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.

Keywords: DNA repair; PARP inhibitors; clinical trials.

Figure 1.

Proposed mechanisms for PARPi activity in HRR-deficient cells. PARP inhibition impairs repair of single strain breaks (SSBs) by disrupting the base excision repair (BER) pathway and also causing PARP1 trapping by inhibiting auto-PARylation and/or PARP release from DNA. These result in unresolved DNA double-strand breaks (DSBs) that in homologous recombination repair (HRR)-deficient cells lead to cell death.

Figure 2.

Described mechanisms of secondary resistance to PARP inhibitors. The potential mechanisms of PARPi resistance can be classified in three main groups: (i) those that result in restoration of homologous recombination repair (HRR), (ii) those leading to mitigation of replication stress (RS) commonly together with slower cell cycle progression, and (iii) other mechanisms not directly related with an HRR or RS pathway but that still alter the response to PARPi, such as mutations in PARP1 or drug effluxion pumps.

Figure 3.

Rational combinations of PARPi with other targeted agents. Hypothesis-driven combinations with PARP inhibitors are summarized; (A) combinations of PARPi with other compounds targeting alternatives DDR nodes aim to maximize accumulation DNA damage during G1 and S phases of the cell cycle, together with preventing its repair during G2 by minimizing the time to repair. This would lead to accumulation of DNA damage during mitosis and cell death. (B) Combinations with drugs targeting other biological pathways which have been shown to be modulated and/or to modulate HRR function, such as the PI3K/AKT pathway, RAS, VEGFR, and AR signalling pathways. (C) Rationale for developing PARPi-immunotherapy combinations; defects in DDR might increase genomic instability, leading to accumulation of mutations and, putatively, increased neoantigen production and T-cell activation. An alternative hypothesis supporting PARPi-immunotherapy combinations is the accumulation of cytosolic DNA induced by DDR defects, which would activate the innate immune system through the cGAS-STING pathway, inducing interferon-mediated response. This pro-inflammatory cascade would result in activation of NK cells and macrophages and the infiltration, proliferation and antitumour response of CD4+ and CD8+ T cells into the tumour. Paradoxically, the STING pathway also activates the expression of PD-L1 in tumour cells, therefore limiting the cytotoxic immune response, but potentially rendering the tumour sensitive to PD-L1 blockade (DC, dendritic cell; M∅, macrophage; NK, natural killer cell; Treg, regulatory T cell).