Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Towards precision oncology in advanced prostate cancer

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1.

    Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2015).

    Article  CAS  Google Scholar 

  2. 2.

    Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 69, 7–34 (2019).

    Article  PubMed  Google Scholar 

  3. 3.

    Lonergan, P. E. & Tindall, D. J. Androgen receptor signaling in prostate cancer development and progression. J. Carcinog. 10, 20 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Huggins, C. & Hodges, C. V. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J. Clin. 22, 232–240 (1972).

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Sweeney, C. J. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N. Engl. J. Med. 373, 737–746 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    James, N. D. et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N. Engl. J. Med. 377, 338–351 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Fizazi, K. et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N. Engl. J. Med. 377, 352–360 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    James, N. D. et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 387, 1163–1177 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Watson, P. A., Arora, V. K. & Sawyers, C. L. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat. Rev. Cancer 15, 701–711 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Beer, T. M. et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371, 424–433 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Smith, M. R. et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N. Engl. J. Med. 378, 1408–1418 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Hussain, M. et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med. 378, 2465–2474 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Fizazi, K. et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med. 380, 1235–1246 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Loriot, Y. et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann. Oncol. 24, 1807–1812 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Noonan, K. L. et al. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann. Oncol. 24, 1802–1807 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Bluemn, E. G. et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell 32, 474–489.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Aggarwal, R. et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J. Clin. Oncol. 36, 2492–2503 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Carreira, S. et al. Tumor clone dynamics in lethal prostate cancer. Sci. Transl Med. 6, 254ra125 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Abida, W. et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc. Natl Acad. Sci. USA 116, 11428–11436 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Armenia, J. et al. The long tail of oncogenic drivers in prostate cancer. Nat. Genet. 50, 645–651 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Beltran, H. et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat. Med. 22, 298–305 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Viswanathan, S. R. et al. Structural alterations driving castration-resistant prostate cancer revealed by linked-read genome sequencing. Cell 174, 433–447.e19 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Takeda, D. Y. et al. A somatically acquired enhancer of the androgen receptor is a noncoding driver in advanced prostate cancer. Cell 174, 422–432.e13 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Quigley, D. A. et al. Genomic hallmarks and structural variation in metastatic prostate Cancer. Cell 174, 758–769.e9 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Bohl, C. E., Gao, W., Miller, D. D., Bell, C. E. & Dalton, J. T. Structural basis for antagonism and resistance of bicalutamide in prostate cancer. Proc. Natl Acad. Sci. USA 102, 6201–6206 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Korpal, M. et al. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov. 3, 1030–1043 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Lallous, N. et al. Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients. Genome Biol. 17, 10 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Romanel, A. et al. Plasma AR and abiraterone-resistant prostate cancer. Sci. Transl Med. 7, 312re310 (2015).

    Article  CAS  Google Scholar 

  33. 33.

    Azad, A. A. et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin. Cancer Res. 21, 2315–2324 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Conteduca, V. et al. Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study. Ann. Oncol. 28, 1508–1516 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Annala, M. et al. Circulating Tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discov. 8, 444–457 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Antonarakis, E. S. et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 371, 1028–1038 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Armstrong, A. J. et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: the PROPHECY study. J. Clin. Oncol. 37, 1120–1129 (2019).

  38. 38.

    Sharp, A. et al. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. J. Clin. Invest. 129, 192–208 (2019).

    Article  PubMed  Google Scholar 

  39. 39.

    Chang, K. H. et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154, 1074–1084 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Hearn, J. W. D. et al. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol. 17, 1435–1444 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Hettel, D. & Sharifi, N. HSD3B1 status as a biomarker of androgen deprivation resistance and implications for prostate cancer. Nat. Rev. Urol. 15, 191–196 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Azad, A. A., Eigl, B. J., Murray, R. N., Kollmannsberger, C. & Chi, K. N. Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer patients. Eur. Urol. 67, 23–29 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Attard, G. et al. Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment. J. Clin. Oncol. 36, 2639–2646 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Morris, M. J. et al. Alliance A031201: a phase III trial of enzalutamide (ENZ) versus enzalutamide, abiraterone, and prednisone (ENZ/AAP) for metastatic castration resistant prostate cancer (mCRPC) [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 5008 (2019).

    Article  Google Scholar 

  45. 45.

    Andersen, R. J. et al. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 17, 535–546 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    Dalal, K. et al. Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer. J. Biol. Chem. 289, 26417–26429 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Zoubeidi, A. et al. Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity. Cancer Res. 67, 10455–10465 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Teply, B. A. et al. Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol. 19, 76–86 (2018).

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Chatterjee, P. et al. Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage. J. Clin. Invest. https://doi.org/10.1172/JCI127613 (2019).

  50. 50.

    Boysen, G. et al. SPOP-mutated/CHD1-deleted lethal prostate cancer and abiraterone sensitivity. Clin. Cancer Res. 24, 5585–5593 (2018).

    Article  PubMed  Google Scholar 

  51. 51.

    Liu, D. et al. Impact of the SPOP mutant subtype on the interpretation of clinical parameters in prostate cancer. JCO Precis. Oncol. 2, 1–13 (2018).

    Article  Google Scholar 

  52. 52.

    Blattner, M. et al. SPOP mutation drives prostate tumorigenesis in vivo through coordinate regulation of PI3K/mTOR and AR signaling. Cancer Cell 31, 436–451 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Carpten, J. D. et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448, 439–444 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    Hyman, D. M. et al. AKT inhibition in solid tumors with AKT1 mutations. J. Clin. Oncol. 35, 2251–2259 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Ferraldeschi, R. et al. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur. Urol. 67, 795–802 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Carver, B. S. et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19, 575–586 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03072238 (2019).

  58. 58.

    Pritchard, C. C. et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl. J. Med. 375, 443–453 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines®). Prostate cancer version 4.2019. NCCN https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (2019).

  60. 60.

    Cheng, H. H., Sokolova, A. O., Schaeffer, E. M., Small, E. J. & Higano, C. S. Germline and somatic mutations in prostate cancer for the clinician. J. Natl. Compr. Canc. Netw. 17, 515–521 (2019).

    Article  PubMed  Google Scholar 

  61. 61.

    Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Konstantinopoulos, P. A., Ceccaldi, R., Shapiro, G. I. & D’Andrea, A. D. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 5, 1137–1154 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Mateo, J. et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373, 1697–1708 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Kumar, A. et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat. Med. 22, 369–378 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Cheng, H. H., Pritchard, C. C., Boyd, T., Nelson, P. S. & Montgomery, B. Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer. Eur. Urol. 69, 992–995 (2016).

    Article  CAS  PubMed  Google Scholar 

  66. 66.

    Pomerantz, M. M. et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer 123, 3532–3539 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Zafeiriou, Z. et al. Genomic analysis of three metastatic prostate cancer patients with exceptional responses to carboplatin indicating different types of DNA repair deficiency. Eur. Urol. 75, 184–192 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    D’Andrea, A. D. Mechanisms of PARP inhibitor sensitivity and resistance. DNA Repair 71, 172–176 (2018).

    Article  CAS  PubMed  Google Scholar 

  69. 69.

    Goodall, J. et al. Circulating cell-free DNA to guide prostate cancer treatment with PARP inhibition. Cancer Discov. 7, 1006–1017 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Quigley, D. et al. Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors. Cancer Discov. 7, 999–1005 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Abida, W. et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 5, 471–478 (2019).

    Article  PubMed  Google Scholar 

  72. 72.

    Nava Rodrigues, D. et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J. Clin. Invest. 128, 4441–4453 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Boyiadzis, M. M. et al. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J. Immunother Cancer 6, 35 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Wu, Y. M. et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell 173, 1770–1782.e14 (2018).

    Article  CAS  PubMed  Google Scholar 

  75. 75.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03570619 (2019).

  76. 76.

    Malumbres, M. & Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 9, 153–166 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. 77.

    Comstock, C. E. et al. Targeting cell cycle and hormone receptor pathways in cancer. Oncogene 32, 5481–5491 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02905318 (2019).

  79. 79.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02555189 (2019).

  80. 80.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02059213 (2019).

  81. 81.

    Chinnam, M. & Goodrich, D. W. RB1, development, and cancer. Curr. Top. Dev. Biol. 94, 129–169 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Aparicio, A. M. et al. Combined tumor suppressor defects characterize clinically defined aggressive variant prostate cancers. Clin. Cancer Res. 22, 1520–1530 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. 83.

    Ku, S. Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78–83 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Beltran, H. et al. The role of lineage plasticity in prostate cancer therapy resistance. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-19-1423 (2019).

  86. 86.

    Palmgren, J. S., Karavadia, S. S. & Wakefield, M. R. Unusual and underappreciated: small cell carcinoma of the prostate. Semin. Oncol. 34, 22–29 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. 87.

    Epstein, J. I. et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am. J. Surg. Pathol. 38, 756–767 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Beltran, H. et al. A phase 2 study of the aurora kinase A inhibitor alisertib for patients with neuroendocrine prostate cancer (NEPC) [abstract]. Ann. Oncol. 27 (Suppl. 6), LBA29 (2016).

    Google Scholar 

  89. 89.

    Gong, X. et al. Aurora A kinase inhibition is synthetic lethal with loss of the RB1 tumor suppressor gene. Cancer Discov. 9, 248–263 (2019).

    Article  PubMed  Google Scholar 

  90. 90.

    Puca, L. et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci. Transl Med. 11, eaav0891 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Baca, S. C. et al. Punctuated evolution of prostate cancer genomes. Cell 153, 666–677 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Taylor, R. A. et al. Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. Nat. Commun. 8, 13671 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Nava Rodrigues, D. et al. RB1 heterogeneity in advanced metastatic castration-resistant prostate cancer. Clin. Cancer Res. 25, 687–697 (2019).

    Article  PubMed  Google Scholar 

  94. 94.

    Easwaran, H., Tsai, H. C. & Baylin, S. B. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol. Cell 54, 716–727 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. 96.

    Beltran, H. et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 1, 487–495 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Dardenne, E. et al. N-myc Induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell 30, 563–577 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03480646 (2019).

  99. 99.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03460977 (2019).

  100. 100.

    Stathis, A. & Bertoni, F. BET proteins as targets for anticancer treatment. Cancer Discov. 8, 24–36 (2018).

    Article  CAS  PubMed  Google Scholar 

  101. 101.

    Asangani, I. A. et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510, 278–282 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Welti, J. et al. Targeting bromodomain and extra-terminal (BET) family proteins in castration-resistant prostate cancer (CRPC). Clin. Cancer. Res. 24, 3149–3162 (2018).

    Article  CAS  PubMed  Google Scholar 

  103. 103.

    Asangani, I. A. et al. BET bromodomain inhibitors enhance efficacy and disrupt resistance to AR antagonists in the treatment of prostate cancer. Mol. Cancer. Res. 14, 324–331 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02711956 (2019).

  105. 105.

    Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. 106.

    Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. 107.

    Sehrawat, A. et al. LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc. Natl Acad. Sci. USA 115, E4179–E4188 (2018).

    Article  CAS  PubMed  Google Scholar 

  108. 108.

    Cai, C. et al. Lysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity. Cell Rep. 9, 1618–1627 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Haffner, M. C. et al. Tracking the clonal origin of lethal prostate cancer. J. Clin. Invest. 123, 4918–4922 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Aryee, M. J. et al. DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases. Sci. Transl Med. 5, 169ra110 (2013).

    Article  CAS  Google Scholar 

  112. 112.

    Wyatt, A. W. et al. Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol. 2, 1598–1606 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Salvi, S. et al. Circulating AR copy number and outcome to enzalutamide in docetaxel-treated metastatic castration-resistant prostate cancer. Oncotarget 7, 37839–37845 (2016).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Conteduca, V. et al. Plasma androgen receptor (pAR) status and activity of taxanes in metastatic castration resistant prostate cancer (mCRPC) [abstract]. J. Clin. Oncol. 36 (15 Suppl.), 5074–5074 (2018).

    Article  Google Scholar 

  115. 115.

    Conteduca, V. et al. Plasma androgen receptor and serum chromogranin A in advanced prostate cancer. Sci. Rep. 8, 15442 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Wyatt, A. W. et al. Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer. J. Natl Cancer Inst. 109, djx118 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  117. 117.

    Beltran, H. et al. The initial detection and partial characterization of circulating tumor cells in neuroendocrine prostate cancer. Clin. Cancer Res. 22, 1510–1519 (2016).

    Article  CAS  PubMed  Google Scholar 

  118. 118.

    Lambros, M. B. et al. Single-cell analyses of prostate cancer liquid biopsies acquired by apheresis. Clin. Cancer Res. 24, 5635–5644 (2018).

    Article  PubMed  Google Scholar 

Download references

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.).

Author information

Affiliations

Authors

Contributions

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

Corresponding author

Correspondence to Himisha Beltran.

Ethics declarations

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing