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:

Non-metastatic castration resistant prostate cancer: a review of current and emerging medical therapies

Prostate Cancer and Prostatic Diseases volume 22, pages 16–23 (2019)Cite this article

Subjects

Abstract

Background

Non-metastatic castration resistant prostate cancer (M0CRPC) is a heterogenous disease state affecting an estimated 100,000 men in the United States. Development of more sensitive modalities for detection of metastasis has altered the landscape of advanced prostate cancer, but M0CRPC has remained a condition that previously lacked FDA-approved treatment. The emerging data on new generation Androgen Receptor (AR) pathway inhibitors should address this gap in the management of such patients.

Methods

We reviewed and summarized the current literature for the definition, diagnosis and treatment of M0CRPC. We highlight the results of recent Phase III trials that show significant impact on the outcomes of M0CRPC.

Results

Androgen deprivation therapy remains the foundation of therapy for M0CRPC. Recently published Phase III trials provided data on improved progression free survival when ADT is augmented with newer AR pathway inhibitors. The SPARTAN trial showed that metastasis-free survival (MFS) for patients treated with apalutamide plus ADT is 40.5 months compared to 16.2 months for patients who received standard ADT plus placebo, a 72% reduction in the risk of distant metastasis or death in apalutamide plus ADT compared to ADT plus placebo. The PROSPER trial demonstrated that MFS for patients treated with enzalutamide plus ADT was 36.6 months compared to 14.7 months for patients who received standard ADT only indicating a 71% reduction in the risk of developing metastatic CRPC or death compared to ADT alone. The ARAMIS trial on darolutamide, another AR pathway inhibitor, is also ongoing, and can potentially be another fitting option for M0CRPC.

Conclusion

The recent Phase III trials SPARTAN and PROPSER demonstrate effective treatment options for the M0CRPC disease state that has historically lacked treatment from high level evidence. In particular, an FDA-approved treatment, Apalutamide, can finally be offered for M0CRPC patients. The newer AR pathway inhibitors should provide a basis for further investigation into treatments for M0CRPC.

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

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.

    PubMed  Google Scholar 

  2. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet‐Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.

    PubMed  Google Scholar 

  3. Schröder FH, Hugosson J, Roobol MJ, Tammela TLJ, Zappa M, Nelen V, et al. The European Randomized Study of Screening for Prostate Cancer—Prostate Cancer Mortality at 13 Years of Follow-up. Lancet. 2014;384(9959):2027–35.

    PubMed  PubMed Central  Google Scholar 

  4. Draft Recommendation Statement: Prostate Cancer: Screening. 2017.

  5. Trapasso JG, Dekernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol. 1994;152(5):1821–5.

    CAS  PubMed  Google Scholar 

  6. Roberts SG, Blute ML, Bergstralh EJ, Slezak JM, Zincke H, editors. PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. Mayo Clinic Proceedings; 2001: Elsevier.

  7. Tombal B, Miller K, Boccon-Gibod L, Schröder F, Shore N, Crawford ED, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010;57(5):836–42.

    CAS  PubMed  Google Scholar 

  8. SEER Cancer Stat Facts: Prostate Cancer.

  9. Karantanos T, Evans CP, Tombal B, Thompson TC, Montironi R, Isaacs WB. Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level. Eur Urol. 2015;67(3):470–9.

    CAS  PubMed  Google Scholar 

  10. Afshar M, Evison F, James ND, Patel P, editors. Shifting paradigms in the estimation of survival for castration-resistant prostate cancer: A tertiary academic center experience. Urologic Oncology: Seminars and Original Investigations; 2015: Elsevier.

  11. Chandrasekar T, Yang JC, Gao AC, Evans CP. Targeting molecular resistance in castration-resistant prostate cancer. BMC Med. 2015;13(1):206.

    PubMed  PubMed Central  Google Scholar 

  12. Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. 2015;4(3):365.

    PubMed  PubMed Central  Google Scholar 

  13. Mohler JL, Gregory CW, Ford OH, Kim D, Weaver CM, Petrusz P, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10(2):440–8.

    CAS  PubMed  Google Scholar 

  14. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Macomson B, Lin JH, Tunceli O, Behl AS, Pericone C, Deshmukh S, et al. Time to metastasis or death in non-metastatic castrate resistant prostate cancer (nmCRPC) patients by National Comprehensive Cancer Network (NCCN) risk groups. American Society of Clinical Oncology; 2017;35:15_suppl, 5027–27.

  16. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402–18.

    PubMed  PubMed Central  Google Scholar 

  17. Smith MR, Saad F, Oudard S, Shore N, Fizazi K, Sieber P, et al. Denosumab and Bone Metastasis–Free Survival in Men With Nonmetastatic Castration-Resistant Prostate Cancer: Exploratory Analyses by Baseline Prostate-Specific Antigen Doubling Time. J Clin Oncol. 2013;31(30):3800–6.

    PubMed  PubMed Central  Google Scholar 

  18. Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model. PLoS ONE. 2015;10(10):e0139440.

    PubMed  PubMed Central  Google Scholar 

  19. Smith MR, Kabbinavar F, Saad F, Hussain A, Gittelman MC, Bilhartz DL, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23(13):2918–25.

    PubMed  Google Scholar 

  20. Crawford ED, Stone NN, Evan YY, Koo PJ, Freedland SJ, Slovin SF, et al. Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology. 2014;83(3):664–9.

    PubMed  Google Scholar 

  21. Sartor AO, Tangen CM, Hussain MH, Eisenberger MA, Parab M, Fontana JA, et al. Antiandrogen withdrawal in castrate‐refractory prostate cancer. Cancer . 2008;112(11):2393–400.

    CAS  PubMed  Google Scholar 

  22. Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of hybrid 68Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med. 2015;56(5):668–74.

    PubMed  Google Scholar 

  23. Morigi JJ, Stricker PD, van Leeuwen PJ, Tang R, Ho B, Nguyen Q, et al. Prospective comparison of 18F-fluoromethylcholine versus 68Ga-PSMA PET/CT in prostate cancer patients who have rising PSA after curative treatment and are being considered for targeted therapy. J Nucl Med. 2015;56(8):1185–90.

    CAS  PubMed  Google Scholar 

  24. Mosavi F, Johansson S, Sandberg DT, Turesson I, Sörensen J, Ahlström H. Whole-body diffusion-weighted MRI compared with 18F-NaF PET/CT for detection of bone metastases in patients with high-risk prostate carcinoma. AJR Am J Roentgenol. 2012;199(5):1114–20.

    PubMed  Google Scholar 

  25. Umbehr MH, Müntener M, Hany T, Sulser T, Bachmann LM. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysis. Eur Urol. 2013;64(1):106–17.

    PubMed  Google Scholar 

  26. Geynisman DM, Plimack ER, Zibelman M. Second-generation Androgen Receptor–targeted Therapies in Nonmetastatic Castration-resistant Prostate Cancer: Effective Early Intervention or Intervening Too Early? Eur Urol. 2016;70(6):971–3.

    PubMed  Google Scholar 

  27. Taylor C, Elson P, Trump D. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol. 1993;11(11):2167–72.

    CAS  PubMed  Google Scholar 

  28. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23(32):8253–61.

    CAS  PubMed  Google Scholar 

  29. Group PCTC. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet. 2000;355(9214):1491–8.

    Google Scholar 

  30. Morote J, Orsola A, Planas J, Trilla E, Raventós CX, Cecchini L, et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol. 2007;178(4):1290–5.

    CAS  PubMed  Google Scholar 

  31. Lawrentschuk N, Fernandes K, Bell D, Barkin J, Fleshner N. Efficacy of a second line luteinizing hormone-releasing hormone agonist after advanced prostate cancer biochemical recurrence. J Urol. 2011;185(3):848–54.

    CAS  PubMed  Google Scholar 

  32. Schröder FH, Tombal B, Miller K, Boccon‐Gibod L, Shore ND, Crawford ED, et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12‐month, comparative, phase III study. BJU Int. 2010;106(2):182–7.

    PubMed  Google Scholar 

  33. Hong JH, Kim IY. Nonmetastatic castration-resistant prostate cancer. Korean J Urol. 2014;55(3):153–60.

    PubMed  PubMed Central  Google Scholar 

  34. Nelson JB, Love W, Chin JL, Saad F, Schulman CC, Sleep DJ, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone‐refractory prostate cancer. Cancer 2008;113(9):2478–87.

    CAS  PubMed  Google Scholar 

  35. Miller K, Moul J, Gleave M, Fizazi K, Nelson J, Morris T, et al. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2013;16(2):187.

    CAS  PubMed  Google Scholar 

  36. Madan RA, Gulley JL, Schlom J, Steinberg SM, Liewehr DJ, Dahut WL, et al. Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy. Clin Cancer Res. 2008;14(14):4526–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Beinart G, Rini BI, Weinberg V, Small EJ. Antigen-presenting cells 8015 (Provenge®) in patients with androgen-dependent, biochemically relapsed prostate cancer. Clin Prostate Cancer. 2005;4(1):55–60.

    CAS  PubMed  Google Scholar 

  38. Ogita S, Tejwani S, Heilbrun L, Fontana J, Heath E, Freeman S, et al. Pilot phase II trial of bevacizumab monotherapy in nonmetastatic castrate-resistant prostate cancer. ISRN oncology. 2012;2012:242850

  39. Ito K, Kimura T, Onuma H, Tabata R, Shimomura T, Miki K, et al. Does docetaxel prolong survival of patients with non-metastatic castration-resistant prostate cancer? Prostate 2018 May;78(7):498-505.

  40. Ryan CJ, Smith MR, De Bono JS, Molina A, Logothetis CJ, De Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. New Engl J Med. 2013;368(2):138–48.

    CAS  PubMed  Google Scholar 

  41. De Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. New Engl J Med. 2011;364(21):1995–2005.

    PubMed  Google Scholar 

  42. Ryan CJ, Crawford ED, Shore ND, Underwood W, Wang J, DePalantino J, et al. Effect of abiraterone acetate and low-dose prednisone on PSA in patients with nonmetastatic castration-resistant prostate cancer: The results from IMAAGEN core study. American Society of Clinical Oncology; 2014 32:15_suppl, 5086–86.

  43. Ryan CJ, Crawford ED, Shore ND, Underwood W, Londhe A, Black SC, et al. IMAAGEN trial update: Effect of abiraterone acetate and low dose prednisone on PSA and radiographic disease progression in patients with non-metastatic castration-resistant prostate cancer. American Society of Clinical Oncology; 2015;33:15_suppl, 5053–53.

  44. Hussain M, Corn P, Michaelson D, Hammers H, Alumkal J, Ryan C, et al. 124 Activity and safety of the investigational agent orteronel (ortl, TAK-700) in men with nonmetastatic castration-resistant prostate cancer (CRPC) and rising prostate-specific antigen (PSA): Results of a phase 2 study. Eur Urol Suppl. 2012;11(1):e124–ea.

    Google Scholar 

  45. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. New Engl J Med. 2014;371(5):424–33.

    PubMed  Google Scholar 

  46. Scher HI, Fizazi K, Saad F, Taplin M-E, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. New Engl J Med. 2012;367(13):1187–97.

    CAS  PubMed  Google Scholar 

  47. Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, et al. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016;34(18):2098–106.

    CAS  PubMed  Google Scholar 

  48. Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Jung ME, Ouk S, Yoo D, Sawyers CL, Chen C, Tran C, et al. Structure− activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC). J Med Chem. 2010;53(7):2779–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Smith MR, Antonarakis ES, Ryan CJ, Berry WR, Shore ND, Liu G, et al. Phase 2 study of the safety and antitumor activity of apalutamide (ARN-509), a potent androgen receptor antagonist, in the high-risk nonmetastatic castration-resistant prostate cancer cohort. Eur Urol. 2016;70(6):963–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018 Apr 12;378(15):1408–18.

  52. Schweizer M, Zhou X, Wang H, Yang T, Shaukat F, Partin A, et al. Metastasis-free survival is associated with overall survival in men with PSA-recurrent prostate cancer treated with deferred androgen deprivation therapy. Ann Oncol. 2013;24(11):2881–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Xie W, Regan M, Buyse M, Halabi S, Kantoff P, Sartor O, et al. Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer. J Clin Oncol. 2017;35(27):3097–114.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Shore ND. Darolutamide (ODM-201) for the treatment of prostate cancer. Expert Opin Pharmacother. 2017;18(9):945–52.

    CAS  PubMed  Google Scholar 

Download references

Funding

Chritopher P. Evans has received research funding, honorarium, consulting and speaking relationships with Medivation, Janssen, Astellas and Sanofi in the past.

Author information

Authors and Affiliations

  1. Department of Urology, University of California Davis Medical Center, Sacramento, CA, 95817, USA

    Sigfred Ian R. Alpajaro & Christopher P. Evans

  2. University of California Davis School of Medicine, Sacramento, CA, 95817, USA

    Jerad A. K. Harris

Authors
  1. Sigfred Ian R. Alpajaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jerad A. K. Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher P. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sigfred Ian R. Alpajaro.

Ethics declarations

Conflict of interest

Sigfred Ian Alpajaro and Jared A.K. Harris do not have any conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alpajaro, S.I.R., Harris, J.A.K. & Evans, C.P. Non-metastatic castration resistant prostate cancer: a review of current and emerging medical therapies. Prostate Cancer Prostatic Dis 22, 16–23 (2019). https://doi.org/10.1038/s41391-018-0078-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41391-018-0078-1

This article is cited by

Search

Advanced search

Quick links