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

December 4, 2023 updated by: Alliance Foundation Trials, LLC.

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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).

Study Type

Interventional

Enrollment (Estimated)

132

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94115
        • Recruiting
        • University of California - San Francisco at Mount Zion
        • Contact:
          • Daniel Kwon, MD
    • Illinois
      • Chicago, Illinois, United States, 60637
        • Recruiting
        • University of Chicago
        • Contact:
          • Russell Szmulewitz, MD
      • Chicago, Illinois, United States, 60611
        • Recruiting
        • Northwestern University Feinberg School of Medicine
        • Contact:
          • David Vanderweele, MD
    • Kansas
      • Fairway, Kansas, United States, 66205
        • Recruiting
        • University of Kansas Cancer Center
        • Contact:
          • Elizabeth Wulff-Burchfield, MD
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Recruiting
        • Dana Farber Cancer Institute
        • Contact:
          • Alicia Morgans, MD
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • Recruiting
        • University of Minnesota
        • Contact:
          • Charles Ryan, MD
    • Missouri
      • Saint Louis, Missouri, United States, 63131
        • Recruiting
        • Missouri Baptist Medical Center
        • Contact:
          • Paul Mehan, MD
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • Recruiting
        • University of Oklahoma
        • Contact:
          • Kelly Stratton
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • Recruiting
        • Froedtert and The Medical College of Wisconsin
        • Contact:
          • Kathryn Bylow, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Darolutamide (DARO)
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 randomized to darolutamide.
Other Names:
  • Nubeqa
Active Comparator: Enzalutamide (ENZ)
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 enzalutamide.
Other Names:
  • Xtandi

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in the maximally changed cognitive domain
Time Frame: 24 weeks
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
Time Frame: 52 weeks

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
Time Frame: 52 weeks
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
Time Frame: 24 weeks
Cumulative proportion of impaired patients in each arm
24 weeks
Proportion of impaired patients
Time Frame: 52 weeks
Cumulative proportion of impaired patients in each arm
52 weeks
Change in lowest ranking domain
Time Frame: 24 weeks
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
Time Frame: 52 weeks
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
Time Frame: 52 weeks
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.
Time Frame: 104 weeks
Estimation of the probability of PSA progression over time using the cumulative incidence function.
104 weeks
Progression free survival
Time Frame: 104 weeks
Progression-free survival will be evaluated for each cohort.
104 weeks
Prostate-specific antigen (PSA) response rate
Time Frame: 24 weeks
Estimation or the proportion PSA responses at 24 weeks (on the basis of a decrease from baseline of ≥ 50%)
24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Alliance Foundation Trials, LLC.

Collaborators

Bayer

Investigators

  • Principal Investigator: Suzanne George, MD, Alliance Foundation Trials

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 17, 2021

Primary Completion (Estimated)

August 1, 2024

Study Completion (Estimated)

August 1, 2024

Study Registration Dates

First Submitted

January 13, 2020

First Submitted That Met QC Criteria

April 3, 2020

First Posted (Actual)

April 6, 2020

Study Record Updates

Last Update Posted (Estimated)

December 5, 2023

Last Update Submitted That Met QC Criteria

December 4, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AFT-47

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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