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Managing Metastatic Prostate Cancer In Your Urological Oncology Practice pp 259–269Cite as

Novel Therapies in Castration-Resistant Prostate Cancer

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Abstract

Over the past several years, there have been significant advances in treatments and outcomes in metastatic castrate resistant prostate cancer (CRPC), with multiple new drugs with varying mechanisms gaining U.S. FDA approval. Despite these improvements, treatment resistance emerges within 1–2 years and metastatic CRPC remains incurable. Novel, rationally designed drugs and combination strategies are under investigation to further improve outcomes. Here we discuss a selection of these promising therapies in metastatic CRPC. Trials of immunotherapy with checkpoint blockade in CRPC are underway to try to match the success already found in melanoma and lung cancer. New drugs are being designed to target the AR-V7 splice variant, which has provided a mechanism for disease evasion of current hormonal therapies such as abiraterone and enzalutamide. Antibody-drug conjugates are being designed to allow for more specific delivery of drug to cancer cells in hopes of improving efficacy while decreasing systemic toxicity. Targeting stemness pathways such as Hedgehog and Notch signaling may provide a way to block self-renewing stem-like cells. Treatment with antisense oligonucleotides may be used to turn off genes of the cancer itself. Finally, identifying each drug’s appropriate place in the treatment algorithm, as well as obtaining synergy through combination therapy, will continue to improve outcomes for men with CRPC.

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References

  1. Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell. 2012;22(3):373–88.

    Article  CAS  PubMed  Google Scholar 

  2. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22.

    Article  CAS  PubMed  Google Scholar 

  3. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol: Official J Am Soc Clin Oncol. 2010;28(7):1099–105.

    Article  CAS  Google Scholar 

  4. Blank C, Brown I, Peterson AC, et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004;64(3):1140–5.

    Article  CAS  PubMed  Google Scholar 

  5. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res: An Official J Am Assoc Cancer Res. 2012;18(24):6580–7.

    Article  CAS  Google Scholar 

  6. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.

    Article  PubMed  Google Scholar 

  7. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.

    Article  CAS  PubMed  Google Scholar 

  8. Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res: An Official J Am Assoc Cancer Res. 2007;13(6):1810–5.

    Article  CAS  Google Scholar 

  9. Slovin SF, Higano CS, Hamid O, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol: Official J Eur Soc Med Oncol/ESMO. 2013;24(7):1813–21.

    Article  CAS  Google Scholar 

  10. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bishop JL, Sio A, Angeles A, et al. PD-L1 is highly expressed in enzalutamide resistant prostate cancer. Oncotarget. 2015;6(1):234–42.

    PubMed  PubMed Central  Google Scholar 

  12. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–97.

    Article  CAS  PubMed  Google Scholar 

  14. Mostaghel EA, Marck BT, Plymate SR, et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res: An Official J Am Assoc Cancer Res. 2011;17(18):5913–25.

    Article  CAS  Google Scholar 

  15. Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 2013;73(2):483–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang X, Morrissey C, Sun S, et al. Androgen receptor variants occur frequently in castration resistant prostate cancer metastases. PLoS ONE. 2011;6(11):e27970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028–38.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Andersen RJ, Mawji NR, Wang 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. 2010;17(6):535–46.

    Article  CAS  PubMed  Google Scholar 

  19. Myung JK, Banuelos CA, Fernandez JG, et al. An androgen receptor N-terminal domain antagonist for treating prostate cancer. J Clin Invest. 2013;123(7):2948–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Martin SK, Banuelos CA, Sadar MD, Kyprianou N. N-terminal targeting of androgen receptor variant enhances response of castration resistant prostate cancer to taxane chemotherapy. Mol Oncol. 2014.

    Google Scholar 

  21. Taplin M, Montgomery RB. Group A. ARMOR2: Galeterone in progressive CRPC patients who have failed oral therapy. J Clin Oncol: Official J Am Soc Clin Oncol. 2014;32(suppl 4):abstr 71.

    Google Scholar 

  22. Fizazi K, Massard C, Bono P, et al. Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Lancet Oncol. 2014;15(9):975–85.

    Article  CAS  PubMed  Google Scholar 

  23. Moilanen AM, Riikonen R, Oksala R, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5:12007.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kong D, Banerjee S, Ahmad A, et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS ONE. 2010;5(8):e12445.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sethi S, Macoska J, Chen W, Sarkar FH. Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasis. Am J Transl Res. 2010;3(1):90–9.

    PubMed  PubMed Central  Google Scholar 

  26. Cui D, Dai J, Keller JM, Mizokami A, Xia S, Keller ET. Notch pathway inhibition using PF-03084014, a gamma-secretase inhibitor (GSI), enhances the antitumor effect of docetaxel in prostate cancer. Clin Cancer Res: An Official J Am Assoc Cancer Res. 2015.

    Google Scholar 

  27. Antonarakis ES, Heath EI, Smith DC, et al. Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer. Oncologist. 2013;18(2):163–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gowda PS, Deng JD, Mishra S, et al. Inhibition of hedgehog and androgen receptor signaling pathways produced synergistic suppression of castration-resistant prostate cancer progression. Mol Cancer Res: MCR. 2013;11(11):1448–61.

    Article  CAS  PubMed  Google Scholar 

  29. Goldstein AS, Huang J, Guo C, Garraway IP, Witte ON. Identification of a cell of origin for human prostate cancer. Science. 2010;329(5991):568–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Suzman DL, Antonarakis ES. Clinical implications of hedgehog pathway signaling in prostate cancer. Cancers. 2015;7(4):1983–93.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783–91.

    Article  CAS  PubMed  Google Scholar 

  32. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol: Official J Am Soc Clin Oncol. 2012;30(18):2183–9.

    Article  CAS  Google Scholar 

  33. Ristau BT, O’Keefe DS, Bacich DJ. The prostate-specific membrane antigen: lessons and current clinical implications from 20 years of research. Urol Oncol. 2014;32(3):272–9.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Von Hoff D, Mita M, Eisenberg P, et al. A phase I study of BIND-014, a PSMA-targeted nanoparticle containing docetaxel, in patients with refractory solid tumors. Cancer Res. 2013;8(suppl):LB-203.

    Google Scholar 

  35. Petrylak D, Kantoff P, Mega A, et al. Prostate-specific membrane antigen antibody drug conjugate: a phase I trial in metastatic castration-resistant prostate cancer previously treated with a taxane. J Clin Oncol: Official J Am Soc Clin Oncol. 2013;31:abstr 5018.

    Google Scholar 

  36. Petrylak DP, Vogelzang NJ, Chatta GS, et al. A phase 2 study of prostate specific membrane antigen antibody drug conjugate in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide. J Clin Oncol: Official J Am Soc Clin Oncol. 2015;33(suppl 7):abstr 144.

    Google Scholar 

  37. Galsky MD, Eisenberger M, Moore-Cooper S, et al. Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer. J Clin Oncol: Official J Am Soc Clin Oncol. 2008;26(13):2147–54.

    Article  CAS  Google Scholar 

  38. Danila D, Szmulewitz RZ, Baron AD, et al. A phase I study of DSTP3086S, an antibody-drug conjugate targeting STEAP-1, in patients with metastatic castration-resistant prostate cancer. J Clin Oncol: Official J Am Soc Clin Oncol. 2014;32(5 s):abstr 5024.

    Google Scholar 

  39. Wright GL Jr, Grob BM, Haley C, et al. Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology. 1996;48(2):326–34.

    Article  PubMed  Google Scholar 

  40. Murga JD, Moorji SM, Han AQ, Magargal WW, DiPippo VA, Olson WC. Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor in prostate cancer. Prostate. 2015;75(3):242–54.

    Article  CAS  PubMed  Google Scholar 

  41. Sensibar JA, Sutkowski DM, Raffo A, et al. Prevention of cell death induced by tumor necrosis factor alpha in LNCaP cells by overexpression of sulfated glycoprotein-2 (clusterin). Cancer Res. 1995;55(11):2431–7.

    CAS  PubMed  Google Scholar 

  42. Zellweger T, Miyake H, Cooper S, et al. Antitumor activity of antisense clusterin oligonucleotides is improved in vitro and in vivo by incorporation of 2′-O-(2-methoxy)ethyl chemistry. J Pharmacol Exp Ther. 2001;298(3):934–40.

    CAS  PubMed  Google Scholar 

  43. Chi KN, Siu LL, Hirte H, et al. A phase I study of OGX-011, a 2′-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer. Clin Cancer Res: An Official J Am Assoc Cancer Res. 2008;14(3):833–9.

    Article  CAS  Google Scholar 

  44. Chi KN, Hotte SJ, Yu EY, et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol: Official J Am Soc Clin Oncol. 2010;28(27):4247–54.

    Article  CAS  Google Scholar 

  45. Chi KN, Higano CS, Blumenstein BA, et al. Phase III SYNERGY trial: Docetaxel ± custirsen and overall survival in patients with metastatic castration-resistant prostate cancer and poor prognosis. J Clin Oncol: Official J Am Soc Clin Oncol. 2015;33(suppl):abstr 5009.

    Google Scholar 

  46. Goldkorn A, Ely B, Quinn DI, et al. Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer. J Clin Oncol: Official J Am Soc Clin Oncol. 2014;32(11):1136–42.

    Article  CAS  Google Scholar 

  47. Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Beltran H, Rickman DS, Park K, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 2011;1(6):487–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bitting RL, Armstrong AJ. Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocrine Relat Cancer. 2013;20(3):R83–99.

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Hematology and Oncology, Wake Forest Baptist Health, Medical Center Blvd, 27103, Winston Salem, NC, USA

    Tyler Lash

  2. Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest University, School of Medicine, Medical Center Blvd, 27157, Winston Salem, NC, USA

    Rhonda L. Bitting

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  1. Tyler Lash
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  2. Rhonda L. Bitting
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Correspondence to Rhonda L. Bitting .

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Editors and Affiliations

  1. School of Medicine, Wake Forest University, Winston Salem, North Carolina, USA

    K.C Balaji

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Lash, T., Bitting, R.L. (2016). Novel Therapies in Castration-Resistant Prostate Cancer. In: Balaji, K. (eds) Managing Metastatic Prostate Cancer In Your Urological Oncology Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-31341-2_15

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  • DOI: https://doi.org/10.1007/978-3-319-31341-2_15

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