Current opportunities of therapy for patients with non-metastatic castration-resistant prostate cancer

Prostate cancer is one of the most common urological malignancies. Improved diagnostic methods and widespread implementation of mandatory prostate specific antigen (PSA) testing in a number of clinics have led to an increase in the number of timely diagnosed cases of localized and locally advanced prostate cancer, as well as to the expansion of indications for radical therapies. Nevertheless, 30 % to 50 % of patients (depending on their risk) develop biochemical relapse after surgery or radiotherapy. Non-metastatic castration-resistant prostate cancer is usually a result of disease progression after radical treatment and long-term androgen-deprivation therapy, which manifests by constant increase in the PSA level along with castrate level of testosterone and no distant metastases according to the results of comprehensive radiological examination. A number of large clinical studies have demonstrated that regular examinations and control of PSA doubling time (main prognostic factor associated with poor disease outcome) are crucial to increase survival and prevent the development of distant metastases.
This paper aims to provide an overview of existing literature on the problems associated with diagnosis and treatment of non-metastatic castration-resistant prostate cancer. We have analyzed large randomized studies that demonstrated an increase in the overall survival of patients receiving selective androgen receptor antagonists.

1. Rawla P. Epidemiology of Prostate Cancer. World J Oncol 2019;10(2):63-89. DOI: 10.14740/wjon1191.

2. Hotte S.J., Saad F. Current management of castrate-resistant prostate cancer. Curr Oncol 2010;17(Suppl 2):S72-9. DOI: 10.3747/co.v17i0.718.

3. Anantharaman A., Small E.J. Tackling non-metastatic castrationresistant prostate cancer: special considerations in treatment. Expert Rev Anticancer Ther 2017;17(7):625-33. DOI: 10.1080/14737140.2017.1333903.

4. Mostaghel E.A., Page S.T., Lin D.W. et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res 2007;67(10):5033-41. DOI: 10.1158/0008-5472.CAN-06-3332.

5. Halabi S., Kelly W.K., Ma H. et al. Metaanalysis evaluating the impact of site of metastasis on overall survival in men with castration-resistant prostate cancer. J Clin Oncol 2016;34(14):1652-9. DOI: 10.1200/JCO.2015.65.7270.

6. Hussain M., Fizazi K., Saad F. et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2018;378(26):2465-74. DOI: 10.1056/NEJMoa1800536.

7. Chi K.N., Agarwal N., Bjartell A. et al. Apalutamide for metastatic, castrationsensitive prostate cancer. N Engl J Med 2019;381(1):13-24. DOI: 10.1056/NEJMoa1903307.

8. Small E., Saad F., Chowdhury S., Hadaschik B.A. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) vs placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). Genitourinary Cancers Symposium, 2018. Abstract No. 161.

9. Sandmann S., Trummel D., Seidel D. et al. Higher blood-brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C] darolutamide in rats using whole-body autoradiography. Presented at the ASCO Genitourinary Cancers Symposium, San Francisco, February 14-16, 2019. Abstract.

10. Zurth C., Sandmann S., Trummel D. et al. Blood-brain barrier penetration of [14C] darolutamide compared with [14C] enzalutamide in rats using whole body autoradiography. J Clin Oncol 2018;36:Suppl 6S:345. Abstract.

11. Moilanen A.M., 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. DOI: 10.1038/srep12007.

12. Moilanen A.M., Riikonen R., Oksala R. et al. ODM-201 - new generation androgen receptor inhibitor with excellent antiandrogenic and antitumor activity in nonclinical models of CRPC. Eur J Cancer 2013;49:Suppl 2:S685. Abstract.

13. Mateo J., Fizazi K., Gillessen S. et al. Managing nonmetastatic castration resistant prostate cancer. Eur Urol 2019;75(2):285-93. DOI: 10.1016/j.eururo.2018.07.035.

14. 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. DOI: 10.1016/S1470-2045(14)70240-2.

15. Massard C., Penttinen H.M., Vjaters E. et al. Pharmacokinetics, antitumor activity, and safety of ODM-201 in patients with chemotherapy-naive metastatic castrationresistant prostate cancer: an open-label phase 1 study. Eur Urol 2016;69:834-40. DOI: 10.1016/j.eururo.2015.09.046.

16. Shore N.D., Tammela T.L., Massard C. et al. Safety and antitumour activity of ODM-201 (BAY-1841788) in chemotherapy-naive and CYP17 inhibitor-naive patients: follow-up from the ARADES and ARAFOR trials. Eur Urol Focus 2018;4:547-53. DOI: 10.1016/j.euf.2017.01.015.

17. Fizazi K., Shore N., Tammela T.L. et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2019;380(13):1235-46. DOI: 10.1056/NEJMoa1815671.

18. ODM-201 in Addition to Standard ADT and Docetaxel in Metastatic Castration Sensitive Prostate Cancer (ARASENS). Available at: https://clinicaltrials.gov/ct2/show/NCT02799602.

19. European Medicines Agency. Xtandi CHMP assessment report. 2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002639/WC500144998.pdf. Accessed 01.10.2018.

20. European Medicines Agency. Erleada CHMP assessment report. 2018. Available at: https://www.ema.europa.eu/en/documents/assessment-report/erleada-epar-public-assessment-report_en.pdf. Accessed 01.10.2018.

21. US Center for Drug Evaluation and Research. NDA/BLA clinical pharmacology and biopharmaceutics review NDA 203415 Xtandi (enzalutamide). 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203415Orig1s000ClinPharmR.pdf. Accessed 26.09.2018.

22. US Center for Drug Evaluation and Research. NDA/BLA multi-disciplinary review and evaluation NDA 210951 Erleada (apalutamide). 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210951Orig1s000MultidisciplineR.pdf. Accessed 26.09.2018.

23. Del Re M., Fogli S., Derosa L. et al. The role of drug-drug interactions in prostate cancer treatment: focus on abiraterone acetate/prednisone and enzalutamide. Cancer Treat Rev 2017;55:71-82. DOI: 10.1016/j.Ctrv.2017.03.001.

24. Benoist G.E., van Oort I.M., Smeenk S. et al. Drug-drug interaction potential in men treated with enzalutamide: mind the gap. Br J Clin Pharmacol 2018;84(1):122-9. DOI: 10.1111/bcp.13425.

25. Benoist G.E., van Oort I.M., Burger D.M. et al. The combination of enzalutamide and opioids: a painful pitfall? Eur Urol 2019;75(2):351-2. DOI: 10.1016/j.eururo.2018.09.011.

26. Astellas Pharma US Inc. Xtandi (enzalutamide) US prescribing information. 2018. Available at: https://www.accessdata.fda.gov/drugsatfdadocs/label/2018/203415s014lbl.pdf. Accessed 11.06.2019.

27. Janssen Ortho LLC. Erleada (apalutamide) US prescribing information. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210951s000lbl.pdf. Accessed 22.07.2019.

28. Bayer HealthCare Pharmaceuticals Inc. Nubeqa (darolutamide) US prescribing information. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212099Orig1s000lbl.pdf. Accessed 31.07.2019.

29. Zurth C., Graudenz K., Denner K. et al. Drug-drug interaction (DDI) of darolutamide with cytochrome P-450 (CYP) and P-glycoprotein (P-gp) substrates: results from clinical and in vitro studies. J Clin Oncol 2019;37(suppl 7S; abstr 297):297. DOI: 10.1200/JCO.2019.37.7_suppl.297.

30. Smith M.R., Saad F., Chowdhury S. et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018;378(15):1408-18. DOI: 10.1056/NEJMoa1715546.