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 considerations for the management of androgen indifferent prostate cancer

Prostate Cancer and Prostatic Diseases volume 24, pages 623–637 (2021)Cite this article

Subjects

Abstract

Background

Many systemic therapies for advanced prostate cancer work by disrupting androgen receptor signaling. Androgen indifferent prostate cancer (AIPC) variants, including aggressive variant prostate cancer (AVPC), neuroendocrine prostate cancer (NEPC), and double-negative prostate cancer (DNPC), are increasingly common and often overlapping resistance phenotypes following treatment with androgen receptor signaling inhibitors in men with metastatic castration-resistant prostate cancer and are associated with poor outcomes. Understanding the underlying biology and identifying effective therapies for AIPC is paramount for improving survival for men with prostate cancer.

Methods

In this review, we summarize the current knowledge on AIPC variants, including our current understanding of the clinical, morphologic, and molecular features as well as current therapeutic approaches. We also explore emerging therapies and biomarkers aimed at improving outcomes for men with AIPC.

Results and conclusions

Establishing consensus definitions, developing novel biomarkers for early and accurate detection, further characterization of molecular drivers of each phenotype, and developing effective therapies will be critical to improving outcomes for men with AIPC. Significant progress has been made toward defining the clinical and molecular characteristics of AVPC, NEPC, and DNPC. Novel diagnostic approaches, including cell-free DNA, circulating tumor cells, and molecular imaging are promising tools for detecting AIPC in clinical practice. Building on previous treatment advances, several clinical trials are underway evaluating novel therapeutic approaches in patients with AIPC informed by an understanding of variant-specific biology. In this review, we discuss how these recent and ongoing studies will help to improve diagnosis, prognosis, and therapy for men with AIPC.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Proposed characteristics of androgen indifferent prostate cancer.

Similar content being viewed by others

References

  1. Epstein JI, Amin MB, Beltran H, Lotan TL, Mosquera JM, Reuter VE, et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol. 2014;38:756–67.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Parimi V, Goyal R, Poropatich K, Yang XJ. Neuroendocrine differentiation of prostate cancer: a review. Am J Clin Exp Urol. 2014;2:273–85.

    PubMed  PubMed Central  Google Scholar 

  3. Wang W, Epstein JI. Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. Am J Surg Pathol. 2008;32:65–71.

    Article  PubMed  Google Scholar 

  4. Yao JL, Madeb R, Bourne P, Lei J, Yang X, Tickoo S, et al. Small cell carcinoma of the prostate: an immunohistochemical study. Am J Surg Pathol. 2006;30:705–12.

    Article  PubMed  Google Scholar 

  5. Manucha V, Henegan J. Clinicopathologic diagnostic approach to aggressive variant prostate cancer. Arch Pathol Lab Med. 2020;144:18–23.

    Article  CAS  PubMed  Google Scholar 

  6. Palmgren JS, Karavadia SS, Wakefield MR. Unusual and underappreciated: small cell carcinoma of the prostate. Semin Oncol. 2007;34:22–9.

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. Nadal R, Schweizer M, Kryvenko ON, Epstein JI, Eisenberger MA. Small cell carcinoma of the prostate. Nat Rev Urol. 2014;11:213–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Spiess PE, Pettaway CA, Vakar-Lopez F, Kassouf W, Wang X, Busby JE, et al. Treatment outcomes of small cell carcinoma of the prostate: a single-center study. Cancer. 2007;110:1729–37.

    Article  PubMed  Google Scholar 

  10. Aparicio AM, Harzstark AL, Corn PG, Wen S, Araujo JC, Tu SM, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clinical cancer research: an official journal of the American Association for. Cancer Res. 2013;19:3621–30.

    CAS  Google Scholar 

  11. Bluemn EG, Coleman IM, Lucas JM, Coleman RT, Hernandez-Lopez S, Tharakan R, et al. Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling. Cancer Cell. 2017;32:474–89.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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. https://doi.org/10.1073/pnas.1902651116.

  13. Aparicio A, Zhang M, Ramesh N, Wang X, Corn PG, Zurita AJ, et al. Aggressive variant prostate cancer (AVPC) molecular signature in castration-sensitive, de novo metastatic prostate cancer (M1PCa). J Clin Oncol. 2019;37:5052.

    Article  Google Scholar 

  14. Amato RJ, Logothetis CJ, Hallinan R, Ro JY, Sella A, Dexeus FH. Chemotherapy for small cell carcinoma of prostatic origin. J Urol. 1992;147:935–7.

    Article  CAS  PubMed  Google Scholar 

  15. Berruti A, Mosca A, Tucci M, Terrone C, Torta M, Tarabuzzi R, et al. Independent prognostic role of circulating chromogranin A in prostate cancer patients with hormone-refractory disease. Endocr Relat Cancer. 2005;12:109–17.

    Article  CAS  PubMed  Google Scholar 

  16. Culine S, El Demery M, Lamy PJ, Iborra F, Avances C, Pinguet F. Docetaxel and cisplatin in patients with metastatic androgen independent prostate cancer and circulating neuroendocrine markers. J Urol. 2007;178:844–8.

    Article  CAS  PubMed  Google Scholar 

  17. Papandreou CN, Daliani DD, Thall PF, Tu SM, Wang X, Reyes A, et al. Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate. J Clin Oncol. 2002;20:3072–80.

    Article  CAS  PubMed  Google Scholar 

  18. Steineck G, Reuter V, Kelly WK, Frank R, Schwartz L, Scher HI. Cytotoxic treatment of aggressive prostate tumors with or without neuroendocrine elements. Acta Oncol. 2002;41:668–74.

    Article  PubMed  Google Scholar 

  19. Taplin ME, George DJ, Halabi S, Sanford B, Febbo PG, Hennessy KT, et al. Prognostic significance of plasma chromogranin a levels in patients with hormone-refractory prostate cancer treated in Cancer and Leukemia Group B 9480 study. Urology. 2005;66:386–91.

    Article  PubMed  Google Scholar 

  20. Deorah S, Rao MB, Raman R, Gaitonde K, Donovan JF. Survival of patients with small cell carcinoma of the prostate during 1973-2003: a population-based study. BJU Int. 2012;109:824–30.

    Article  PubMed  Google Scholar 

  21. Conteduca V, Oromendia C, Eng KW, Bareja R, Sigouros M, Molina A, et al. Clinical features of neuroendocrine prostate cancer. Eur J Cancer. 2019;121:7–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura T, et al. Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. JNCI. 1991;83:855–61.

    Article  CAS  PubMed  Google Scholar 

  23. Joss RA, Alberto P, Hürny C, Bacchi M, Leyvraz S, Thürlimann B, et al. Quality versus quantity of life in the treatment of patients with advanced small-cell lung cancer? A randomized phase III comparison of weekly carboplatin and teniposide versus cisplatin, adriamycin, etoposide alternating with cyclophosphamide, methotrexate, vincristine and lomustine. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol. 1995;6:41–8.

    Article  CAS  PubMed  Google Scholar 

  24. Lee SM, James L, Qian W, Spiro S, Eisen T, Gower N, et al. Comparison of gemcitabine and carboplatin versus cisplatin and etoposide for patients with poor-prognosis small cell lung cancer. Thorax. 2009;64:75–80.

    Article  CAS  PubMed  Google Scholar 

  25. Okamoto H, Watanabe K, Kunikane H, Yokoyama A, Kudoh S, Asakawa T, et al. Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer. 2007;97:162–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol. 1992;10:282–91.

    Article  CAS  PubMed  Google Scholar 

  27. Skarlos DV, Samantas E, Kosmidis P, Fountzilas G, Angelidou M, Palamidas P, et al. Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study. Ann Oncol. 1994;5:601–7.

    Article  CAS  PubMed  Google Scholar 

  28. Sundstrøm S, Bremnes RM, Kaasa S, Aasebø U, Hatlevoll R, Dahle R, et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol. 2002;20:4665–72.

    Article  PubMed  Google Scholar 

  29. Mohler JL, Antonarakis ES. NCCN guidelines updates: management of prostate cancer. J Natl Compr Cancer Netw. 2019;17:583–6.

    Google Scholar 

  30. Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220–9.

    Article  CAS  PubMed  Google Scholar 

  31. Chung HC, Piha-Paul SA, Lopez-Martin J, Schellens JHM, Kao S, Miller WH Jr, et al. Pembrolizumab after two or more lines of previous therapy in patients with recurrent or metastatic SCLC: results from the KEYNOTE-028 and KEYNOTE-158 studies. J Thorac Oncol. 2020;15:618–27.

    Article  CAS  PubMed  Google Scholar 

  32. Humeniuk MS, Gupta RT, Healy P, McNamara M, Ramalingam S, Harrison M, et al. Platinum sensitivity in metastatic prostate cancer: does histology matter? Prostate Cancer Prostatic Dis. 2018;21:92–9.

    Article  CAS  PubMed  Google Scholar 

  33. Sella A, Konichezky M, Flex D, Sulkes A, Baniel J. Low PSA metastatic androgen-independent prostate cancer. Eur Urol. 2000;38:250–4.

    Article  CAS  PubMed  Google Scholar 

  34. Flechon A, Pouessel D, Ferlay C, Perol D, Beuzeboc P, Gravis G, et al. Phase II study of carboplatin and etoposide in patients with anaplastic progressive metastatic castration-resistant prostate cancer (mCRPC) with or without neuroendocrine differentiation: results of the French Genito-Urinary Tumor Group (GETUG) P01 trial. Ann Oncol. 2011;22:2476–81.

    Article  CAS  PubMed  Google Scholar 

  35. Corn PG, Heath EI, Zurita A, Ramesh N, Xiao L, Sei E, et al. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1-2 trial. Lancet Oncol. 2019;20:1432–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 

  37. Scheble VJ, Braun M, Wilbertz T, Stiedl AC, Petersen K, Schilling D, et al. ERG rearrangement in small cell prostatic and lung cancer. Histopathology. 2010;56:937–43.

    Article  PubMed  Google Scholar 

  38. Lotan TL, Gupta NS, Wang W, Toubaji A, Haffner MC, Chaux A, et al. ERG gene rearrangements are common in prostatic small cell carcinomas. Mod Pathol. 2011;24:820–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bhagirath D, Yang TL, Tabatabai ZL, Majid S, Dahiya R, Tanaka Y, et al. BRN4 is a novel driver of neuroendocrine differentiation in castration-resistant prostate cancer and is selectively released in extracellular vesicles with BRN2. Clin Cancer Res. 2019;25:6532–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bishop JL, Thaper D, Vahid S, Davies A, Ketola K, Kuruma H, et al. The master neural transcription factor BRN2 is an androgen receptor-suppressed driver of neuroendocrine differentiation in prostate cancer. Cancer Discov. 2017;7:54–71.

    Article  CAS  PubMed  Google Scholar 

  41. Dardenne E, Beltran H, Benelli M, Gayvert K, Berger A, Puca L, et al. N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell. 2016;30:563–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Park JW, Lee JK, Witte ON, Huang J. FOXA2 is a sensitive and specific marker for small cell neuroendocrine carcinoma of the prostate. Mod Pathol. 2017;30:1262–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tsai HK, Lehrer J, Alshalalfa M, Erho N, Davicioni E, Lotan TL. Gene expression signatures of neuroendocrine prostate cancer and primary small cell prostatic carcinoma. BMC Cancer. 2017;17:759.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Karanikolas BD, Figueiredo ML, Wu L. Comprehensive evaluation of the role of EZH2 in the growth, invasion, and aggression of a panel of prostate cancer cell lines. Prostate. 2010;70:675–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yu J, Yu J, Rhodes DR, Tomlins SA, Cao X, Chen G, et al. A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer Res. 2007;67:10657–63.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang Y, Zheng D, Zhou T, Song H, Hulsurkar M, Su N, et al. Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers. Nat Commun. 2018;9:4080.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Su W, Han HH, Wang Y, Zhang B, Zhou B, Cheng Y, et al. The polycomb repressor complex 1 drives double-negative prostate cancer metastasis by coordinating stemness and immune suppression. Cancer Cell. 2019;36:139–55.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Steffan JJ, Koul S, Meacham RB, Koul HK. The transcription factor SPDEF suppresses prostate tumor metastasis. J Biol Chem. 2016;291:20826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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 

  50. Choi YJ, Lin CP, Ho JJ, He X, Okada N, Bu P, et al. miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol. 2011;13:1353–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kareta MS, Gorges LL, Hafeez S, Benayoun BA, Marro S, Zmoos AF, et al. Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis. Cell Stem Cell. 2015;16:39–50.

    Article  CAS  PubMed  Google Scholar 

  52. Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, 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 

  53. Park JW, Lee JK, Sheu KM, Wang L, Balanis NG, Nguyen K, et al. Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage. Science. 2018;362:91–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  55. Aparicio AM, Shen L, Tapia EL, Lu JF, Chen HC, 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 

  56. Gingrich JR, Barrios RJ, Foster BA, Greenberg NM. Pathologic progression of autochthonous prostate cancer in the TRAMP model. Prostate Cancer Prostatic Dis. 1999;2:70–5.

    Article  CAS  PubMed  Google Scholar 

  57. Karanika S, Karantanos T, Li L, Corn PG, Thompson TC. DNA damage response and prostate cancer: defects, regulation and therapeutic implications. Oncogene. 2015;34:2815–22.

    Article  CAS  PubMed  Google Scholar 

  58. Kwabi-Addo B, Giri D, Schmidt K, Podsypanina K, Parsons R, Greenberg N, et al. Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc Natl Acad Sci USA. 2001;98:11563–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhou Z, Flesken-Nikitin A, Corney DC, Wang W, Goodrich DW, Roy-Burman P, et al. Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. Cancer Res. 2006;66:7889–98.

    Article  CAS  PubMed  Google Scholar 

  60. Zou M, Toivanen R, Mitrofanova A, Floch N, Hayati S, Sun Y, et al. Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer. Cancer Discov. 2017;7:736–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kivinummi K, Urbanucci A, Leinonen K, Tammela TLJ, Annala M, Isaacs WB, et al. The expression of AURKA is androgen regulated in castration-resistant prostate cancer. Sci Rep. 2017;7:17978.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 2011;1:487–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Li L, Chang W, Yang G, Ren C, Park S, Karantanos T, et al. Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer. Sci Signal. 2014;7:ra47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Tzelepi V, Zhang J, Lu JF, Kleb B, Wu G, Wan X, et al. Modeling a lethal prostate cancer variant with small-cell carcinoma features. Clin Cancer Res. 2012;18:666–77.

    Article  CAS  PubMed  Google Scholar 

  65. Chakraborty G, Armenia J, Mazzu YZ, Nandakumar S, Stopsack KH, Atiq MO, et al. Significance of BRCA2 and RB1 co-loss in aggressive prostate cancer progression. Clin Cancer Res. 2020;26:2047–64.

    Article  CAS  PubMed  Google Scholar 

  66. Conteduca V, Ku S-Y, Puca L, Slade M, Fernandez L, Hess J, et al. SLFN11 expression in advanced prostate cancer and response to platinum-based chemotherapy. Mol Cancer Ther. 2020;19:1157–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Nappi L, Kesch C, Vahid S, Fazli L, Eigl BJ, Kollmannsberger CK, et al. Immunogenomic landscape of neuroendocrine small cell prostate cancer. J Clin Oncol. 2019;37:217.

    Article  Google Scholar 

  68. Ferguson AM, Bhinder B, Conteduca V, Sigouros M, Sboner A, Nanus D, et al. Abstract 134: Immunogenomic landscape of neuroendocrine prostate cancer (NEPC). Cancer Res. 2019;79:134.

    Google Scholar 

  69. Puca L, Gavyert K, Sailer V, Conteduca V, Dardenne E, Sigouros M, et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med. 2019;11:eaav0891.

  70. Rudin CM, Pietanza MC, Bauer TM, Ready N, Morgensztern D, Glisson BS, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18:42–51.

    Article  CAS  PubMed  Google Scholar 

  71. Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7:302ra136.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Coleman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, Friedlander M, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381:317–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. González-Martín A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381:2391–402.

    Article  PubMed  Google Scholar 

  76. Allen-Petersen BL, Sears RC. Mission possible: advances in MYC therapeutic targeting in cancer. BioDrugs. 2019;33:539–53.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Otto T, Horn S, Brockmann M, Eilers U, Schüttrumpf L, Popov N, et al. Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell. 2009;15:67–78.

    Article  CAS  PubMed  Google Scholar 

  78. Beltran H, Oromendia C, Danila DC, Montgomery B, Hoimes C, Szmulewitz RZ, et al. A phase II trial of the aurora kinase A inhibitor alisertib for patients with castration-resistant and neuroendocrine prostate cancer: efficacy and biomarkers. Clin Cancer Res. 2019;25:43–51.

    Article  CAS  PubMed  Google Scholar 

  79. Taplin M-E, Hussain A, Shah S, Shore ND, Edenfield WJ, Sartor OA, et al. Abstract CT094: Phase Ib results of ProSTAR: CPI-1205, EZH2 inhibitor, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC). Cancer Res. 2019;79:CT094.

    Google Scholar 

  80. Casella R, Bubendorf L, Sauter G, Moch H, Mihatsch MJ, Gasser TC. Focal neuroendocrine differentiation lacks prognostic significance in prostate core needle biopsies. J Urol. 1998;160:406–10.

    Article  CAS  PubMed  Google Scholar 

  81. Cohen MK, Arber DA, Coffield KS, Keegan GT, McClintock J, Speights VO Jr. Neuroendocrine differentiation in prostatic adenocarcinoma and its relationship to tumor progression. Cancer. 1994;74:1899–903.

    Article  CAS  PubMed  Google Scholar 

  82. Ishida E, Nakamura M, Shimada K, Tasaki M, Konishi N. Immunohistochemical analysis of neuroendocrine differentiation in prostate cancer. Pathobiology. 2009;76:30–8.

    Article  CAS  PubMed  Google Scholar 

  83. 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 Investig. 2020;130:1653–68.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JMC, Papaemmanuil E, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520:353–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Alumkal JJ, Sun D, Lu E, Beer TM, Thomas GV, Latour E, et al. Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance. Proc Natl Acad Sci USA. 2020;117:12315–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mahal BA, Yang DD, Wang NQ, Alshalalfa M, Davicioni E, Choeurng V, et al. Clinical and genomic characterization of low-prostate-specific antigen, high-grade prostate cancer. Eur Urol. 2018;74:146–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. De Mattos-Arruda L, Weigelt B, Cortes J, Won HH, Ng CK, Nuciforo P, et al. Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle. Ann Oncol. 2014;25:1729–35.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Mayrhofer M, De Laere B, Whitington T, Van Oyen P, Ghysel C, Ampe J, et al. Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis. Genome Med. 2018;10:85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 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 

  90. Ramesh N, Sei E, Tsai PC, Logothetis C, Corn P, Aparicio A, et al. Abstract 446: plasma genome sequencing identifies prostate cancer patients that are sensitive to platinum-based therapy. Cancer Res. 2019;79:446.

    Google Scholar 

  91. de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14:6302–9.

    Article  PubMed  CAS  Google Scholar 

  92. Beltran H, Jendrisak A, Landers M, Mosquera JM, Kossai M, Louw J, et al. The initial detection and partial characterization of circulating tumor cells in neuroendocrine prostate cancer. Clin Cancer Res. 2016;22:1510–9.

    Article  CAS  PubMed  Google Scholar 

  93. Malihi PD, Graf RP, Rodriguez A, Ramesh N, Lee J, Sutton R, et al. Single-cell circulating tumor cell analysis reveals genomic instability as a distinctive feature of aggressive prostate cancer. Clin Cancer Res. 2020;26:4143–53.

  94. Brown LC, Halabi S, Schonhoft J, Luo J, Nanus DM, Giannakakou P, et al. Association of circulating tumor cell chromosomal instability with worse outcomes in men with mCRPC treated with abiraterone or enzalutamide. J Clin Oncol. 2020;38:183.

    Article  CAS  PubMed  Google Scholar 

  95. Boustani AM, Pucar D, Saperstein L. Molecular imaging of prostate cancer. Br J Radiol. 2018;91:20170736.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Spratt DE, Gavane S, Tarlinton L, Fareedy SB, Doran MG, Zelefsky MJ, et al. Utility of FDG-PET in clinical neuroendocrine prostate cancer. Prostate. 2014;74:1153–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Chu C, Alshalalfa M, Sjöström M, Zhao S, Herlemann A, Chou J, et al. Differential expression of PSMA and 18F-fluciclovine transporter genes in metastatic castrate-resistant and treatment-emergent small cell/neuroendocrine prostate cancer. J Clin Oncol. 2020;38:24.

    Article  Google Scholar 

  98. Thang SP, Violet J, Sandhu S, Iravani A, Akhurst T, Kong G, et al. Poor outcomes for patients with metastatic castration-resistant prostate cancer with low prostate-specific membrane antigen (PSMA) expression deemed ineligible for (177)Lu-labelled PSMA radioligand therapy. Eur Urol Oncol. 2019;2:670–6.

    Article  PubMed  Google Scholar 

  99. Fox JJ, Gavane SC, Blanc-Autran E, Nehmeh S, Gönen M, Beattie B, et al. Positron emission tomography/computed tomography-based assessments of androgen receptor expression and glycolytic activity as a prognostic biomarker for metastatic castration-resistant prostate cancer. JAMA Oncol. 2018;4:217–24.

    Article  PubMed  Google Scholar 

  100. Bakht MK, Derecichei I, Li Y, Ferraiuolo RM, Dunning M, Oh SW, et al. Neuroendocrine differentiation of prostate cancer leads to PSMA suppression. Endocr Relat Cancer. 2018;26:131–46.

    Article  PubMed  Google Scholar 

  101. Tosoian JJ, Gorin MA, Rowe SP, Andreas D, Szabo Z, Pienta KJ, et al. Correlation of PSMA-targeted (18)F-DCFPyL PET/CT findings with immunohistochemical and genomic data in a patient with metastatic neuroendocrine prostate cancer. Clin Genitourin Cancer. 2017;15:e65–8.

    Article  PubMed  Google Scholar 

  102. Luboldt W, Zophel K, Wunderlich G, Abramyuk A, Luboldt HJ, Kotzerke J. Visualization of somatostatin receptors in prostate cancer and its bone metastases with Ga-68-DOTATOC PET/CT. Mol Imaging Biol. 2010;12:78–84.

    Article  PubMed  Google Scholar 

  103. Beltran H, Hruszkewycz A, Scher HI, Hildesheim J, Isaacs J, Yu EY, et al. The role of lineage plasticity in prostate cancer therapy resistance. Clin Cancer Res. 2019;25:6916–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Têtu B, Ro JY, Ayala AG, Johnson DE, Logothetis CJ, Ordonez NG. Small cell carcinoma of the prostate. Part I. A clinicopathologic study of 20 cases. Cancer. 1987;59:1803–9.

    Article  PubMed  Google Scholar 

  105. Labrecque MP, Coleman IM, Brown LG, True LD, Kollath L, Lakely B, et al. Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer. J Clin Investig. 2019;130:4492–505.

    Article  Google Scholar 

Download references

Acknowledgements

JEB is supported by the Department of Defense (W81XWH-20-1-0118). HB is supported by the Prostate Cancer Foundation, National Cancer Institute (1R37 CA241486-01A1, P50 CA211024) and Department of Defense (W81XWH-17-1-0653). AA is supported by the MD Anderson Moonshot Program, the Prostate Cancer Foundation, the Emerson Collective, National Cancer Institute (P50 CA140388-08A1, U01 CA224044) and Department of Defense (PC190353 and PC200135).

Author information

Author notes

  1. These authors contributed equally: Jacob E. Berchuck, Paul V. Viscuse

  2. These authors jointly supervised this work: Himisha Beltran, Ana Aparicio

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Jacob E. Berchuck & Himisha Beltran

  2. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Paul V. Viscuse & Ana Aparicio

Authors
  1. Jacob E. Berchuck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul V. Viscuse
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Himisha Beltran
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ana Aparicio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Himisha Beltran or Ana Aparicio.

Ethics declarations

Conflict of interest

HB has received research funding from Janssen, AbbVie Stemcentrx, Astellas, Eli Lilly, and Millennium, and has served as advisor/consultant for Janssen, Astellas, Amgen, Astra Zeneca, Pfizer, Blue Earth Diagnostics, and Sanofi Genzyme. AA has received research funding from Janssen, Bristol Myers Squibb, Sanofi Genzyme, Glaxo Smith Kline, Daiichi Sankyo and Astra Zeneca, and has served as advisor/consultant for Janssen, Sanofi Genzyme, Glaxo Smith Kline, Astellas, Amgen and Astra Zeneca.

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

Berchuck, J.E., Viscuse, P.V., Beltran, H. et al. Clinical considerations for the management of androgen indifferent prostate cancer. Prostate Cancer Prostatic Dis 24, 623–637 (2021). https://doi.org/10.1038/s41391-021-00332-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41391-021-00332-5

This article is cited by

Search

Advanced search

Quick links