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Appraising iniparib, the PARP inhibitor that never was—what must we learn?

Nature Reviews Clinical Oncology volume 10, pages 688–696 (2013)Cite this article

Subjects

Key Points

  • Iniparib is not a bona fide inhibitor of poly(ADP-ribose) polymerase (PARP), so the clinical results in this context should not be extrapolated to other PARP inhibitors in development

  • Preclinical data on iniparib did not sufficiently elucidate the mechanism of action of this agent before clinical trials were initiated

  • Phase I trials should provide proof of mechanism and, ideally, proof of concept, in expansion cohorts to test biological hypotheses; early clinical trials of iniparib lacked proof of mechanism

  • Selection of a patient population, and implementation and validation of predictive biomarkers, are critical to optimize drug development

  • Randomized phase II trials have a significant rate of false positivity, so promising results should be interpreted prudently until other confirmatory studies are reported

  • Preclinical and clinical studies with negative results and efforts evaluating reproducibility of previously published data should be publically available to minimize the risk of publication bias

Abstract

Several drugs targeting poly(ADP-ribose) polymerase (PARP) enzymes are under development. Responses have been observed in patients with germline mutations in BRCA1 and BRCA2, with further data supporting antitumour activity of PARP inhibitors in sporadic ovarian cancer. Strategies to identify other predictive biomarkers remain under investigation. Iniparib was purported to be a PARP inhibitor that showed promising results in randomized phase II trials in patients with triple-negative breast cancer. Negative results from a phase III study in this disease setting, however, tempered enthusiasm for this agent. Recently, data from in vitro experiments suggest that iniparib is not only structurally distinct from other described PARP inhibitors, but is also a poor inhibitor of PARP activity. In this context, the negative iniparib phase III data might have erroneously promulgated the notion that PARP inhibition is not an effective therapeutic strategy. Here, we scrutinize the development of iniparib from preclinical studies to registration trials, and identify and discuss the pitfalls in the development of anticancer drugs to prevent future late-stage trial failures.

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Figure 1: Confronting the Pharmacological Audit Trail (PhAT).

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Acknowledgements

The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a programme grant from Cancer Research UK. Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research).

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  1. Division of Cancer Therapeutics and Division of Clinical Studies, Drug Development Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, SM2 5PT, UK

    Joaquin Mateo, Michael Ong, David S. P. Tan, Michael A. Gonzalez & Johann S. de Bono

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All authors researched data for the article and made a substantial contribution to discussions of the content and contributed to writing the manuscript. J. Mateo, M. Ong, and J. S. de Bono reviewed and edited the manuscript before submission.

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Mateo, J., Ong, M., Tan, D. et al. Appraising iniparib, the PARP inhibitor that never was—what must we learn?. Nat Rev Clin Oncol 10, 688–696 (2013). https://doi.org/10.1038/nrclinonc.2013.177

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