ADP ribose polymerase inhibitors for treating non-small cell lung cancer: new additions to the pharmacotherapeutic armamentarium

ABSTRACT

Introduction

Poly (ADP-ribose) polymerase inhibitors (PARPi) are already part of the armamentarium of drugs available against ovarian and breast cancer. There is less data available on the efficacy of these drugs in the treatment of non-small cell lung cancer (NSCLC).

Areas covered

The authors have analyzed the preclinical studies that justified the use of PARPi in NSCLC. They then evaluate the in vivo efficacy of the combination of these drugs with chemotherapy, radiotherapy, and immunotherapy.

Expert opinion

Data from clinical trials available to date have discouraged the use of PARPi in association with chemotherapy or radiotherapy in NSCLC. The knowledge available to date opens the door to the use of PARPi in association with immunotherapy. In fact, the activity of these drugs would not be based only on direct cytotoxic action, but also on the modification of the intra-tumor microenvironment, in particular by increasing the expression of PD-L1 on tumor cells. This action might potentially enhance available treatments with a modest increase in toxicity.

KEYWORDS:

• PARPi
• lung cancer
• immunotherapy
• olaparib
• rucaparib
• veliparib
• iniparib

Article highlights

• The role of PARP in repairing platinum-induced adducts has been investigated in preclinical and clinical studies, with some data suggesting that it could represent an important molecular resistance mechanism to platinum chemotherapy and, thus, a possible target of therapy.

• Veliparib, versus placebo, in association with platinum-based doublet chemotherapy in advanced squamous lung cancer is currently studied in a phase III trial on the basis of promising results obtained in early phase and phase II studies.

• Despite significant preclinical data supporting combination of radiotherapy and PARP inhibition in NSCLC, only few trials have tested this combination, so far.

• A relevant application of this synergism might be unresectable stage III NSCLC, for which the standard is concurrent chemo-radiotherapy. The use of PARPi could represent an alternative to toxic and poorly tolerated drugs in this setting. Some clinical trials with olaparib and veliparib are currently ongoing in this setting.

• Preclinical studies showed an uprising of PD-L1 level in cell lines, when treated with PARP inhibitors. These findings have been validated in human cancer samples, suggesting that high PARP enzyme activity suppresses PD-L1 expression. Currently, no published data on combinations of PARP inhibitors and ICI in NSCLC are available.

Declaration of interest

G Rossi declares receiving honoraria from Amgen Inc, Roche, Novartis and Bristol-Myers Squibb while C Genova has received honoraria from Bristol-Myers Squibb, AstraZeneca, Merck Sharp and Dohme and Roche. Meanwhile, L Longo is a researcher supported by the Compagnia di San Paolo (2017-0529). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

All authors are supported by the Italian Ministry of Health (5x1000 funds; CO-2016-02361470).