Apalutamide, Darolutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC): A Critical Review

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Apr 12

PMID 35406564

Authors

Carlo Cattrini

Orazio Caffo

Ugo De Giorgi

Alessia Mennitto

Alessandra Gennari

David Olmos

Elena Castro

Affiliations

Soon will be listed here.

Abstract

Nonmetastatic castration-resistant prostate cancer (nmCRPC) represents a condition in which patients with prostate cancer show biochemical progression during treatment with androgen-deprivation therapy (ADT) without signs of radiographic progression according to conventional imaging. The SPARTAN, ARAMIS and PROSPER trials showed that apalutamide, darolutamide and enzalutamide, respectively, prolong metastasis-free survival (MFS) and overall survival (OS) of nmCRPC patients with a short PSA doubling time, and these antiandrogens have been recently introduced in clinical practice as a new standard of care. No direct comparison of these three agents has been conducted to support treatment choice. In addition, a significant proportion of nmCRPC on conventional imaging is classified as metastatic with new imaging modalities such as the prostate-specific membrane antigen positron emission tomography (PSMA-PET). Some experts posit that these "new metastatic" patients should be treated as mCRPC, resizing the impact of nmCRPC trials, whereas other authors suggest that they should be treated as nmCRPC patients, based on the design of pivotal trials. This review discusses the most convincing evidence regarding the use of novel antiandrogens in patients with nmCRPC and the implications of novel imaging techniques for treatment selection.

Citing Articles

PSMA-PET/CT Findings in Patients With High-Risk Biochemically Recurrent Prostate Cancer With No Metastatic Disease by Conventional Imaging.

Holzgreve A, Armstrong W, Clark K, Benz M, Smith C, Djaileb L JAMA Netw Open. 2025; 8(1):e2452971.

PMID: 39752157 PMC: 11699533. DOI: 10.1001/jamanetworkopen.2024.52971.

Comparative analysis of novel hormonal agents in non-metastatic castration-resistant prostate cancer: A Taiwanese perspective.

Huang P, Huang L, Yang C, Li J, Chen C, Wang S PLoS One. 2024; 19(8):e0306900.

PMID: 39110673 PMC: 11305548. DOI: 10.1371/journal.pone.0306900.

Design, Characterization and Biopharmaceutical Applications of Novel Green Boron-Carbon Quantum Dots for Quantification of Apalutamide; Greenness Evaluations.

Hassan Y, AlZahrani E, Abdel-Lateef M, Salman B, Ibrahim A J Fluoresc. 2024; .

PMID: 38976089 DOI: 10.1007/s10895-024-03802-w.

Practical implications of androgen receptor inhibitors for prostate cancer treatment.

Campodonico F, Foppiani L, Campodonico V, Introini C Explor Target Antitumor Ther. 2024; 5(3):543-550.

PMID: 38966166 PMC: 11220289. DOI: 10.37349/etat.2024.00234.

Improving the identification of high-risk non-metastatic castration-resistant prostate cancer patients in clinical practice.

Rosinha A, Rabaca C, Calais F, Pinto J, Vasco Barreira J, Fernandes R Front Oncol. 2024; 13:1266369.

PMID: 38322282 PMC: 10844520. DOI: 10.3389/fonc.2023.1266369.

References

Galletti G, Leach B, Lam L, Tagawa S . Mechanisms of resistance to systemic therapy in metastatic castration-resistant prostate cancer. Cancer Treat Rev. 2017; 57:16-27. DOI: 10.1016/j.ctrv.2017.04.008. View

Lodde M, Lacombe L, Fradet Y . Salvage therapy with bicalutamide 150 mg in nonmetastatic castration-resistant prostate cancer. Urology. 2010; 76(5):1189-93. DOI: 10.1016/j.urology.2009.12.057. View

Clegg N, Wongvipat J, Joseph J, Tran C, Ouk S, Dilhas A . ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012; 72(6):1494-503. PMC: 3306502. DOI: 10.1158/0008-5472.CAN-11-3948. View

Armstrong A, Halabi S, Luo J, Nanus D, Giannakakou P, Szmulewitz R . Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study. J Clin Oncol. 2019; 37(13):1120-1129. PMC: 6494355. DOI: 10.1200/JCO.18.01731. View

Zumsteg Z, Spratt D, Romesser P, Pei X, Zhang Z, Polkinghorn W . The natural history and predictors of outcome following biochemical relapse in the dose escalation era for prostate cancer patients undergoing definitive external beam radiotherapy. Eur Urol. 2014; 67(6):1009-1016. PMC: 5002994. DOI: 10.1016/j.eururo.2014.09.028. View

Robinson D, Van Allen E, Wu Y, Schultz N, Lonigro R, Mosquera J . Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161(5):1215-1228. PMC: 4484602. DOI: 10.1016/j.cell.2015.05.001. View

Delanoy N, Hardy-Bessard A, Efstathiou E, Moulec S, Basso U, Birtle A . Sequencing of Taxanes and New Androgen-targeted Therapies in Metastatic Castration-resistant Prostate Cancer: Results of the International Multicentre Retrospective CATS Database. Eur Urol Oncol. 2019; 1(6):467-475. DOI: 10.1016/j.euo.2018.05.009. View

Ryan C, Smith M, de Bono J, Molina A, Logothetis C, de Souza P . Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2012; 368(2):138-48. PMC: 3683570. DOI: 10.1056/NEJMoa1209096. View

Penson D, Armstrong A, Concepcion R, Agarwal N, Olsson C, Karsh L . Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. J Clin Oncol. 2016; 34(18):2098-106. DOI: 10.1200/JCO.2015.64.9285. View

10.

Hofman M, Lawrentschuk N, Francis R, Tang C, Vela I, Thomas P . Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020; 395(10231):1208-1216. DOI: 10.1016/S0140-6736(20)30314-7. View

11.

. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet. 2000; 355(9214):1491-8. View

12.

Abida W, Cheng M, Armenia J, Middha S, Autio K, Vargas H . Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. 2018; 5(4):471-478. PMC: 6459218. DOI: 10.1001/jamaoncol.2018.5801. View

13.

Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M . Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013; 31(14):1748-57. PMC: 3641696. DOI: 10.1200/JCO.2012.43.1882. View

14.

Moilanen A, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G . 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. PMC: 4490394. DOI: 10.1038/srep12007. View

15.

Teply B, Wang H, Luber B, Sullivan R, Rifkind I, Bruns A . Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol. 2017; 19(1):76-86. PMC: 5875180. DOI: 10.1016/S1470-2045(17)30906-3. View

16.

Cattrini C, Zanardi E, Vallome G, Cavo A, Cerbone L, Di Meglio A . Targeting androgen-independent pathways: new chances for patients with prostate cancer?. Crit Rev Oncol Hematol. 2017; 118:42-53. DOI: 10.1016/j.critrevonc.2017.08.009. View

17.

Smith M, Antonarakis E, Ryan C, Berry W, Shore N, Liu G . 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):963-970. PMC: 5568792. DOI: 10.1016/j.eururo.2016.04.023. View

18.

Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U . Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2018; 378(26):2465-2474. PMC: 8288034. DOI: 10.1056/NEJMoa1800536. View

19.

Smith M, Saad F, Coleman R, Shore N, Fizazi K, Tombal B . Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2011; 379(9810):39-46. PMC: 3671878. DOI: 10.1016/S0140-6736(11)61226-9. View

20.

Aggarwal R, Huang J, Alumkal J, Zhang L, Feng F, Thomas G . Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. J Clin Oncol. 2018; 36(24):2492-2503. PMC: 6366813. DOI: 10.1200/JCO.2017.77.6880. View