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.

  • Review Article
  • Published:

Clinical implications of genomic alterations in metastatic prostate cancer

Abstract

There has been a rapid expansion in treatment options for the management of metastatic prostate cancer, but individual patient outcomes can be variable due to inter-patient tumor heterogeneity. Fortunately, the disease can be stratified on the basis of common somatic features, providing potential for the development of clinically useful prognostic and predictive biomarkers. Tissue biopsy programs and studies leveraging circulating tumor DNA (ctDNA) have revealed specific genomic alterations that are associated with aggressive disease biology. In this review, we discuss the potential for genomic subtyping to improve prognostication and to help guide treatment selection. We summarize data on associations between AR pathway alterations and patient response to AR signaling inhibitors and other standards of care. We describe the links between detection of different types of DNA damage repair defects and clinical outcomes with targeted therapies such as poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors or immune checkpoint inhibitors. PI3K signaling pathway inhibitors are also in advanced clinical development and we report upon the potential for these and other novel targeted therapies to have impact in specific molecular subsets of metastatic prostate cancer. Finally, we discuss the growing use of blood-based analytes for prognostic and predictive biomarker development, and summarize ongoing prospective biomarker-driven clinical trials.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Design of two ongoing clinical trials testing ctDNA-based biomarkers in mCRPC.

Similar content being viewed by others

References

  1. Sartor O, de Bono JS. Metastatic prostate cancer. N Engl J Med. 2018;378:645–57.

    Article  CAS  PubMed  Google Scholar 

  2. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377:352–60.

    Article  CAS  PubMed  Google Scholar 

  4. Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N. Engl J Med. 2019;381:121–31.

    Article  CAS  PubMed  Google Scholar 

  5. Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N. Engl J Med. 2019;381:13–24.

    Article  CAS  PubMed  Google Scholar 

  6. Khalaf DJ, Annala M, Taavitsainen S, Finch DL, Oja C, Vergidis J, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 2019;20:1730–9.

    Article  CAS  PubMed  Google Scholar 

  7. de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wülfing C, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381:2506–18.

    Article  PubMed  Google Scholar 

  8. Parker CC, James ND, Brawley CD, Clarke NW, Hoyle AP, Ali A, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392:2353–66.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat J-P, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012;44:685–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.

    Article  Google Scholar 

  11. Stopsack KH, Nandakumar S, Wibmer AG, Haywood S, Weg ES, Barnett ES, et al. Oncogenic genomic alterations, clinical phenotypes, and outcomes in metastatic castration-sensitive prostate cancer. Clin Cancer Res. 2020;26:3230–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vandekerkhove G, Struss WJ, Annala M, Kallio HML, Khalaf D, Warner EW, et al. Circulating tumor DNA abundance and potential utility in de novo metastatic prostate cancer. Eur Urol. 2019;75:667–75.

    Article  CAS  PubMed  Google Scholar 

  13. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera J-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci USA. 2019;116:11428–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Annala M, Vandekerkhove G, Khalaf D, Taavitsainen S, Beja K, Warner EW, et al. Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discov. 2018;8:444–57.

    Article  CAS  PubMed  Google Scholar 

  16. Abida W, Armenia J, Gopalan A, Brennan R, Walsh M, Barron D, et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precis Oncol. 2017;1:1–16.

    Google Scholar 

  17. Zhao SG, Chang SL, Erho N, Yu M, Lehrer J, Alshalalfa M, et al. Associations of luminal and basal subtyping of prostate cancer with prognosis and response to androgen deprivation therapy. JAMA Oncol. 2017;3:1663–72.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Spratt DE, Zhang J, Santiago-Jiménez M, Dess RT, Davis JW, Den RB, et al. Development and validation of a novel integrated clinical-genomic risk group classification for localized prostate cancer. J Clin Oncol. 2018;36:581–90.

    Article  PubMed  Google Scholar 

  19. Ku SY, Gleave ME, Beltran H. Towards precision oncology in advanced prostate cancer. Nat Rev Urol. 2019;16:645–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Olaparib for metastatic castration-resistant prostate cancer. N. Engl J Med. 2020;382:2091–102.

    Article  PubMed  Google Scholar 

  21. Quigley DA, Dang HX, Zhao SG, Lloyd P, Aggarwal R, Alumkal JJ, et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell. 2018;174:758–769.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Beltran H, Wyatt AW, Chedgy EC, Donoghue A, Annala M, Warner EW, et al. Impact of therapy on genomics and transcriptomics in high-risk prostate cancer treated with neoadjuvant docetaxel and androgen deprivation therapy. Clin Cancer Res. 2017;23:6802–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Armenia J, Wankowicz SAM, Liu D, Gao J, Kundra R, Reznik E, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet. 2018;50:645–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mateo J, Seed G, Bertan C, Rescigno P, Dolling D, Figueiredo I, et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J Clin Invest. 2020;130:1743–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Maia MC, Salgia M, Pal SK. Harnessing cell-free DNA: plasma circulating tumour DNA for liquid biopsy in genitourinary cancers. Nat Rev Urol. 2020;17:271–91.

    Article  PubMed  Google Scholar 

  26. Lorente D, Olmos D, Mateo J, Bianchini D, Seed G, Fleisher M, et al. Decline in Circulating Tumor Cell Count and Treatment Outcome in Advanced Prostate Cancer. Eur Urol. 2016;70:985–92.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wyatt AW, Annala M, Aggarwal R, Beja K, Feng F, Youngren J, et al. Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer. J Natl Cancer Inst. 2017;109. https://doi.org/10.1093/jnci/djx118.

  28. Sharp A, Welti JC, Lambros MBK, Dolling D, Rodrigues DN, Pope L, et al. Clinical utility of circulating tumour cell androgen receptor splice variant-7 status in metastatic castration-resistant prostate cancer. Eur Urol. 2019;76:676–85.

    Article  CAS  PubMed  Google Scholar 

  29. De Bono JS, Scher HI, Montgomery RB, Parker C. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14:6302–9.

    Article  PubMed  Google Scholar 

  30. Heller G, McCormack R, Kheoh T, Molina A, Smith MR, Dreicer R, et al. Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate-Specific Antigen Across Five Randomized Phase III Clinical Trials. J Clin Oncol. 2018;36:572–80.

    Article  CAS  PubMed  Google Scholar 

  31. Romanel A, Gasi Tandefelt D, Conteduca V, Jayaram A, Casiraghi N, Wetterskog D, et al. Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med. 2015;7:312re10.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Khalaf D, Annala M, Finch DL, Oja CD, Vergidis J, Zulfiqar M, et al. Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI+P) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mCPRC): Results for 2nd-line therapy. J Clin Oncol. 2018;36:5015.

    Article  Google Scholar 

  33. Chi KN, Taavitsainen S, Iqbal N, Ferrario C, Ong M, Wadhwa D, et al. Updated results from a randomized phase II study of cabazitaxel (CAB) versus abiraterone (ABI) or enzalutamide (ENZ) in poor prognosis metastatic CRPC. J Clin Oncol. 2019;37:5003.

    Article  Google Scholar 

  34. Goodall J, Mateo J, Yuan W, Mossop H, Porta N, Miranda S, et al. Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition. Cancer Disco. 2017;7:1006–17.

    Article  CAS  Google Scholar 

  35. Choudhury AD, Werner L, Francini E, Wei XX, Ha G, Freeman SS, et al. Tumor fraction in cell-free DNA as a biomarker in prostate cancer. JCI Insight. 2018;3:e122109.

    Article  PubMed Central  Google Scholar 

  36. Conteduca V, Wetterskog D, Scarpi E, Romanel A, Gurioli G, Jayaram A, et al. Plasma tumour DNA as an early indicator of treatment response in metastatic castration-resistant prostate cancer. Br J Cancer. 2020;123:982–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ritch E, Fu SYF, Herberts C, Wang G, Warner EW, Schönlau E, et al. Identification of Hypermutation and Defective Mismatch Repair in ctDNA from Metastatic Prostate Cancer. Clin Cancer Res 2020;26:1114–25.

    Article  CAS  PubMed  Google Scholar 

  38. Beltran H, Romanel A, Conteduca V, Casiraghi N, Sigouros M, Franceschini GM, et al. Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer. J Clin Invest. 2020;130:1653–68.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lohr JG, Adalsteinsson VA, Cibulskis K, Choudhury AD, Rosenberg M, Cruz-Gordillo P, et al. Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer. Nat Biotechnol. 2014;32:479–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lambros MB, Seed G, Sumanasuriya S, Gil V, Crespo M, Fontes M, et al. Single-Cell Analyses of Prostate Cancer Liquid Biopsies Acquired by Apheresis. Clin Cancer Res. 2018;24:5635–44.

    Article  CAS  PubMed  Google Scholar 

  41. Faugeroux V, Lefebvre C, Pailler E, Pierron V, Marcaillou C, Tourlet S, et al. An accessible and unique insight into metastasis mutational content through whole-exome sequencing of circulating tumor cells in metastatic prostate cancer. Eur Urol Oncol. 2019;3:498–508.

    Article  PubMed  Google Scholar 

  42. Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li Y, Yang R, Henzler CM, Ho Y, Passow C, Auch B, et al. Diverse AR gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer. Clin Cancer Res. 2020;26:1965–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chang K-H, Li R, Kuri B, Lotan Y, Roehrborn CG, Liu J, et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell. 2013;154:1074–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Parolia A, Cieslik M, Chu S-C, Xiao L, Ouchi T, Zhang Y, et al. Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer. Nature. 2019;571:413–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lorente D, Mateo J, Zafeiriou Z, Smith AD, Sandhu S, Ferraldeschi R, et al. Switching and withdrawing hormonal agents for castration-resistant prostate cancer. Nat Rev Urol. 2015;12:37–47.

    Article  CAS  PubMed  Google Scholar 

  47. Sumiyoshi T, Mizuno K, Yamasaki T, Miyazaki Y, Makino Y, Okasho K, et al. Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer. Sci Rep. 2019;9:4030.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Romero-Laorden N, Lozano R, Jayaram A, López-Campos F, Saez MI, Montesa A, et al. Phase II pilot study of the prednisone to dexamethasone switch in metastatic castration-resistant prostate cancer (mCRPC) patients with limited progression on abiraterone plus prednisone (SWITCH study). Br J Cancer. 2018;119:1052–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jayaram A, Wingate A, Wetterskog D, Conteduca V, Khalaf D, Sharabiani MTA, et al. Plasma androgen receptor copy number status at emergence of metastatic castration-resistant prostate cancer: a pooled multicohort analysis. JCO Precis Oncol. 2019;3:1–13.

    Google Scholar 

  50. Viswanathan SR, Ha G, Hoff AM, Wala JA, Carrot-Zhang J, Whelan CW, et al. Structural alterations driving castration-resistant prostate cancer revealed by linked-read genome sequencing. Cell. 2018;174:433–447.e19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Takeda DY, Spisák S, Seo J-H, Bell C, O’Connor E, Korthauer K, et al. A somatically acquired enhancer of the androgen receptor is a noncoding driver in advanced prostate cancer. Cell. 2018;174:422–432.e13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Waltering KK, Helenius MA, Sahu B, Manni V, Linja MJ, Jänne OA, et al. Increased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens. Cancer Res. 2009;69:8141–9.

    Article  CAS  PubMed  Google Scholar 

  53. Azad AA, Volik SV, Wyatt AW, Haegert A, Le Bihan S, Bell RH, et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin Cancer Res. 2015;21:2315–24.

    Article  CAS  PubMed  Google Scholar 

  54. Wyatt AW, Azad AA, Volik SV, Annala M, Beja K, McConeghy B, et al. Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol. 2016;2:1598–606.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Torquato S, Pallavajjala A, Goldstein A, Toro PV, Silberstein JL, Lee J, et al. Genetic alterations detected in cell-free DNA are associated with enzalutamide and abiraterone resistance in castration-resistant prostate cancer. JCO Precis Oncol. 2019;3:1–14.

    Google Scholar 

  56. Conteduca V, Jayaram A, Romero-Laorden N, Wetterskog D, Salvi S, Gurioli G, et al. Plasma androgen receptor and docetaxel for metastatic castration-resistant prostate cancer. Eur Urol. 2019;75:368–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, Rodrigues DN, et al. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. J Clin Invest. 2019;129:192–208.

    Article  PubMed  Google Scholar 

  58. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl J Med. 2014;371:1028–38.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Armstrong AJ, Halabi S, Luo J, Nanus DM, Giannakakou P, Szmulewitz RZ, 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. 2019;37:1120–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Scher HI, Graf RP, Schreiber NA, Jayaram A, Winquist E, McLaughlin B, et al. Assessment of the validity of nuclear-localized androgen receptor splice variant 7 in circulating tumor cells as a predictive biomarker for castration-resistant prostate cancer. JAMA Oncol. 2018;4:1179–86.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Brown LC, Lu C, Antonarakis ES, Luo J, Armstrong AJ. Androgen receptor variant-driven prostate cancer II: advances in clinical investigation. Prostate Cancer Prostatic Dis. 2020;23:367–80.

    Article  CAS  PubMed  Google Scholar 

  62. Henzler C, Li Y, Yang R, McBride T, Ho Y, Sprenger C, et al. Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer. Nat Commun. 2016;7:13668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. De Laere B, van Dam PJ, Whitington T, Mayrhofer M, Diaz EH, Van den Eynden G, et al. Comprehensive profiling of the androgen receptor in liquid biopsies from castration-resistant prostate cancer reveals novel intra-AR structural variation and splice variant expression patterns. Eur Urol. 2017;72:192–200.

    Article  PubMed  Google Scholar 

  64. Hearn JWD, AbuAli G, Reichard CA, Reddy CA, Magi-Galluzzi C, Chang K-H, et al. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol. 2016;17:1435–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hearn JWD, Sweeney CJ, Almassi N, Reichard CA, Reddy CA, Li H, et al. HSD3B1 genotype and clinical outcomes in metastatic castration-sensitive prostate cancer. JAMA Oncol. 2020;6:e196496.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Khalaf DJ, Aragón IM, Annala M, Lozano R, Taavitsainen S, Lorente D, et al. HSD3B1 (1245A> C) germline variant and clinical outcomes in metastatic castration-resistant prostate cancer patients treated with abiraterone and enzalutamide: results from two prospective studies. Ann Oncol. 2020;31:1186–97.

    Article  CAS  PubMed  Google Scholar 

  67. Lu C, Terbuch A, Dolling D, Yu J, Wang H, Chen Y, et al. Treatment with abiraterone and enzalutamide does not overcome poor outcome from metastatic castration-resistant prostate cancer in men with the germline homozygous HSD3B1 c. 1245C genotype. Ann Oncol. 2020;31:1178–85.

    Article  CAS  PubMed  Google Scholar 

  68. Shiota M, Narita S, Akamatsu S, Fujimoto N, Sumiyoshi T, Fujiwara M, et al. Association of missense polymorphism in HSD3B1 with outcomes among men with prostate cancer treated with androgen-deprivation therapy or abiraterone. JAMA Netw Open. 2019;2:e190115.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Yepuru M, Wu Z, Kulkarni A, Yin F, Barrett CM, Kim J, et al. Steroidogenic enzyme AKR1C3 is a novel androgen receptor-selective coactivator that promotes prostate cancer growth. Clin Cancer Res. 2013;19:5613–25.

    Article  CAS  PubMed  Google Scholar 

  70. Liu C, Lou W, Zhu Y, Yang JC, Nadiminty N, Gaikwad NW, et al. Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer. Cancer Res. 2015;75:1413–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Blattner M, Liu D, Robinson BD, Huang D, Poliakov A, Gao D, et al. SPOP mutation drives prostate tumorigenesis in vivo through coordinate regulation of PI3K/mTOR and AR signaling. Cancer Cell. 2017;31:436–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Boysen G, Rodrigues DN, Rescigno P, Seed G, Dolling D, Riisnaes R, et al. SPOP-mutated/CHD1-deleted lethal prostate cancer and abiraterone sensitivity. Clin Cancer Res. 2018;24:5585–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Swami U, Isaacsson Velho P, Nussenzveig R, Chipman J, Sacristan Santos V, Erickson S, et al. Association of SPOP mutations with outcomes in men with de novo metastatic castration-sensitive prostate cancer. Eur Urol. 2020;78:652–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375:443–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Castro E, Romero-Laorden N, Del Pozo A, Lozano R, Medina A, Puente J, et al. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2019;37:490–503.

    Article  CAS  PubMed  Google Scholar 

  76. Wu YM, Cieślik M, Lonigro RJ, Vats P, Reimers MA, Cao X, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell. 2018;173:1770–1782.e14.

    Article  CAS  PubMed  Google Scholar 

  77. Annala M, Struss WJ, Warner EW, Beja K, Vandekerkhove G, Wong A, et al. Treatment outcomes and tumor loss of heterozygosity in germline DNA repair-deficient prostate cancer. Eur Urol. 2017;72:34–42.

    Article  CAS  PubMed  Google Scholar 

  78. Castro E, Goh C, Leongamornlert D, Saunders E, Tymrakiewicz M, Dadaev T, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68:186–93.

    Article  CAS  PubMed  Google Scholar 

  79. Reimers MA, Yip SM, Zhang L, Cieslik M, Dhawan M, Montgomery B, et al. Clinical outcomes in cyclin-dependent kinase 12 mutant advanced prostate cancer. Eur Urol. 2020;77:333–41.

    Article  CAS  PubMed  Google Scholar 

  80. Antonarakis ES, Isaacsson Velho P, Fu W, Wang H, Agarwal N, Santos VS, et al. CDK12-altered prostate cancer: Clinical features and therapeutic outcomes to standard systemic therapies, poly (ADP-ribose) polymerase inhibitors, and PD-1 inhibitors. JCO Precis Oncol. 2020;4:370–81.

    Article  PubMed  Google Scholar 

  81. Schweizer MT, Ha G, Gulati R, Brown LC, McKay RR, Dorff T, et al. CDK12-mutated prostate cancer: clinical outcomes with standard therapies and immune checkpoint blockade. JCO Precis Oncol. 2020;4:382–92.

    Article  PubMed  Google Scholar 

  82. Abida W, Campbell D, Patnaik A, Shapiro JD, Sautois B, Vogelzang NJ, et al. Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase II TRITON2 study. Clin Cancer Res. 2020;26:2487–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mateo J, Cheng HH, Beltran H, Dolling D, Xu W, Pritchard CC, et al. Clinical outcome of prostate cancer patients with germline DNA repair mutations: retrospective analysis from an international study. Eur Urol. 2018;73:687–93.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Antonarakis ES, Lu C, Luber B, Liang C, Wang H, Chen Y, et al. Germline DNA-repair gene mutations and outcomes in men with metastatic castration-resistant prostate cancer receiving first-line abiraterone and enzalutamide. Eur Urol. 2018;74:218–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hussain M, Daignault-Newton S, Twardowski PW, Albany C, Stein MN, Kunju LP, et al. Targeting androgen receptor and DNA repair in metastatic castration-resistant prostate cancer: results from NCI 9012. J Clin Oncol. 2018;36:991–9.

    Article  CAS  PubMed  Google Scholar 

  86. Cheng HH, Pritchard CC, Boyd T, Nelson PS, Montgomery B. Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer. Eur Urol. 2016;69:992–5.

    Article  CAS  PubMed  Google Scholar 

  87. Pomerantz MM, Spisák S, Jia L, Cronin AM, Csabai I, Ledet E, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer. 2017;123:3532–9.

    Article  CAS  PubMed  Google Scholar 

  88. Mota JM, Barnett E, Nauseef JT, Nguyen B, Stopsack KH, Wibmer A, et al. Platinum-based chemotherapy in metastatic prostate cancer with DNA repair gene alterations. JCO Precis Oncol. 2020;4:355–66.

    Article  PubMed  Google Scholar 

  89. Schmid S, Omlin A, Higano C, Sweeney C, Martinez Chanza N, Mehra N, et al. Activity of platinum-based chemotherapy in patients with advanced prostate cancer with and without DNA repair gene aberrations. JAMA Netw Open. 2020;3:e2021692.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Ashworth A, Lord CJ. Synthetic lethal therapies for cancer: what’s next after PARP inhibitors? Nat Rev Clin Oncol. 2018;15:564–76.

    Article  CAS  PubMed  Google Scholar 

  91. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Mateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21:162–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383:2345–57.

    Article  CAS  PubMed  Google Scholar 

  94. Ratta R, Guida A, Scotté F, Neuzillet Y, Teillet AB, Lebret T, et al. PARP inhibitors as a new therapeutic option in metastatic prostate cancer: a systematic review. Prostate Cancer Prostatic Dis. 2020;23:549–60.

    Article  CAS  PubMed  Google Scholar 

  95. Rafiei S, Fitzpatrick K, Liu D, Cai M-Y, Elmarakeby HA, Park J, et al. ATM loss confers greater sensitivity to ATR inhibition than PARP inhibition in prostate cancer. Cancer Res. 2020;80:2094–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Neeb A, Herranz N, Arce-Gallego S, Miranda S, Buroni L, Yuan W, et al. Advanced prostate cancer with ATM loss: PARP and ATR inhibitors. Eur Urol. 2020. https://doi.org/10.1016/j.eururo.2020.10.029.

  97. Mohler JL, Antonarakis ES, Armstrong AJ, D’Amico AV, Davis BJ, Dorff T, et al. Prostate cancer, version 2.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2019;17:479–505.

    Article  CAS  PubMed  Google Scholar 

  98. Parker C, Castro E, Fizazi K, Heidenreich A, Ost P, Procopio G, et al. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31:1119–34.

    Article  CAS  PubMed  Google Scholar 

  99. Lowrance W, Breau R, Chou R, Jarrard DF, Kibel AS, Morgan TM, et al. Advanced prostate cancer: AUA/ASTRO/SUO GUIDELINE. 2020. https://www.auanet.org/Documents/Guidelines/PDF/Advanced%20Prostate%20Cancer%20Guideline.pdf.

  100. Giri VN, Knudsen KE, Kelly WK, Cheng HH, Cooney KA, Cookson MS, et al. Implementation of germline testing for prostate cancer: Philadelphia prostate cancer consensus conference 2019. J Clin Oncol. 2020;38:2798–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5:471–8.

    Article  PubMed  Google Scholar 

  102. Pritchard CC, Morrissey C, Kumar A, Zhang X, Smith C, Coleman I, et al. Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer. Nat Commun. 2014;5:4988.

    Article  CAS  PubMed  Google Scholar 

  103. Antonarakis ES, Shaukat F, Isaacsson Velho P, Kaur H, Shenderov E, Pardoll DM, et al. Clinical features and therapeutic outcomes in men with advanced prostate cancer and DNA mismatch repair gene mutations. Eur Urol. 2019;75:378–82.

    Article  CAS  PubMed  Google Scholar 

  104. Lee L, Ali S, Genega E, Reed D, Sokol E, Mathew P. Aggressive-variant microsatellite-stable POLE mutant prostate cancer with high mutation burden and durable response to immune checkpoint inhibitor therapy. JCO Precis Oncol. 2018;2:1–8.

    PubMed  Google Scholar 

  105. Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J, Ojamaa K, Hoimes CJ, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. J Clin Oncol. 2020;38:395–405.

    Article  CAS  PubMed  Google Scholar 

  106. Jamaspishvili T, Berman DM, Ross AE, Scher HI, De Marzo AM, Squire JA, et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol. 2018;15:222–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. de Bono JS, De Giorgi U, Rodrigues DN, Massard C, Bracarda S, Font A, et al. Randomized phase II study evaluating akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res. 2019;25:928–36.

    Article  PubMed  Google Scholar 

  108. de Bono JS, Bracarda S, Sternberg CN, Chi KN, Olmos D, Sandhu S, et al. LBA4 IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2020;31:S1153–54.

    Article  Google Scholar 

  109. Herberts C, Murtha AJ, Fu S, Wang G, Schönlau E, Xue H, et al. Activating AKT1 and PIK3CA Mutations in Metastatic Castration-Resistant Prostate Cancer. Eur Urol. 2020;78:834–44.

    Article  CAS  PubMed  Google Scholar 

  110. Hyman DM, Smyth LM, Donoghue MTA, Westin SN, Bedard PL, Dean EJ, et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35:2251–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bielski CM, Donoghue MTA, Gadiya M, Hanrahan AJ, Won HH, Chang MT, et al. Widespread selection for oncogenic mutant allele imbalance in cancer. Cancer Cell. 2018;34:852–862.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380:1929–40.

    Article  PubMed  Google Scholar 

  113. De Laere B, Oeyen S, Mayrhofer M, Whitington T, van Dam P-J, Van Oyen P, et al. TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2019;25:1766–73.

    Article  PubMed  Google Scholar 

  114. Hamid AA, Gray KP, Shaw G, MacConaill LE, Evan C, Bernard B, et al. Compound genomic alterations of TP53, PTEN, and RB1 tumor suppressors in localized and metastatic prostate cancer. Eur Urol. 2019;76:89–97.

    Article  CAS  PubMed  Google Scholar 

  115. Chen WS, Aggarwal R, Zhang L, Zhao SG, Thomas GV, Beer TM, et al. Genomic drivers of poor prognosis and enzalutamide resistance in metastatic castration-resistant prostate cancer. Eur Urol. 2019;76:562–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rodrigues DN, Casiraghi N, Romanel A, Crespo M, Miranda S, Rescigno P, et al. RB1 heterogeneity in advanced metastatic castration-resistant prostate cancer. Clin Cancer Res. 2019;25:687–97.

    Article  CAS  Google Scholar 

  117. Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22:298–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen C-C, et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 2017;355:84–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science. 2017;355:78–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Aparicio AM, Shen L, Tapia ELN, Lu J-F, Chen H-C, Zhang J, et al. Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers. Clin Cancer Res. 2016;22:1520–30.

    Article  CAS  PubMed  Google Scholar 

  121. Chedgy ECP, Vandekerkhove G, Herberts C, Annala M, Donoghue AJ, Sigouros M, et al. Biallelic tumour suppressor loss and DNA repair defects in de novo small-cell prostate carcinoma. J Pathol. 2018;246:244–53.

    Article  CAS  PubMed  Google Scholar 

  122. Aggarwal R, Huang J, Alumkal JJ, Zhang L, Feng FY, Thomas GV, et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J Clin Oncol. 2018;36:2492–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Nyquist MD, Corella A, Coleman I, De Sarkar N, Kaipainen A, Ha G, et al. Combined TP53 and RB1 loss promotes prostate cancer resistance to a spectrum of therapeutics and confers vulnerability to replication stress. Cell Rep. 2020;31:107669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Palmbos PL, Tomlins SA, Daignault S, Agarwal N, Twardowski P, Morgans AK, et al. Clinical outcomes and markers of treatment response in a randomized phase II study of androgen deprivation therapy with or without palbociclib in RB-intact metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol. 2020;38:5573.

    Article  Google Scholar 

  125. Chi KN, Mukherjee S, Saad F, Winquist E, Ong M, Kolinsky MP, et al. Prostate cancer biomarker enrichment and treatment selection (PC-BETS) study: A Canadian cancer trials group phase II umbrella trial for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38:5551.

    Article  Google Scholar 

  126. Crippa A, De Laere B, Discacciati A, Larsson B, Connor JT, Gabriel EE, et al. The ProBio trial: molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer. Trials. 2020;21:579.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Pederzoli F, Bandini M, Marandino L, Ali SM, Madison R, Chung J, et al. Targetable gene fusions and aberrations in genitourinary oncology. Nat Rev Urol. 2020;17:613–25.

    Article  CAS  PubMed  Google Scholar 

  128. Wang L, Dehm SM, Hillman DW, Sicotte H, Tan W, Gormley M, et al. A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate–prednisone. Ann Oncol. 2018;29:352–60.

    Article  CAS  PubMed  Google Scholar 

  129. Isaacsson Velho P, Fu W, Wang H, Mirkheshti N, Qazi F, Lima FAS, et al. Wnt-pathway activating mutations are associated with resistance to first-line abiraterone and enzalutamide in castration-resistant prostate cancer. Eur Urol. 2020;77:14–21.

    Article  CAS  PubMed  Google Scholar 

  130. Zhao SG, Chen WS, Li H, Foye A, Zhang M, Sjöström M, et al. The DNA methylation landscape of advanced prostate cancer. Nat Genet. 2020;52:778–89.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Andrew Murtha for help with figure creation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alexander W. Wyatt.

Ethics declarations

Conflict of interest

K.C reports honoraria and/or consulting fees from Astellas, AstraZeneca, Constellation Pharmaceuticals, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Point Biopharma, Roche, Sanofi. Grants and research funding from Astellas, AstraZeneca, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi. A.W. reports receiving a commercial research grant from Janssen and honorarium from AstraZeneca, Astellas, Janssen, and Merck.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sumiyoshi, T., Chi, K.N. & Wyatt, A.W. Clinical implications of genomic alterations in metastatic prostate cancer. Prostate Cancer Prostatic Dis 24, 310–322 (2021). https://doi.org/10.1038/s41391-020-00308-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41391-020-00308-x

This article is cited by

Search

Quick links