Androgen Receptor Directed Therapy on Cognitive Function in Patients Treated With Darolutamide or Enzalutamide

Study Overview
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Brief Summary
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This is a prospective, randomized, open-label phase II study comparing cognitive outcomes between men with non-metastatic and metastatic castration-resistant prostate cancer (mCRPC or M0CRPC) treated with darolutamide or enzalutamide. 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.

Detailed Description
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The goal of the trial is to assess cognitive and quality of life outcomes over the 52-week primary data collection period of the trial. This is a prospective, randomized, open-label phase II study comparing cognitive outcomes between men with metastatic or non-metastatic CRPC (mCRPC or M0CRPC) treated with darolutamide or enzalutamide. This will be a multicenter trial conducted at 12 sites across the US. 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 52 weeks or/and cross-over/end of treatment visit (if applicable).

Official Title
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A Randomized Phase II Study of Androgen Receptor Directed Therapy on COGnitive Function in Patients Treated With Darolutamide or Enzalutamide (ARACOG)

Conditions
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Metastatic Prostate Cancer, Prostate Cancer Metastatic, Prostate Cancer, Castrate Resistant Prostate Cancer

Intervention / Treatment
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* Drug: Darolutamide
* Drug: Enzalutamide


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria include: Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features Progressive disease per PCWG3 criteria Metastatic CRPC or non-metastatic CRPC (M0CRPC) Castration-resistant prostate cancer demonstrated during continuous ADT, defined as 3 PSA rises at least 1 week apart, with the last PSA >2 ng/mL. For mCRPC: metastatic disease documented by standard or novel imaging techniques OR for M0CPRC: no evidence of metastatic disease on standard imaging. Surgically or medically castrated, with testosterone levels of <50 ng/dL. If the patient is medically castrated, continuous dosing with GnRHa must have been initiated at least 4 weeks prior to randomization and must be continued throughout the study. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 Able to complete cognitive testing and patient reported outcome surveys in English. Ability to swallow study tablets whole. Able to provide informed consent. Key exclusion criteria include: Prior chemotherapy for treatment of CRPC. Patients who received chemotherapy for castrate-sensitive prostate cancer are still eligible provided chemotherapy was completed >6 months prior to study entry. Use of investigational agents for the treatment of prostate cancer within 4 weeks of study entry. Prior usage of ENZ or DARO. Prior use of apalutamide Prior use of investigational agents that act on the androgen axis. Progression during treatment with abiraterone (PSA or radiographic progression). Must have < 12 weeks of abiraterone exposure prior to enrollment if given for treatment of CRPC. If used with radiation for high risk localized hormone sensitive disease, can enroll if no progression of disease during treatment with abiraterone (PSA or radiographic) and >6 months since last exposure to abiraterone. Planned radiation treatment > 21 days during enrollment in the study. Any active, or prior history of, brain metastasis that have not been treated and stabilized. Active or history of seizures or seizure disorder. Prior diagnosis of dementia or other neurologic impairment. Use of chronic opiates (other than stable doses of opioids that in the view of the patient and investigator do not affect cognition). Clinically significant history of falls or risk of falls at baseline (timed up-and-go (TUG) test time of >12 seconds).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Darolutamide (DARO)<br>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<br>* Patients randomized to darolutamide.<br>* Other names: Nubeqa;|
| Active Comparator: Enzalutamide (ENZ)<br>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<br>* Patients randomized to enzalutamide.<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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.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. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 52 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. | 52 weeks | 
| Proportion of impaired patients | Cumulative proportion of impaired patients in each arm | 24 weeks | 
| Proportion of impaired patients | Cumulative proportion of impaired patients in each arm | 52 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. | 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. | 52 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. | 52 weeks | 
| Prostate-specific antigen (PSA) progression. | Estimation of the probability of PSA progression over time using the cumulative incidence function. | 104 weeks | 
| Progression free survival | Progression-free survival will be evaluated for each cohort. | 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%) | 24 weeks |