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Clinical Trial
. 2025 May 1;8(5):e258751.
doi: 10.1001/jamanetworkopen.2025.8751.

Enzalutamide and Prostate-Specific Antigen Levels in Metastatic Prostate Cancer: A Secondary Analysis of the ARCHES Randomized Clinical Trial

Arun A Azad  1 , Daniel P Petrylak  2 , Taro Iguchi  3 , Neal D Shore  4 , Arnauld Villers  5 , Francisco Gomez-Veiga  6 , Antonio Alcaraz  7 , Boris Alekseev  8 , Russell Z Szmulewitz  9 , Jeffrey Holzbeierlein  10 , Brad Rosbrook  11 , Jie Ma  12 , Fabian Zohren  13 , Nader N El-Chaar  14 , Gabriel P Haas  15 , Arnulf Stenzl  16 , Andrew J Armstrong  17
Affiliations
Clinical Trial

Enzalutamide and Prostate-Specific Antigen Levels in Metastatic Prostate Cancer: A Secondary Analysis of the ARCHES Randomized Clinical Trial

Arun A Azad et al. JAMA Netw Open. .

Abstract

Importance: In men with metastatic hormone-sensitive prostate cancer (mHSPC), prostate-specific antigen (PSA) decline after treatment has been associated with improved survival. However, the data on PSA decline are limited in men with mHSPC after treatment with enzalutamide plus androgen deprivation therapy (ADT).

Objective: To evaluate the association of enzalutamide plus ADT in men with mHSPC by PSA level at study enrollment in individuals with prior ADT and by degree of PSA reduction with clinical end points.

Design, setting, and participants: This post hoc secondary analysis was performed on data collected from the ARCHES multinational, double-blind, phase 3 randomized clinical trial. In the ARCHES trial, men with mHSPC were randomized between March 21, 2016, and January 12, 2018. Analyses were performed in October 2018 (median follow-up, 14.4 months; IQR, 11.2-17.7 months) and May 2021 (median follow-up, 44.6 months; IQR, 41.3-48.6 months).

Intervention: Patients were randomized 1:1 to enzalutamide (160 mg/d) plus ADT or placebo plus ADT. ADT received for 3 to 6 months before study enrollment was permitted.

Main outcomes and measures: Radiographic progression-free survival (rPFS) and overall survival (OS) were correlated post hoc with PSA level at enrollment in patients with prior ADT and additionally with PSA decline at 6 months or undetectable PSA (<0.2 ng/mL) during study treatment.

Results: A total of 1150 men (median age, 70 years; range, 46-92 years) were enrolled. Improvement in clinical outcomes such as rPFS was seen with enzalutamide plus ADT in men with PSA levels at enrollment of 0.2 to 4 ng/mL and above 4 ng/mL. Hazard ratios (HRs) for improved rPFS in men with PSA levels up to 0.2 ng/mL, above 0.2 to 4 ng/mL, and above 4 ng/mL were 0.59 (95% CI, 0.27-1.30), 0.32 (95% CI, 0.20-0.50), and 0.44 (95% CI, 0.32-0.62), respectively. Patients treated with enzalutamide plus ADT who achieved undetectable PSA had an 86.0% reduced risk of radiographic disease progression (HR, 0.14 [95% CI, 0.09-0.23]; P < .001) and a 76.0% reduced risk of death (HR, 0.24 [95% CI, 0.17-0.34]; P < .001).

Conclusions and relevance: In this secondary analysis of a randomized clinical trial, patients with mHSPC treated with enzalutamide plus ADT vs placebo plus ADT had improved clinical outcomes regardless of PSA level at enrollment. Undetectable PSA was associated with improved clinical outcomes with enzalutamide treatment. Future studies are required to further characterize the clinical utility of further treatment intensification among men with mHSPC for whom ADT plus enzalutamide fails to achieve undetectable PSA.

Trial registration: ClinicalTrials.gov Identifier: NCT02677896.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Azad reported receiving personal fees from Aculeus Therapeutics, Amgen, Arvinas, Astellas, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Janssen, Merck Serono, Merck Sharpe & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar and receiving travel expenses from Amgen, Astellas, Bayer, Hinova, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar outside the submitted work. In addition, Dr Azad reported receiving grants from Aptevo Therapeutics, Astellas, AstraZeneca, Bayer, Bionomics, Bristol Myers Squibb, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Hinova, Ipsen, Janssen, MedImmune, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Sanofi Aventis, and Synthorx outside the submitted work. Dr Azad also reported serving as a clinical trial steering committee member for Arvinas, Astellas, AstraZeneca, Exelixis, Janssen, and Pfizer; as a Scientific Advisory Committee member and chair of the Translational Research Subcommittee for the ANZUP Cancer Trials Group; and as Chair of Urologic Oncology for the Clinical Oncology Society of Australia outside the submitted work. Dr Petrylak reported receiving personal fees from Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Exelixis, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Ipsen, Janssen, Merck & Co Inc, Mirati, Monopteros, Pfizer, Pharmacyclics, Regeneron, Roche, Sanofi Aventis Pharmaceuticals, Seattle Genetics, and Urogen outside the submitted work. In addition, Dr Petrylak reported receiving grants from Ada Cap (Advanced Accelerator Applications), Agensys Inc, Arvinas, Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Daiichi Sankyo, Eisai, Eli Lilly, Endocyte, Ferring, Genentech, Gilead Sciences, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics, Replimune, Roche, Sanofi Aventis, and Seattle Genetics outside the submitted work. Dr Iguchi reported receiving grants from Astellas and Bayer and personal fees from Astellas, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Janssen, Kissei, Merck Sharpe & Dohme, Nippon Shinyaku, Novartis, Sanofi, Takeda, and Teleflex outside the submitted work. Dr Shore reported receiving consulting fees from Astellas, AstraZeneca, Bayer, Daiichi Sankyo, Janssen, and Novartis outside the submitted work. Dr Alekseev reported receiving grants from Astellas during the conduct of the study. In addition, Dr Alekseev reported receiving personal fees from Astellas, AstraZeneca, Bayer, Eisai, Ipsen, Janssen, Merck, Pfizer, and Roche outside the submitted work. Dr Szmulewitz reported receiving grants from Astellas and Pfizer during the conduct of the study. In addition, Dr Szmulewitz reported receiving personal fees from Bayer and Janssen outside the submitted work. Dr Zohren reported being employed by and owning stock in Immunogen and Pfizer during the conduct of the study. Dr El-Chaar reported being employed by Astellas Pharma during the conduct of the study. Dr Haas reported being employed by Astellas Pharma Global Development during the conduct of the study. Dr Armstrong reported receiving grants and personal fees from Astellas and Pfizer during the conduct of the study. In addition, Dr Armstrong reported receiving grants from Amgen, AstraZeneca, Bristol Myers Squibb, Janssen, and Merck as well as personal fees from AstraZeneca, Bayer, Myovant, and Novartis outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Efficacy Outcomes of Enzalutamide Plus Androgen Deprivation Therapy (ADT) vs Placebo Plus ADT in Prostate-Specific Antigen (PSA) Categories (≤0.2, >0.2-4, or >4 ng/mL) at Study Enrollment
Analysis was conducted in intention-to-treat patients with prior ADT use. The data cutoff date was May 28, 2021 (median follow-up, 44.6 months; IQR, 41.3-48.6 months). To convert PSA to micrograms per liter, multiply by 1.0. HR indicates hazard ratio; ICR, independent central review; NR, not reached; OS, overall survival; QOL, quality of life; rPFS, radiographic progression-free survival.
Figure 2.
Figure 2.. Kaplan-Meier Plots of Overall Survival (OS) Adjusted for Crossover by Prostate-Specific Antigen (PSA) Categories (≤0.2, >0.2-4, or >4 ng/mL) at Study Enrollment
Analysis was conducted in intention-to-treat patients with prior androgen deprivation therapy (ADT) use. The data cutoff date was May 28, 2021. Events were death from any cause. Time from randomization to death from any cause. For patients still alive at the date of the analysis cutoff point, OS was censored on the last date the patient was known to be alive. For the overall population, the log-rank test was stratified by treatment group, volume of disease, and prior docetaxel use. Within each treatment group, the log-rank test was stratified by volume of disease and prior docetaxel use. To convert PSA to micrograms per liter, multiply by 1.0. HR indicates hazard ratio.
Figure 3.
Figure 3.. Kaplan-Meier Plots of Radiographic Progression-Free Survival (rPFS) and Overall Survival (OS) by Prostate-Specific Antigen (PSA) Decline (to <0.2, 0.2-4, or >4 ng/mL) at 6 Months
Analysis was conducted in intention-to-treat patients treated with enzalutamide plus androgen deprivation therapy (ADT) with detectable PSA at baseline and available 6-month PSA values. The data cutoff date was May 28, 2021. To convert PSA to micrograms per liter, multiply by 1.0. HR indicates hazard ratio.
Figure 4.
Figure 4.. Kaplan-Meier Plot of Time to Achieve Undetectable Prostate-Specific Antigen (PSA) by Treatment Group
Analysis was conducted in intention-to-treat patients treated with enzalutamide plus androgen deprivation therapy (ADT) with detectable PSA at baseline. The data cutoff date was October 14, 2018. Note that the additional patient in the placebo plus ADT group was included at the later data cutoff date of May 28, 2021. To convert PSA to micrograms per liter, multiply by 1.0. HR indicates hazard ratio.
Figure 5.
Figure 5.. Kaplan-Meier Plots of Radiographic Progression-Free Survival (rPFS) and Overall Survival (OS) by Prostate-Specific Antigen (PSA) Decline to Undetectable (<0.2 ng/mL) at Any Time During the Treatment Period
Analysis was conducted in intention-to-treat patients treated with enzalutamide plus androgen deprivation therapy (ADT) with detectable PSA at baseline. Events were death from any cause. Time from randomization to death from any cause. For patients still alive at the date of the analysis cutoff point, OS was censored on the last date the patient was known to be alive. The data cutoff dates for OS and rPFS were May 28, 2021, and October 14, 2018, respectively. To convert PSA to micrograms per liter, multiply by 1.0. HR indicates hazard ratio.
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