Role of darolutamide in intensification of treatment of patients with hormone-sensitive prostate cancer: who needs the triplet combination?
https://doi.org/10.17650/1726-9776-2025-21-2-89-103
Abstract
The article presents a review of the results of the ARASENS registration study of darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel. This is the only triplet registered in Russia for treatment of metastatic hormone-sensitive prostate cancer. Darolutamide-based triplet showed significant benefits in overall survival and progression-free survival compared to hormone and chemotherapy combination in randomized phase III trial ARASENS, as well as better progression-free survival compared to ADT and androgen signal inhibitor duplets in meta-analyses of phase III randomized trials. Patients with de novo metastatic hormone-sensitive prostate cancer and high metastatic load receive the highest clinical benefit from darolutamide in combination with ADT and docetaxel. Darolutamide-based triplet demonstrated good safety profile comparable to duplet combination of ADT and docetaxel.
About the Authors
M. I. Volkova
Oncology Center No. 1, Moscow City Hospital named after S.S. Yudin, Moscow Healthcare Department;
Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia
Russian Federation
Russian Federation
Mariya Igorevna Volkova
Build. 7, 18A Zagorodnoe Shosse, Moscow 117152;
Build. 1, 2/1 Barrikadnaya St., Moscow 125993
K. A. Turupaev
N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
Russian Federation
Russian Federation
24 Kashirskoe Shosse, Moscow 115522
References
1. Davis I.D., Martin A.J., Stockler M.R. et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 2019;381(2):121–31. DOI: 10.1056/NEJMoa1903835
2. Kyriakopoulos C.E., Chen Y.H., Carducci M.A. 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(11):1080–7. DOI: 10.1200/JCO.2017.75.3657
3. Gravis G., Boher J.M., Joly F. et al.; GETUG. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol 2016;70(2):256–62. DOI: 10.1016/j.eururo.2015.11.005
4. James N., Sydes M., Clarke N. 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(10024):1163–77. DOI: 10.1016/S0140-6736(15)01037-5
5. 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. DOI: 10.1016/S1470-2045(19)30082-8
6. James N.D., de Bono J.S., Spears M.R. et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 2017;377(4):338–51. DOI: 10.1056/NEJMoa1702900
7. Chi K.N., Chowdhury S., Bjartell A. et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol 2021;39(20):2294–303. DOI: 10.1200/JCO.20.03488
8. Armstrong A.J. Final overall survival analysis from ARCHES: a phase 3, randomized, double-blind, placebo-controlled study of enzalutamide + ADT in men with mHSPC. 2021 European Society for Medical Oncology (ESMO) Annual Congress, 2021.
9. Fizazi K., Foulon S., Carles J. et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 2022;399(10336):1695–707. DOI: 10.1016/S0140-6736(22)00367-1
10. Saad F., Vjaters E., Shore N. et al. ARANOTE Study Investigators. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol 2024;42(36):4271–81. DOI: 10.1200/JCO-24-01798
11. Nosov D.A., Volkova M.I., Gladkov O.A. et al. Prostate cancer. RUSSCO practical guidelines, part 1.2. Zlokachestvennye opukholi = Malignant Tumors 2024;14(3s2):242–69. (In Russ.).
12. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Prostate Cancer. Version 1.2025. December 4, 2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
13. EAU Guidelines. Edn. presented at the EAU Annual Congress Paris, 2024.
14. Sweeney C.J., Chen Y.H., Carducci M. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015;373(8):737–46. DOI: 10.1056/NEJMoa1503747
15. Clarke N.W., Ali A., Ingleby F.C. et al. Addition of docetaxel to hormonal therapy in lowand high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol 2019;30(12):1992–2003. DOI: 10.1093/annonc/mdz396
16. Smith M.R., Hussain M., Saad F. et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med 2022;386(12):1132–42. DOI: 10.1056/NEJMoa2119115
17. Hussain M., Tombal B., Saad F. et al. Darolutamide plus androgendeprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer by disease volume and risk subgroups in the phase III ARASENS trial. J Clin Oncol 2023;41(20):3595–607. DOI: 10.1200/JCO.23.00041
18. Zurth C., Koskinen M., Fricke R. et al. Drug-drug interaction potential of darolutamide: in vitro and clinical studies. Eur J Drug Metab Pharmacokinet 2019;44(6):747–59. DOI: 10.1007/s13318-019-00577-5
19. Shore N., Zurth C., Fricke R. et al. Evaluation of clinically relevant drug-drug interactions and population pharmacokinetics of darolutamide in patients with nonmetastatic castration-resistant prostate cancer: results of pre-specified and post hoc analyses of the phase III ARAMIS trial. Target Oncol 2019;14(5):527–39. DOI: 10.1007/s11523-019-00674-0
20. Williams S., Mazibuko N., O’Daly O. et al. Significant localized reduction in cerebral blood flow (CBF) in regions relevant to cognitive function with enzalutamide (ENZA) compared to darolutamide (DARO) and placebo (PBO) in healthy volunteers. J Clin Oncol 2020;38:Suppl:326.
21. Zurth C., Sandman S., Trummel D. et al. Higher blood–brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]darolutamide in rats using whole-body autoradiography. J Clin Oncol 2019;37:Suppl:156.
22. Fizazi K., Shore N., Tammela T.L. et al. Nonmetastatic, castrationresistant prostate cancer and survival with darolutamide. N Engl J Med 2020;383(11):1040–9. DOI: 10.1056/NEJMoa2001342
23. Hussain M., Tombal B., Saad F. et al. Efficacy and safety of darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel (DOC) by disease volume and disease risk in the phase 3 ARASENS study. J Clin Oncol 2023;41(6):suppl. DOI: 10.1200/JCO.2023.41.6_suppl.15
24. Hussain M., Tombal B.F., Saad F. et al. Efficacy and safety of darolutamide in combination with ADT and docetaxel by disease volume and disease risk in the phase 3 ARASENS study. 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, 2023.
25. Shore N.D. Overall survival with darolutamide vs placebo in combination with androgen-deprivation therapy (ADT) and docetaxel: A sensitivity analysis from ARASENS accounting for subsequent therapy. J Clin Oncol 2024;42:166. DOI: 10.1200/JCO.2024.42.4_suppl.166
26. Shore N.D. Overall survival with darolutamide versus placebo in combination with androgen deprivation therapy and docetaxel: a sensitivity analysis from ARASENS accounting for subsequent therapy 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, 2024. Available at: https://www.urotoday.com/conference-highlights/asco-gu-2024/asco-gu-2024-prostate-cancer/149314-asco-gu-2024-overall-survival-with-darolutamide-versus-placebo-in-combination-with-androgen-deprivation-therapy-and-docetaxel-a-sensitivity-analysis-from-arasens-accounting-for-subsequent-therapy.html
27. Rezazadeh A., Tombal B.F., Hussain M.H.A. et al. Dosing, safety, and pharmacokinetics (PK) of combination therapy with darolutamide (DARO), androgen-deprivation therapy (ADT), and docetaxel (DOC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the ARASENS study. J Clin Oncol 2023;41:148.
28. Rezazadeh A.R. Dosing, safety, and pharmacokinetics of combination therapy with darolutamide, ADT, and docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the ARASENS study. 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, 2023. Available at: https://www.urotoday.com/conference-highlights/asco-gu-2023/asco-gu-2023-prostate-cancer/142481-asco-gu-2023-dosing-safety-and-pharmacokinetics-of-combination-therapy-with-darolutamide-adt-and-docetaxel-in-patients-with-metastatic-hormone-sensitive-prostate-cancer-mhspc-in-the-arasens-study.html
29. Sweeney C.J., Martin A.J., Stockler M.R. et al; ENZAMET trial investigators and Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol 2023;24(4):323–34. DOI: 10.1016/S1470-2045(23)00063-3
30. Matsukawa A., Litterio G., Cormio A. et al. An updated systematic review and network meta-analysis of first-line triplet vs. doublet therapies for metastatic hormone-sensitive prostate cancer. Cancers (Basel) 2025;17(2):205. DOI: 10.3390/cancers17020205
31. Vale C.L., Fisher D., Godolphin P. et al. Defining more precisely the effects of docetaxel plus ADT for men with mHSPC: meta-analysis of individual participant data from randomized trials. J Clin Oncol 2022;40:16s (suppl; abstr 5070).
32. Yanagisawa T., Rajwa P., Thibault C. et al. Androgen receptor signaling inhibitors in addition to docetaxel with androgen deprivation therapy for metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis. Eur Urol 2022;82(6):584–98. DOI: 10.1016/j.eururo.2022.08.002
33. Riaz I.B., Naqvi S.A.A., He H. et al. First-line systemic treatment options for metastatic castration-sensitive prostate cancer: a living systematic review and network meta-analysis. JAMA Oncol 2023;9(5):635–45. DOI: 10.1001/jamaoncol.2022.7762
34. Mourey L., Boyle H.J., Roubaud G. et al. Efficacy and safety of abiraterone acetate plus prednisone and androgen deprivation therapy +/– docetaxel in older patients (≥70 years), with de novo metastatic-castration sensitive prostate cancer, compared with younger patients (<70 years): the PEACE-1 trial. J Clin Oncol 2023;41:6s (suppl; abstr 20).
35. Carles J. Age-related efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) and docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC): a subgroup analysis of ARASENS. J Clin Oncol 2025;43:143.
36. Swami U., Sinnott J.A., Haaland B. et al. Treatment pattern and outcomes with systemic therapy in men with metastatic prostate cancer in the real-world patients in the United States. Cancers (Basel) 2021;13(19):4951. DOI: 10.3390/cancers13194951
37. Martini A., Mottet N., Montorsi F. et al. A plea for economically sustainable evidence-based guidelines. Eur Urol 2022;82(5):449–51. DOI: 10.1016/j.eururo.2022.08.001
Review
For citations:
Volkova M.I., Turupaev K.A. Role of darolutamide in intensification of treatment of patients with hormone-sensitive prostate cancer: who needs the triplet combination? Cancer Urology. 2025;21(2):89-103. (In Russ.) https://doi.org/10.17650/1726-9776-2025-21-2-89-103
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