Efficacy and Safety of Darolutamide in Patients with Nonmetastatic Castration-resistant Prostate Cancer Stratified by Prostate-specific Antigen Doubling Time: Planned Subgroup Analysis of the Phase 3 ARAMIS Trial. 2023

Martin Bögemann, and Neal D Shore, and Matthew R Smith, and Teuvo L J Tammela, and Albertas Ulys, and Egils Vjaters, and Sergey Polyakov, and Mindaugas Jievaltas, and Murilo Luz, and Boris Alekseev, and Thierry Lebret, and Martin Schostak, and Frank Verholen, and Marie-Aude Le Berre, and Shankar Srinivasan, and Jorge Ortiz, and Ateesha F Mohamed, and Toni Sarapohja, and Karim Fizazi
Department of Urology, Münster University Medical Center, Münster, Germany. Electronic address: martin.boegemann@ukmuenster.de.

Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have a high risk of progression to metastatic disease, particularly if their prostate-specific antigen doubling time (PSADT) is ≤6 mo. However, patients remain at a high risk with a PSADT of >6 mo. To evaluate the efficacy and safety of darolutamide versus placebo in patients stratified by PSADT >6 or ≤6 mo. A planned subgroup analysis of a global multicenter, double-blind, randomized, phase 3 trial in men with nmCRPC and PSADT ≤10 mo was conducted. Patients were randomized 2:1 to oral darolutamide 600 mg twice daily or placebo, while continuing androgen-deprivation therapy. The primary endpoint was metastasis-free survival (MFS). Secondary endpoints were overall survival (OS) and times to pain progression, first cytotoxic chemotherapy, and symptomatic skeletal events. Quality of life (QoL) was measured using validated prostate-relevant tools. Safety was recorded throughout the study. Of 1509 patients enrolled, 469 had PSADT >6 mo (darolutamide n = 286; placebo n = 183) and 1040 had PSADT ≤6 mo (darolutamide n = 669; placebo n = 371). Baseline characteristics were balanced between subgroups. Darolutamide significantly prolonged MFS versus placebo in both subgroups (unstratified hazard ratio [95% confidence interval]: PSADT >6 mo, 0.38 [0.26-0.55]; PSADT ≤6 mo, 0.41 [0.33-0.52]). OS and other efficacy and QoL endpoints favored darolutamide with significant improvement over placebo in both subgroups. The incidence of adverse events, including events commonly associated with androgen receptor inhibitors (fractures, falls, hypertension, and mental impairment), and discontinuations due to adverse events were low and similar to placebo. Limitations include small subgroup populations. In patients with nmCRPC and PSADT >6 mo (maximum 10 mo), darolutamide provided a favorable benefit/risk ratio, characterized by significant improvements in MFS, OS, and other clinically relevant endpoints; maintenance of QoL; and favorable tolerability. In patients with prostate cancer that has stopped responding to standard hormonal therapy (indicated by an increase in prostate-specific antigen [PSA] levels), there is a risk that the cancer will spread to other parts of the body. This risk is highest when the time it takes for the PSA level to double (ie, "PSA doubling time" [PSADT]) is less than 6 mo. However, there is still a risk that the cancer will spread even if the PSADT is longer than 6 mo. In a group of patients whose PSADT was more than 6 mo but no more than 10 mo, treatment with darolutamide slowed the cancer spread and allowed them to live longer than patients who received placebo (inactive drug). Darolutamide treatment did not cause many side effects and helped maintain patients' quality of life without disruptions.

UI MeSH Term Description Entries
D008297 Male Males
D011788 Quality of Life A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral, social environment as well as health and disease. HRQOL,Health-Related Quality Of Life,Life Quality,Health Related Quality Of Life
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000726 Androgen Antagonists Compounds which inhibit or antagonize the biosynthesis or actions of androgens. Androgen Antagonist,Antiandrogen,Antiandrogens,Anti-Androgen Effect,Anti-Androgen Effects,Antiandrogen Effect,Antiandrogen Effects,Antagonist, Androgen,Antagonists, Androgen,Anti Androgen Effect,Anti Androgen Effects,Effect, Anti-Androgen,Effect, Antiandrogen,Effects, Anti-Androgen,Effects, Antiandrogen
D017430 Prostate-Specific Antigen A glycoprotein that is a kallikrein-like serine proteinase and an esterase, produced by epithelial cells of both normal and malignant prostate tissue. It is an important marker for the diagnosis of prostate cancer. Kallikrein hK3,gamma-Seminoprotein,hK3 Kallikrein,Prostate Specific Antigen,Semenogelase,Seminin,Kallikrein, hK3,gamma Seminoprotein
D064129 Prostatic Neoplasms, Castration-Resistant Tumors or cancer of the PROSTATE which can grow in the presence of low or residual amount of androgen hormones such as TESTOSTERONE. Androgen-Independent Prostatic Cancer,Androgen-Independent Prostatic Neoplasms,Androgen-Insensitive Prostatic Cancer,Androgen-Insensitive Prostatic Neoplasms,Androgen-Resistant Prostatic Cancer,Androgen-Resistant Prostatic Neoplasms,Castration-Resistant Prostatic Cancer,Castration-Resistant Prostatic Neoplasms,Hormone Refractory Prostatic Cancer,Hormone Refractory Prostatic Neoplasms,Prostatic Cancer, Androgen-Independent,Prostatic Cancer, Androgen-Insensitive,Prostatic Cancer, Androgen-Resistant,Prostatic Cancer, Castration-Resistant,Prostatic Cancer, Hormone Refractory,Prostatic Neoplasms, Androgen-Independent,Prostatic Neoplasms, Androgen-Insensitive,Prostatic Neoplasms, Androgen-Resistant,Prostatic Neoplasms, Hormone Refractory,Androgen Independent Prostatic Cancer,Androgen Independent Prostatic Neoplasms,Androgen Insensitive Prostatic Cancer,Androgen Insensitive Prostatic Neoplasms,Androgen Resistant Prostatic Cancer,Androgen Resistant Prostatic Neoplasms,Androgen-Independent Prostatic Cancers,Androgen-Independent Prostatic Neoplasm,Androgen-Insensitive Prostatic Cancers,Androgen-Insensitive Prostatic Neoplasm,Androgen-Resistant Prostatic Cancers,Androgen-Resistant Prostatic Neoplasm,Cancer, Androgen-Independent Prostatic,Cancer, Androgen-Insensitive Prostatic,Cancer, Androgen-Resistant Prostatic,Cancer, Castration-Resistant Prostatic,Cancers, Androgen-Independent Prostatic,Cancers, Androgen-Insensitive Prostatic,Cancers, Androgen-Resistant Prostatic,Cancers, Castration-Resistant Prostatic,Castration Resistant Prostatic Cancer,Castration Resistant Prostatic Neoplasms,Castration-Resistant Prostatic Cancers,Castration-Resistant Prostatic Neoplasm,Neoplasm, Androgen-Independent Prostatic,Neoplasm, Androgen-Insensitive Prostatic,Neoplasm, Androgen-Resistant Prostatic,Neoplasm, Castration-Resistant Prostatic,Neoplasms, Androgen-Independent Prostatic,Neoplasms, Androgen-Insensitive Prostatic,Neoplasms, Androgen-Resistant Prostatic,Neoplasms, Castration-Resistant Prostatic,Prostatic Cancer, Androgen Independent,Prostatic Cancer, Androgen Insensitive,Prostatic Cancer, Androgen Resistant,Prostatic Cancer, Castration Resistant,Prostatic Cancers, Androgen-Independent,Prostatic Cancers, Androgen-Insensitive,Prostatic Cancers, Androgen-Resistant,Prostatic Cancers, Castration-Resistant,Prostatic Neoplasm, Androgen-Independent,Prostatic Neoplasm, Androgen-Insensitive,Prostatic Neoplasm, Androgen-Resistant,Prostatic Neoplasm, Castration-Resistant,Prostatic Neoplasms, Androgen Independent,Prostatic Neoplasms, Androgen Insensitive,Prostatic Neoplasms, Androgen Resistant,Prostatic Neoplasms, Castration Resistant

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