Repositioning PARP inhibitors in the treatment of thoracic malignancies

Our plain-English summary of Repositioning PARP inhibitors in the treatment of thoracic malignancies, by F. Passiglia, M.L. Reale, V. Cetoretta, et al (Cancer Treatment Reviews, 2021).

The study

• Authors: F. Passiglia, M.L. Reale, V. Cetoretta, E. Parlagreco, F. Jacobs, A. Listì, L. Righi, P. Bironzo, S. Novello, G.V. Scagliotti
• Journal: Cancer Treatment Reviews
• Published: 2021;99:102256
• Type of article: Review
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The evaluation of the homologous recombination repair (HRR) status is emerging as a predictive tumor agnostic biomarker for poly (ADP-ribose) polymerase (PARP) inhibition across different tumor types and testing for HRR-signature is currently a developing area with promising therapeutic implications. Treatment with PARP inhibitors (PARPi) either as single agent or in combination with chemotherapy have shown so far limited activity in patients with thoracic malignancies. A deeper understanding of the biological background underlying HRR-deficient tumors, along with the recent advent of new effective targeted and immunotherapeutic agents, prompted the design of a new generation of clinical trials investigating novel PARPi-combinations in patients with lung cancer as well as malignant pleural mesothelioma. In this review we briefly summarize the biological basis of the DNA damage response pathway inhibition and provide an updated and detailed overview of clinical trials testing different PARPi-combinations strategies in patients with thoracic malignancies.

Copyright © 2021 Elsevier Ltd. All rights reserved.

In plain English

This article was a narrative review, not a new study. The authors, from the University of Turin, Italy, summarized the biology of PARP inhibitor drugs, which act on DNA repair. They gave an overview of finished and ongoing clinical trials of these drugs, alone or combined with chemotherapy, immunotherapy, other DNA-repair inhibitors, EGFR inhibitors or radiotherapy, in non-small cell lung cancer, small cell lung cancer and malignant pleural mesothelioma. For mesothelioma, they cited other work reporting that 5 to 10% of patients carry inherited (germline) mutations in DNA-repair genes. They described a phase II trial of olaparib in previously treated advanced pleural or peritoneal mesothelioma with DNA-repair gene mutations, which reported 4% partial response and 77% stable disease. A phase II trial of rucaparib in mesothelioma with BAP1 or BRCA deficiency reported disease control at 12 weeks of 57.7%. The authors concluded that clinical expectations for these drugs in chest cancers had so far been largely disappointed, and that new combination trials were under way. They noted that most ongoing trials lacked adequate patient selection. The review did not study asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of the biology and of clinical trials of PARP inhibitors in thoracic cancers
• Who was studied: Published and ongoing clinical trials, plus laboratory studies, in patients with non-small cell lung cancer, small cell lung cancer and malignant pleural mesothelioma. No single study population.
• Exposure: No asbestos exposure was studied. The subject was treatment with PARP inhibitor drugs (for example olaparib, niraparib, rucaparib, talazoparib, veliparib), alone or in combination with other treatments.
• Main results:
  • The review cited other work reporting that 5 to 10% of malignant pleural mesothelioma patients carry germline mutations in DNA damage response genes.
  • A phase II trial described by the review gave olaparib to previously treated patients with advanced pleural or peritoneal mesothelioma who had somatic or germline DNA-repair gene mutations. It reported 4% partial response and 77% stable disease.
  • A phase II single-arm trial described by the review gave rucaparib to mesothelioma patients enriched for BAP1 or BRCA deficiency. It reported a disease control rate at 12 weeks of 57.7%.
  • In laboratory studies cited by the review, niraparib and olaparib were lethal to all mesothelioma cell lines tested, regardless of BAP1 mutation status.
• The authors' conclusion: The authors concluded that, despite a strong biological rationale and promising laboratory data, clinical expectations for PARP inhibitors in thoracic cancers had so far been largely disappointed, and that a new generation of combination trials was under way.
• Limitations the authors state:
  • The authors stated that the definition of homologous recombination repair deficiency varies between studies, and that standardization is needed.
  • The authors stated that most ongoing clinical trials lack adequate selection of patients by biomarker.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Chemotherapy, Clinical Trial, Lung Cancer, Pleural Mesothelioma.

Related studies

• Phase I combination study of the PARP inhibitor veliparib plus carboplatin and gemcitabine in patients with advanced ovarian cancer and other solid malignancies — H.J. Gray, K. Bell-McGuinn, et al. (2018)
• Immune checkpoint inhibitors a new player in the therapeutic game of mesothelioma: New reality with new challenges — K. Parikh, L.E.L. Hendriks, et al. (2021)
• Proton therapy for thoracic malignancies: a review of oncologic outcomes — N.V. Patel, N.Y. Yu, et al. (2021)
• Antibody drug conjugates in thoracic malignancies — J.M. Pacheco, D.R. Camidge (2018)
• [18F]Fluorodeoxyglucose PET in Thoracic Malignancies — M.H. Vilstrup, D.A. Torigian (2014)
• Dual-input tracer kinetic modeling of dynamic contrast-enhanced MRI in thoracic malignancies — S.H. Lee, A. Rimner, et al. (2019)

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