Towards precision oncology in advanced prostate cancer

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Abstract

Metastatic biopsy programmes combined with advances in genomic sequencing have provided new insights into the molecular landscape of castration-resistant prostate cancer (CRPC), identifying actionable targets, and emerging resistance mechanisms. The detection of DNA repair aberrations, such as mutation of BRCA2, could help select patients for poly(ADP-ribose) polymerase (PARP) inhibitor or platinum chemotherapy, and mismatch repair gene defects and microsatellite instability have been associated with responses to checkpoint inhibitor immunotherapy. Poor prognostic features, such as the presence of RB1 deletion, might help guide future therapeutic strategies. Our understanding of the molecular features of CRPC is now being translated into the clinic in the form of increased molecular testing for use of these agents and for clinical trial eligibility. Genomic testing offers opportunities for improving patient selection for systemic therapies and, ultimately, patient outcomes. However, challenges for precision oncology in advanced prostate cancer still remain, including the contribution of tumour heterogeneity, the timing and potential cooperation of multiple driver gene aberrations, and diverse resistant mechanisms. Defining the optimal use of molecular biomarkers in the clinic, including tissue-based and liquid biopsies, is a rapidly evolving field.

Key points

  • Studies investigating the genomic landscape of metastatic prostate cancer have identified targetable molecular alterations and emerging resistance mechanisms.

  • Alterations in the androgen receptor (AR) gene are a key driver of castration resistance in prostate cancer; AR mutation, amplification and the V7 splice variant can be detected non-invasively in patients, and have been associated with resistance to AR pathway inhibitors.

  • A subset of advanced prostate cancers harbour germline or somatic alterations involving DNA repair genes; homologous repair gene DNA repair defects have been associated with platinum chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitor sensitivity. Mismatch repair gene and CDK12 loss have been associated with responses to immunotherapy.

  • Combined loss of tumour suppressors RB1 and TP53 has been associated with lineage plasticity and the development of non-AR driven therapy resistance, which is enriched in tumours with small-cell and/or neuroendocrine pathological features on metastatic biopsy and aggressive clinical features.

  • Several biomarker-driven clinical trials are underway in patients with advanced prostate cancer that might ultimately lead to increasingly precise therapeutic strategies in patients.

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Fig. 1: Precision medicine in mCRPC.
Fig. 2: Altered AR signalling in mCRPC.
Fig. 3: Dysregulated PI3K–AKT signalling in mCRPC.
Fig. 4: DNA repair pathway in mCRPC.
Fig. 5: Dysregulated cell cycle in mCRPC.
Fig. 6: Lineage plasticity in mCRPC.

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Acknowledgements

The authors acknowledge research support from the Prostate Cancer Foundation (S.-Y.K., M.E.G., H.B.), the Terry Fox Research Institute (M.E.G.), Prostate Cancer Canada (M.E.G.), the National Cancer Institute SPORE (H.B.) and the Department of Defense Prostate Cancer Research Program (H.B.).

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All authors researched data for the article, made substantial contributions to discussion of content, and wrote, reviewed, and edited the manuscript before submission.

Correspondence to Himisha Beltran.

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Competing interests

H.B. has received research funding from Janssen, Abbvie Stemcentryx, Astellas, Eli Lilly and Millennium, and has served as advisor/consultant for Janssen, Astellas, Amgen, Astra Zeneca and Sanofi Genzyme. M.E.G is listed as inventor on patents granted to the University of British Columbia on antisense and small-molecule inhibitors of HSP27 for the treatment of cancer. S.-Y. K. declares no competing interests.

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Ku, S., Gleave, M.E. & Beltran, H. Towards precision oncology in advanced prostate cancer. Nat Rev Urol 16, 645–654 (2019) doi:10.1038/s41585-019-0237-8

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