Update on the Management of Non-Metastatic Castration-Resistant Prostate Cancer

Main Article Content

Fernández-Hernandez L Vives-Dilmes R Redondo-Gonzalez E Vives-Dilmes R Vidal-Cassinello N Puente-Vazquez J Fernandez-Montarroso L Galante-Romo M Jesus Moreno Sierra

Abstract

Background: Non-metastatic Castration Resistant Prostate Cancer (nmCRPC) is a heterogenous disease state in which the epidemiology is not completely known. Development of more sensitive modalities for detection of metastasis as well as the emerging data on new generation Androgen Receptor (AR) pathway inhibitors, has changed the paradigm in the management of such patients.


 


Methods: This is a clinical descriptive review. Using the key words “Non-metastatic castration resistant prostate cancer” and “Androgen receptor targeted agents” in PubMed database, we reviewed and summarized the current literature about the definition, diagnosis and treatment of nmCRPC. We highlight the results of recent Phase III trials that showed significant impact on the outcomes of treatment of nmCRPC. Primary outcome was Metastasis-free Survival (MFS) and secondary outcomes included were Overall Survival (OS) among others as well as rates of Adverse Events (AEs).


 


Development and Discussion: The SPARTAN trial showed a median MFS for patients treated with apalutamide plus Androgen Deprivation Therapy (ADT) of 40.5 months compared to 16.2 months for patients who received ADT plus placebo [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.24-0.36; p < 0.0001). Apalutamide also showed a statistically significant benefit in OS compared to placebo, with a median of 73.9 versus 59.9 months [HR: 0.78 (95% CI: 0.64-0.96), p: 0.016]. In the PROSPER trial, the median MFS for the enzalutamide group was 36.6 months compared to 14.7 months for the placebo group [HR: 0.29 (95% CI: 0.24-0.35), p < 0.0001]. OS was significantly higher in the enzalutamide group (67 versus 56.3 months in the placebo group), reaching the statiscal significance [HR: 0.73 (95% CI: 0.61-0.89), p: 0.001]. The ARAMIS trial showed a median MFS for patients treated with darolutamide plus ADT of 40.4 months compared to 18 months for the placebo group [HR: 0.41; (95% CI: 0.34-0.5); p<0.001]. The benefit of darolutamide in OS was also clear, with a HR of 0.69 (95% CI: 0.53-0.88), p: 0.003].


 


Conclusions: Apalutamide, enzalutamide and darolutamide have demostrated an increase in MFS and OS with a good safety profile in patients with high risk nmCRPC. There are no recommendations in favor of any drug so far, comparative studies are needed.


 

Article Details

How to Cite
L, Fernández-Hernandez et al. Update on the Management of Non-Metastatic Castration-Resistant Prostate Cancer. Medical Research Archives, [S.l.], v. 9, n. 3, mar. 2021. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2348>. Date accessed: 11 apr. 2021. doi: https://doi.org/10.18103/mra.v9i3.2348.
Section
Research Articles

References

1. Spanish Network of Cancer Registres (REDECAN). Estimates the incidence of cancer in Spain. Available at: http:/www. Redecan.org. Accessed September 20, 2020.
2. Larrañaga N, Galceran J, Ardanaz E, et al. The Prostate Cancer Working Group. Annals Oncol. 2010; 21(Suppl 3): 83-89.
3. De Angelis R, Sant M, Coleman MP, et al. Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE-5-a population-based study. Lancet Oncol. 2014; 15(1): 23-34.
4. Freedland SJ, Humphreys E, Mangold L, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005; 294(4): 433-439.
5. Kupelian PA, Mahadevan A, Reddy C, Reuther A, Klein E. Use of different definitions of biochemical failure after external beam radiotherapy changes conclusions about relative treatment efficacy for localized prostate cancer. Urology. 2006; 68(3): 593-598.
6. Luo J, Beer TM, Graff JN. Treatment of nonmetastatic castration-resistant prostate cancer. Oncology (Williston Park). 2016; 30(4): 336-344.
7. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228.
8. Hong JH, Kim IY. Nonmetastatic castration-resistant prostate cancer. Korean J Urol. 2014; 55(3): 153-160.
9. Liede A, Arellano J, Hechmati G, Bennett B, Wong S. International prevalence of nonmetastatic (M0) castration-resistant prostate cancer (CRPC). J Clin Oncol. 2013; 31.
10. Afshar M, Evison F, James ND, Patel P. Shifting paradigms in the estimation of survival for castration-resistant prostate cancer: A tertiary academic center experience. Urol Oncol. 2015; 33(8): 338.
11. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011; 65(11): 1180-1192.
12. Murray NP, Reyes E, Tapia P, Badínez L, Orellana N. Differential expression of matrix metalloproteinase-2 expression in disseminated tumor cells and micrometastasis in bone marrow of patients with nonmetastatic and metastatic prostate cancer: theoretical considerations and clinical implications-an immunocytochemical study. Bone Marrow Res. 2012; 2012: 259-351.
13. Crawford ED, Stone N, Yu E, et al. Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology. 2014; 83(3): 664-669.
14. Fendler WP, Weber M, Iravani A, et al. Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography in Men with Nonmetastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2019; 25(24): 7448-7454.
15. Crawford ED, Koo P, Shore N, et al. A Clinician's Guide to Next Generation Imaging in Patients With Advanced Prostate Cancer (RADAR III). J Urol. 2019; 201(4): 682-692.
16. Smith MR, Kabbinavar F, Saad F, Hussain A, Gittelman MC, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005; 23(13): 2918-2925.
17. Nelson JB, Love W, Chin JL, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. 2008; 113(9): 2478-2487.
18. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012; 379(9810): 39-46.
19. Smith MR, Saad F, Coleman R, 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): 3800-3807.
20. Tombal B. What is the pathophysiology of a hormone-resistant prostate tumour? Eur J Cancer. 2011; 47(Suppl.3): 179-188.
21. Tombal B. Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment for which patient? Ann Oncol. 2012; 23(Suppl.10): 251-258.
22. Nelson P. Targeting the Androgen Receptor en Prostate Cancer. N Engl J Med. 2014; 371(11): 1067-9.
23. Penson D, Armstrong A, Concepcion R, et al. Enzalutamide versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. J Clin Oncol. 2016; 34(18): 2098-106.
24. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2018; 378: 2465-2474.
25. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2020; 382(23): 2197-2206.
26. Smith MR, Antonarakis ES, Ryan CJ, 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 castrationresistant prostate cancer cohort. Eur Urol. 2016; 70(6): 963-970.
27. Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018; 378(15): 1408-1418.
28. Small EJ, Saad F, Chowdhury S, et al. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019; 30(11): 1813‐1820.
29. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol. 2021; 79(1): 150-158.
30. Wallis CJD, Thenappan C, Goldberg H, et al. Advanced androgen blockage in nonmetastatic castration-resistant prostate cancer: an indirect comparison of apalutamide and enzalutamide. Eur Urol Oncol. 2018; 1(3): 238–241.
31. Chowdhury S, Oudard S, Uemura H, et al. Matching-Adjusted Indirect Comparison of the Efficacy of Apalutamide and Enzalutamide with ADT in the Treatment of Non-Metastatic Castration-Resistant Prostate Cancer. Adv Ther. 2020; 37(1): 501‐511.
32. Fizari 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): 975-985.
33. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2019; 380(13): 1235-1246.
34. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020; 383(11): 1040-1049.
35. Di Nunno V, Mollica V, Santoni M, et al. New Hormonal Agents in Patients With Nonmetastatic Castration-Resistant Prostate Cancer: Meta-Analysis of Efficacy and Safety Outcomes. Clin Genitourin Cancer. 2019; 17(5): 871‐877.
36. Mottet N, Cornford P, Van der Bergt RCN, et al. Guidelines on Prostate Cancer. European Association of Urology. 2020: p93-94.
37. Schaeffer E, Srinivas S, Antonarakis ES, et al. Clinical Practise Guidelines in Oncology. Guidelines on Prostate Cancer (Version 2.2020). National Comprehensive Cancer Network. 2020: p23-24.

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.