A Phase 2 interventional study of Darolutamide and Enzalutamide in Metastatic Prostate Cancer, Prostate Cancer Metastatic and Prostate Cancer, sponsored by Alliance Foundation Trials, LLC.. Completed at 8 sites in United States. Open to male participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-21.
Sponsored by Alliance Foundation Trials, LLC. · Phase 2, Interventional, and Other
This is a prospective, randomized, open-label phase II study comparing cognitive outcomes between men with metastatic and non-metastatic castration resistant prostate cancer (CRPC) or metastatic hormone sensitive prostate cancer (HSPC). Approximately 132 patients will be enrolled. Eligible patients will be randomized in a 1:1 fashion to treatment with enzalutamide 160 mg orally daily or darolutamide 600 mg orally twice daily, in combination with standard LHRH agonist based treatment. Cognitive assessments will be performed using modules from Cambridge Neuropsychological Test Automated Battery (CANTAB) an internationally recognized software for assessing cognitive function and impairment.
The goal of the trial is to assess cognitive and quality of life outcomes over the 48-week primary data collection period of the trial. This is a prospective, randomized, open-label phase II study comparing cognitive outcomes between men with Advanced prostate cancer: metastatic and non-metastatic castration resistant prostate cancer (CRPC) or metastatic hormone sensitive prostate cancer (HSPC).
The primary endpoint will be the percent change in the maximally changed cognitive domain by 24 weeks in each study arm. Patients will be stratified by age (\<65, 65-80, > 80). Patients will be allowed to cross over from either treatment to the opposite treatment arm at 12 and 24 weeks if they meet any of the cross-over criteria as described in the protocol.
Cognitive assessments will be performed using Cambridge Neuropsychological Test Automated Battery (CANTAB), an internationally recognized software for assessing cognitive function and impairment. Tests available in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time. The maximally changed cognitive domain is defined as the domain most changed from baseline in each individual.
Blood samples will be collected for exploratory genomic analyses (AR CAG repeat length, PHS, exosome analysis).
Patients will have the option to opt into an additional separate MRI sub-study. A subset of 40 patients (20 per arm) will undergo fMRI to measure percent signal change in the HP PFC circuit at baseline, 24 and 48 weeks or/and cross-over/end of treatment visit (if applicable).
7,046 studies on the registry are indexed under Prostatic Neoplasms; 1,580 are open to participants now.
This study's enrollment of 111 is above the median of 60 across 5,348 interventional studies indexed under Prostatic Neoplasms.
Browse Prostatic Neoplasms studies →Alliance Foundation Trials, LLC. is the lead sponsor of 22 studies on the registry; 3 are open to participants now.
Of its 6 completed or terminated interventional studies of FDA-regulated products, 5 (83%) have results posted.
Counted across the registry records on this site, refreshed daily.
Key inclusion criteria include:
Progressive disease per PCWG3 criteria with EITHER: CRPC or non- metastatic CRPC (M0CRPC)
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Histologically or cytologically confirmed
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Metastases
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECOG performance status
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patients will take DARO at a dose of 600 mg (300 mg ×2 tablets) by mouth twice daily beginning on Day 1, of Week 1. Patients will take DARO throughout planned treatment period or withdrawal of consent or progression of disease requiring change in therapy.
Drug: Darolutamide
Patients will take ENZ at a dose of 160 mg PO once daily (QD), beginning on Day 1, of Week 1. Patients will take ENZ throughout planned treatment period or withdrawal of consent or progression of disease requiring change in therapy.
Drug: Enzalutamide
Patients randomized to darolutamide.
Also known as: Nubeqa
Patients randomized to enzalutamide.
Also known as: Xtandi
Change in the Maximally Changed Cognitive Domain
To compare the effects of treatment with enzalutamide (ENZ) versus darolutamide (DARO) on the cognitive function of men with non-metastatic and metastatic castration-resistant prostate cancer by comparing the change in the maximally changed cognitive domain utilizing Cambridge Neuropsychological Test Automated Battery \[CANTAB\] cognitive tests from baseline in patients in each study arm. The maximally changed cognitive domain is defined as the domain most changed from baseline in each individual. CANTAB is the max score from 5 subscores Paired Associates Learning (0-20, Higher scores = better performance), Spatial Working Memory (0-63, Higher scores = worse performance), Rapid Visual Information Processing (0-1, Higher scores = better performance), Spatial Span (2-9, Higher scores = better performance), and One Touch Stockings of Cambridge (1-7, Higher scores = worse performance).
Time frame: 24 weeks
Crossover From Enzalutamide to Darolutamide and Darolutamide to Enzalutamide
Proportion of patients crossing over from each treatment arm based on subjective (self-reported, FACT-Cognitive Function \[Version 3\], FACT-Cog V3, decline by \>10 points from baseline score) cognitive effects. * Proportion of patients crossing over from each treatment arm based on objective cognitive effects (the Cambridge Neuropsychological Test Automated Battery \[CANTAB\] , decline by \> 30% from baseline on any cognitive domain). * Proportion of patients crossing over from ENZ to DARO based on Timed Up and Go (TUG) times \>12 seconds or 12 seconds or increase from baseline by \>1 second. * Proportion of patient crossing over due to neurologic toxicity (fatigue) with a preference to cross over (ENZ or DARO) or severe neurological toxicity \[seizures or posterior reversible encephalopathy syndrome PRES\]). Cross over for severe neurologic toxicity is allowed for patients on ENZ only.
Time frame: 48 weeks
Maximally Changed Cognitive Domain
Average decline in maximally changed cognitive domain in patients in each arm based on self-reported cognitive tests (Cambridge Neuropsychological Test Automated Battery \[CANTAB\]). Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time. The maximally changed cognitive domain is defined as the domain most changed from baseline in each individual.
Time frame: 48 weeks
Proportion of Impaired Patients
Cumulative proportion of impaired patients in each arm
Time frame: 24 weeks
Proportion of Impaired Patients
Cumulative proportion of impaired patients in each arm
Time frame: 48 weeks
Change in Lowest Ranking Domain
Average change in lowest ranking domain Cambridge Neuropsychological Test Automated Battery \[CANTAB\] questionnaire outcomes at baseline (in a given individual). Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time.
Time frame: 24 weeks
Change in Lowest Ranking Domain
Average change in lowest ranking domain in Cambridge Neuropsychological Test Automated Battery \[CANTAB\] outcomes at baseline (in a given individual). Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time.
Time frame: 48 weeks
Improve in Cognitive Function After Crossover
Improvement in cognitive function after crossover from each treatment arm based on Cambridge Neuropsychological Test Automated Battery \[CANTAB\] modules. Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time.
Time frame: 48 weeks
Prostate-specific Antigen (PSA) Progression.
Estimation of the probability of PSA progression over time using the cumulative incidence function.
Time frame: 104 weeks
Progression Free Survival
Progression-free survival will be evaluated for each cohort.
Time frame: 104 weeks
Prostate-specific Antigen (PSA) Response Rate
Estimation or the proportion PSA responses at 24 weeks (on the basis of a decrease from baseline of ≥ 50%)
Time frame: 24 weeks
| Milestone | Darolutamide (DARO) First, Then Enzalutamide (ENZ) | Enzalutamide (ENZ) First, Then Darolutamide (DARO) |
|---|---|---|
| Started | 55 | 56 |
| Completed | 48 | 47 |
| Not completed | 7 | 9 |
| Milestone | Darolutamide (DARO) First, Then Enzalutamide (ENZ) | Enzalutamide (ENZ) First, Then Darolutamide (DARO) |
|---|---|---|
| Started | 0 | 18 |
| Completed | 0 | 18 |
| Not completed | 0 | 0 |
| Milestone | Darolutamide (DARO) First, Then Enzalutamide (ENZ) | Enzalutamide (ENZ) First, Then Darolutamide (DARO) |
|---|---|---|
| Started | 0 | 12 |
| Completed | 0 | 12 |
| Not completed | 0 | 0 |
To compare the effects of treatment with enzalutamide (ENZ) versus darolutamide (DARO) on the cognitive function of men with non-metastatic and metastatic castration-resistant prostate cancer by comparing the change in the maximally changed cognitive domain utilizing Cambridge Neuropsychological Test Automated Battery \[CANTAB\] cognitive tests from baseline in patients in each study arm. The maximally changed cognitive domain is defined as the domain most changed from baseline in each individual. CANTAB is the max score from 5 subscores Paired Associates Learning (0-20, Higher scores = better performance), Spatial Working Memory (0-63, Higher scores = worse performance), Rapid Visual Information Processing (0-1, Higher scores = better performance), Spatial Span (2-9, Higher scores = better performance), and One Touch Stockings of Cambridge (1-7, Higher scores = worse performance).
| Percent change | Darolutamide (DARO) First, Then Enzalutamide (ENZ) | Enzalutamide (ENZ) First, Then Darolutamide (DARO) |
|---|---|---|
| Change in the Maximally Changed Cognitive Domain | -15.8 (-38.8 to -2.6) | -36.1 (-59.3 to -16.7) |
Proportion of patients crossing over from each treatment arm based on subjective (self-reported, FACT-Cognitive Function \[Version 3\], FACT-Cog V3, decline by \>10 points from baseline score) cognitive effects. * Proportion of patients crossing over from each treatment arm based on objective cognitive effects (the Cambridge Neuropsychological Test Automated Battery \[CANTAB\] , decline by \> 30% from baseline on any cognitive domain). * Proportion of patients crossing over from ENZ to DARO based on Timed Up and Go (TUG) times \>12 seconds or 12 seconds or increase from baseline by \>1 second. * Proportion of patient crossing over due to neurologic toxicity (fatigue) with a preference to cross over (ENZ or DARO) or severe neurological toxicity \[seizures or posterior reversible encephalopathy syndrome PRES\]). Cross over for severe neurologic toxicity is allowed for patients on ENZ only.
| Participants | Darolutamide (DARO) First, Then Enzalutamide (ENZ) | Enzalutamide (ENZ) First, Then Darolutamide (DARO) |
|---|---|---|
| Subjective Decline (FACT-COG) Only | 0 | 2 |
| Objective Decline (CANTAB) Only | 0 | 9 |
| Increased Risk of Falls Only | 0 | 1 |
| Neurologic Toxicity (Fatigue / AE grade ≥ 2) Only | 0 | 3 |
| Severe Neurologic Toxicity (seizure, falls, PRES) Only | 0 | 1 |
| TUG Time Increase (removed as crossover reason after 1/5/2023) Only | 0 | 2 |
| Multiple Crossover Reasons | 0 | 12 |
Average decline in maximally changed cognitive domain in patients in each arm based on self-reported cognitive tests (Cambridge Neuropsychological Test Automated Battery \[CANTAB\]). Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time. The maximally changed cognitive domain is defined as the domain most changed from baseline in each individual.
Results for this outcome have not been posted.
Cumulative proportion of impaired patients in each arm
Results for this outcome have not been posted.
Cumulative proportion of impaired patients in each arm
Results for this outcome have not been posted.
Average change in lowest ranking domain Cambridge Neuropsychological Test Automated Battery \[CANTAB\] questionnaire outcomes at baseline (in a given individual). Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time.
Results for this outcome have not been posted.
Average change in lowest ranking domain in Cambridge Neuropsychological Test Automated Battery \[CANTAB\] outcomes at baseline (in a given individual). Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time.
Results for this outcome have not been posted.
Improvement in cognitive function after crossover from each treatment arm based on Cambridge Neuropsychological Test Automated Battery \[CANTAB\] modules. Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time.
Results for this outcome have not been posted.
Estimation of the probability of PSA progression over time using the cumulative incidence function.
Results for this outcome have not been posted.
Progression-free survival will be evaluated for each cohort.
Results for this outcome have not been posted.
Estimation or the proportion PSA responses at 24 weeks (on the basis of a decrease from baseline of ≥ 50%)
Results for this outcome have not been posted.
Collected over Up to 24 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Darolutamide (DARO) | 0/55 (0%) | 52/55 (94.5%) | 12/55 (21.8%) |
| Enzalutamide (ENZ) | 2/56 (3.6%) | 51/56 (91.1%) | 7/56 (12.5%) |
| Crossover Enzalutamide (ENZ) | 0/30 (0%) | 27/30 (90%) | 3/30 (10%) |
| Event | Darolutamide (DARO) | Enzalutamide (ENZ) | Crossover Enzalutamide (ENZ) |
|---|---|---|---|
| FatigueGeneral disorders | 33/55 | 35/56 | 12/30 |
| AnemiaBlood and lymphatic system disorders | 28/55 | 20/56 | 10/30 |
| Hot flashesVascular disorders | 18/55 | 22/56 | 4/30 |
| HypertensionVascular disorders | 19/55 | 21/56 | 7/30 |
| HyperlipidemiaMetabolism and nutrition disorders | 15/55 | 10/56 | 0/30 |
| Cognitive disturbanceNervous system disorders | 6/55 | 7/56 | 7/30 |
| Urinary frequencyRenal and urinary disorders | 12/55 | 10/56 | 5/30 |
| ConstipationGastrointestinal disorders | 9/55 | 6/56 | 6/30 |
| DiarrheaGastrointestinal disorders | 11/55 | 10/56 | 2/30 |
| Back painMusculoskeletal and connective tissue disorders | 8/55 | 11/56 | 4/30 |
| Event | Darolutamide (DARO) | Enzalutamide (ENZ) | Crossover Enzalutamide (ENZ) |
|---|---|---|---|
| Neoplasms benign, mal, uncpec - Oth specNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 2/55 | 0/56 | 0/30 |
| Vascular disorders - Other, specifyVascular disorders | 2/55 | 0/56 | 0/30 |
| Heart failureCardiac disorders | 0/55 | 0/56 | 1/30 |
| Generalized muscle weaknessMusculoskeletal and connective tissue disorders | 0/55 | 0/56 | 1/30 |
| HematuriaRenal and urinary disorders | 0/55 | 0/56 | 1/30 |
| Renal and urinary disorders - Oth specRenal and urinary disorders | 0/55 | 0/56 | 1/30 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 0/55 | 0/56 | 1/30 |
| Blurred visionEye disorders | 1/55 | 0/56 | 0/30 |
| Duodenal perforationGastrointestinal disorders | 1/55 | 0/56 | 0/30 |
| Small intestinal obstructionGastrointestinal disorders | 1/55 | 0/56 | 0/30 |
| Age, Continuous(years) | Darolutamide (DARO) First, Then Enzalutamide (ENZ) | Enzalutamide (ENZ) First, Then Darolutamide (DARO) | Total |
|---|---|---|---|
| Median | 70.7 (66.0 to 75.4) | 71.3 (66.4 to 77.0) | 71.1 (66.3 to 76.0) |
| Sex: Female, Male(Participants) | Darolutamide (DARO) First, Then Enzalutamide (ENZ) | Enzalutamide (ENZ) First, Then Darolutamide (DARO) | Total |
|---|---|---|---|
| Female | 0 | 0 | 0 |
| Male | 55 | 56 | 111 |
| Ethnicity (NIH/OMB)(Participants) | Darolutamide (DARO) First, Then Enzalutamide (ENZ) | Enzalutamide (ENZ) First, Then Darolutamide (DARO) | Total |
|---|---|---|---|
| Hispanic or Latino | 3 | 3 | 6 |
| Not Hispanic or Latino | 50 | 49 | 99 |
| Unknown or Not Reported | 2 | 4 | 6 |
| Race (NIH/OMB)(Participants) | Darolutamide (DARO) First, Then Enzalutamide (ENZ) | Enzalutamide (ENZ) First, Then Darolutamide (DARO) | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 1 | 1 |
| Asian | 1 | 1 | 2 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 1 | 7 | 8 |
| White | 51 | 41 | 92 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 2 | 6 | 8 |
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Studies of the drugs tested here: Darolutamide · Enzalutamide
Alliance Foundation Trials, LLC.