation of inhibitors active at millimolar concentrations, were replaced by 2-nitro-6[5H] phenanthridinone, 1,5-dihydroisoquinoline, and others, active at mid-micromolar concentrations. The present third generation includes inhibitors effective at low micromolar/high nanomolar concentrations, several of which proceeded to clinical development or were already approved by regulatory agencies [132].…”

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

“…Studies based on the role of these PARPs in the DDR in cancer cells have led to the development of PARP inhibitors as new therapeutic tools in cancer, both as adjuvant treatment potentiating chemotherapy, radiotherapy, and immunotherapy and as monotherapy exploiting cancer cell-specific defects in DNA repair, such as BRCA mutations [6][7][8][9]. However, the tumor microenvironment is formed from more than just tumor cells, and also includes stromal cells and infiltrating cells of the innate and adaptive immune system, which are likely to also be affected by PARP inhibition.…”