Skip to main content

Advertisement

SpringerLink
Log in

Triple-arm androgen blockade for advanced prostate cancer: a review

  • Review Article
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Prostate cancer is estimated to be the second most common malignancy in men in the USA in 2020 and represents the second highest mortality from cancer behind lung and bronchial neoplasms. Management of advanced prostate cancer is evolving. Medical androgen deprivation therapy is currently a cornerstone of therapy for prostate cancer; however molecular mechanisms of resistance have emerged leading to castration-resistant prostate cancer that is proliferation of prostate cancer in the setting of low testosterone (< 50 ng/dl). The benefit of double androgen blockade like ADT plus abiraterone acetate or androgen receptor blockers is proven in many clinical trials; however multiple mechanisms of resistance still exist. In theory, another layer of androgen blockade will prevent, or at least slow, prostate cancer proliferation. This direction of thought has recently been explored with multiple clinical trials. In this review article, we summarize the current knowledge regarding androgen resistance, newer androgen inhibition therapies, and the implications of a triple-arm anti-androgen blockade in advanced prostate cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  1. American Cancer Society. Facts & Figures. In: Factora RM, editor. Aging and Money: Reducing Risk of Financial Exploitation and Protecting Financial Resources. Cham: American Cancer Society; 2021.

    Google Scholar 

  2. Huggins C, Stevens RE, Hodges CV. Studies on prostatic cancer: ii. The effects of castration on advanced carcinoma of the prostate gland. Archives of Surgery. 1941;43:209–23.

    Article  CAS  Google Scholar 

  3. Quigley DA, Dang HX, Zhao SG, et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell. 2018;174:758-769.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Takeda DY, Spisák S, Seo JH, 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 

  5. Hu R, Lu C, Mostaghel EA, et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res. 2012;72:3457–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20:686–700.

    Article  CAS  PubMed  Google Scholar 

  7. Davis ID, Martin AJ, Stockler MR, 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 

  8. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13–24.

    Article  CAS  PubMed  Google Scholar 

  9. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A randomized, phase iii study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37:2974–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chang CS, Kokontis J, Liao ST. Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors. Proc Natl Acad Sci. 1988;85:7211–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ciccarese C, Santoni M, Brunelli M, et al. AR-V7 and prostate cancer: The watershed for treatment selection? Cancer Treat Rev. 2016;43:27–35.

    Article  CAS  PubMed  Google Scholar 

  13. Paschalis A, Sharp A, Welti JC, et al. Alternative splicing in prostate cancer. Nat Rev Clin Oncol. 2018;15:663–75.

    Article  CAS  PubMed  Google Scholar 

  14. Schally AV, Coy DH, Arimura A. LH-RH agonists and antagonists. Int J Gynecol Obstet. 1980;18:318–24.

    Article  CAS  Google Scholar 

  15. Smith MR, Lee WC, Brandman J, et al. Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol. 2005;23:7897–903.

    Article  CAS  PubMed  Google Scholar 

  16. Saad F, Adachi JD, Brown JP, et al. Cancer treatment-induced bone loss in breast and prostate cancer. J Clin Oncol. 2008;26:5465–76.

    Article  PubMed  Google Scholar 

  17. Diamond T, Campbell J, Bryant C, et al. The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: longitudinal evaluation and response to intermittent cyclic etidronate therapy. Cancer. 1998;83:1561–6.

    Article  CAS  PubMed  Google Scholar 

  18. Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002;87:599–603.

    Article  CAS  PubMed  Google Scholar 

  19. Keating NL, O’Malley AJ, Freedland SJ, et al. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. JNCI: Journal of the National Cancer Institute. 2010;102:39–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nancy LK, O’Malley AJ, Matthew RS. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448–56.

    Article  CAS  Google Scholar 

  21. Saigal CS, Gore JL, Krupski TL, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer. 2007;110:1493–500.

    Article  CAS  PubMed  Google Scholar 

  22. Tsai HK, D’Amico AV, Sadetsky N, et al. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst. 2007;99:1516–24.

    Article  PubMed  Google Scholar 

  23. Nanda A, Chen MH, Braccioforte MH, et al. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. JAMA. 2009;302:866–73.

    Article  CAS  PubMed  Google Scholar 

  24. Albertsen PC, Klotz L, Tombal B, et al. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol. 2014;65:565–73.

    Article  CAS  PubMed  Google Scholar 

  25. Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382:2187–96.

    Article  CAS  PubMed  Google Scholar 

  26. Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol. 2009;27:3452–8.

    Article  PubMed  Google Scholar 

  27. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448–56.

    Article  CAS  PubMed  Google Scholar 

  28. Gardner JR, Livingston PM, Fraser SF. Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: a systematic review. J Clin Oncol. 2014;32:335–46.

    Article  PubMed  Google Scholar 

  29. Gregory CW, He B, Johnson RT, et al. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res. 2001;61:4315–9.

    CAS  PubMed  Google Scholar 

  30. Tilley WD, Buchanan G, Hickey TE, et al. Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res. 1996;2:277–85.

    CAS  PubMed  Google Scholar 

  31. Guo Z, Yang X, Sun F, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009;69:2305–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sun S, Sprenger CC, Vessella RL, et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. 2010;120:2715–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Steketee K, Timmerman L, Ziel-van der Made AC, et al. Broadened ligand responsiveness of androgen receptor mutants obtained by random amino acid substitution of H874 and mutation hot spot T877 in prostate cancer. Int J Cancer. 2002;100:309–17.

    Article  CAS  PubMed  Google Scholar 

  34. Culig Z, Hobisch A, Cronauer MV, et al. Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol. 1993;7:1541–50.

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Barrie SE, Potter GA, Goddard PM, et al. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol. 1994;50:267–73.

    Article  CAS  PubMed  Google Scholar 

  37. Morris MJ, Rumble RB, Basch E, et al. Optimizing anticancer therapy in metastatic non-castrate prostate cancer: american society of clinical oncology clinical practice guideline. J Clin Oncol. 2018;36:1521–39.

    Article  CAS  PubMed  Google Scholar 

  38. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408–18.

    Article  CAS  PubMed  Google Scholar 

  40. 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 

  41. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2019;380:1235–46.

    Article  CAS  PubMed  Google Scholar 

  42. (NCCN). NCCN: NCCN clinical practice guidelines in oncology.

  43. Han M, Partin AW, Piantadosi S, et al. Era specific biochemical recurrence-free survival following radical prostatectomy for clinically localized prostate cancer. J Urol. 2001;166:416–9.

    Article  CAS  PubMed  Google Scholar 

  44. Zietman AL, Coen JJ, Dallow KC, et al. The treatment of prostate cancer by conventional radiation therapy: an analysis of long-term outcome. Int J Radiat Oncol Biol Phys. 1995;32:287–92.

    Article  CAS  PubMed  Google Scholar 

  45. Kuban DA, Thames HD, Levy LB, et al. Long-term multi-institutional analysis of stage T1–T2 prostate cancer treated with radiotherapy in the PSA era. Int J Radiat Oncol Biol Phys. 2003;57:915–28.

    Article  PubMed  Google Scholar 

  46. McKay RR, Xie W, Lis R, et al. Results of a phase II trial of neoadjuvant abiraterone + prednisone+ enzalutamide + leuprolide (APEL) versus enzalutamide + leuprolide (EL) for patients with high-risk localized prostate cancer (PC) undergoing radical prostatectomy (RP). J Clin Oncol. 2018;36:79.

    Article  Google Scholar 

  47. McKay RR, Xie W, Fennessy FM, et al. Results of a phase II trial of intense androgen deprivation therapy prior to radical prostatectomy (RP) in men with high-risk localized prostate cancer (PC). J Clin Oncol. 2020;38:5503.

    Article  Google Scholar 

  48. Efstathiou E, Boukovala MA, Spetsieris N, et al. Neoadjuvant apalutamide (APA) plus leuprolide (LHRHa) with or without abiraterone (AA) in localized high-risk prostate cancer (LHRPC). J Clin Oncol. 2020;38:5504.

    Article  Google Scholar 

  49. Sterling J, Chua K, Patel H, et al. PD10-09°;Interim analysis of phase 2 randomized prospective study on neoadjuvant apalutamide/abiraterone acetate with prednisone and the feasibility of performing nerve-sparing radical prostatectomy in men with high-risk prostate cancer (NCT02949284). J Urol. 2020;203:e249.

    Article  Google Scholar 

  50. Efstathiou E, Davis JW, Titus MA, et al. Neoadjuvant enzalutamide (ENZA) and abiraterone acetate (AA) plus leuprolide acetate (LHRHa) versus AA+ LHRHa in localized high-risk prostate cancer (LHRPC). J Clin Oncol. 2016;34:5002.

    Article  Google Scholar 

  51. Roberts SG, Blute ML, Bergstralh EJ, et al. PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. Mayo Clin Proc. 2001;76:576–81.

    Article  CAS  PubMed  Google Scholar 

  52. Roach M 3rd, Hanks G, Thames H Jr, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys. 2006;65:965–74.

    Article  PubMed  Google Scholar 

  53. Cookson MS, Aus G, Burnett AL, et al. Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes. J Urol. 2007;177:540–5.

    Article  CAS  PubMed  Google Scholar 

  54. Amico D. Conventional ADT w/ or w/out abiraterone acetate + prednisone and apalutamide following a detectable PSA after radiation and ADT. 2018. clinicaltrials.gov.

  55. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. J Clin Oncol. 2018;36:1080–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. James ND, Sydes MR, Clarke NW, 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. 2016;387:1163–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gravis G, Fizazi K, Joly F, et al. Androgen deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:149–58.

    Article  CAS  PubMed  Google Scholar 

  58. Maluf FC, Fay AP, Souza VC, et al. Phase II randomized study of abiraterone acetate plus prednisone (AAP) added to ADT versus apalutamide alone (APA) versus AAP+APA in patients with advanced prostate cancer with noncastrate testosterone levels: (LACOG-0415). J Clin Oncol. 2020;38:5505–5505.

    Article  Google Scholar 

  59. Tangen CM, Hussain MH, Higano CS, et al. Improved overall survival trends of men with newly diagnosed M1 prostate cancer: a SWOG phase III trial experience (S8494, S8894 and S9346). J Urol. 2012;188:1164–9.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Maximum androgen blockade in advanced prostate cancer. an overview of the randomised trials. Prostate Cancer Trialists’ Collaborative Group Lancet. 2000;355:1491–8.

    Google Scholar 

  61. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. N Engl J Med. 2004;351:1502–12.

    Article  CAS  PubMed  Google Scholar 

  62. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513–20.

    Article  CAS  PubMed  Google Scholar 

  63. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147–54.

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  65. Efstathiou E, Titus MA, Wen S, et al. Enzalutamide (ENZA) in combination with abiraterone acetate (AA) in bone metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2014;32:5000–5000.

    Article  Google Scholar 

  66. Morris MJ, Heller G, Bryce AH, 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). J Clin Oncol. 2019;37:5008–5008.

    Article  Google Scholar 

  67. Attard G, Borre M, Gurney H, et al. A phase IV, randomized, double-blind, placebo (PBO)-controlled study of continued enzalutamide (ENZA) post prostate-specific antigen (PSA) progression in men with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2017;35:5004–5004.

    Article  Google Scholar 

  68. Janssen Research & Development (October 2016) An efficacy and safety study of apalutamide (JNJ-56021927) in combination with abiraterone acetate and prednisone versus abiraterone acetate and prednisone in participants with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Identifier: NCT02257736. https://clinicaltrials.gov/ct2/show/NCT02257736.

  69. Rathkopf DE, Attard G, Efstathiou E, et al. A phase 3 randomized, placebo-controlled double-blind study of ARN-509 plus abiraterone acetate (AA) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2015;33:TPS5071–TPS5071.

    Article  Google Scholar 

  70. Feng Q, He B. Androgen Receptor Signaling in the Development of Castration-Resistant Prostate Cancer. Front Oncol. 2019;9:858–858.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Bastos AD (June 2016). Neoadjuvant androgen deprivation therapy plus abiraterone with or without apalutamide for high-risk prostate cancer.  Identifier: NCT02789878. https://clinicaltrials.gov/ct2/show/NCT02789878.

  72. Teo MY, Taplin M-E, Eastham JA, et al. Metacure: Multi-arm multimodality therapy for very high-risk localized and low volume metastatic prostatic adenocarcinoma. J Clin Oncol. 2019;37:TPS349.

    Article  Google Scholar 

  73. Bertagnolli M (January 2017) A study of androgen annihilation in high-risk biochemically relapsed prostate cancer. Identifier: NCT03009981. https://clinicaltrials.gov/ct2/show/NCT03009981.

  74. Dahut LW (March 2019) Neoadjuvant androgen deprivation therapy combined with enzalutamide and abiraterone using multiparametric MRI and 18FDCFPyL PET/CT in newly diagnosed prostate cancer. Identifier: NCT03860987. https://clinicaltrials.gov/ct2/show/NCT03860987.

  75. Graff NJ (February 2020) Advanced chemoHormonal therapy for treatment naive metastatic prostate cancer. Identifier: NCT04267887. https://clinicaltrials.gov/ct2/show/NCT04267887.

  76. Nickols N (April 2019) Antiandrogen therapy and SBRT in treating patients with recurrent, metastatic prostate cancer. Identifier: NCT03902951. https://clinicaltrials.gov/ct2/show/NCT03902951.

  77. Nguyen P (May 2017) Randomized phase II study of salvage XRT + ADT +/- abiraterone and apalutamide for rising PSA after RP (FORMULA-509). Identifier: NCT03141671. https://clinicaltrials.gov/ct2/show/NCT03141671.

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA, 19129, USA

    Milap H. Desai

  2. Crozer-Chester Medical Center, Upland, PA, USA

    Meghana Parsi & Rashmika R. Potdar

Authors
  1. Milap H. Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meghana Parsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rashmika R. Potdar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Not applicable.

Corresponding author

Correspondence to Milap H. Desai.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

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

Desai, M.H., Parsi, M. & Potdar, R.R. Triple-arm androgen blockade for advanced prostate cancer: a review. Med Oncol 38, 75 (2021). https://doi.org/10.1007/s12032-021-01520-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-021-01520-y

Keywords

Search

Navigation