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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
111
Patients randomized to darolutamide.
Patients randomized to enzalutamide.
University of California - San Francisco at Mount Zion
San Francisco, California, United States
Northwestern University Feinberg School of Medicine
Chicago, Illinois, United States
University of Chicago
Chicago, Illinois, United States
University of Kansas Cancer Center
Fairway, Kansas, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
University of Minnesota
Minneapolis, Minnesota, United States
University of Oklahoma
Oklahoma City, Oklahoma, United States
Froedtert and the Medical College of Wisconsin
Milwaukee, Wisconsin, United States
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.
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
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