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

Primary Purpose

Metastatic Prostate Cancer, Prostate Cancer Metastatic, Prostate Cancer

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Darolutamide

Enzalutamide

About this trial

This is an interventional other trial for Metastatic Prostate Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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).

Sites / Locations

University of California - San Diego Moores Cancer Center
University of California - San Francisco at Mount ZionRecruiting
Northwestern University Feinberg School of MedicineRecruiting
University of ChicagoRecruiting
University of Kansas Cancer CenterRecruiting
Dana Farber Cancer Institute
University of Minnesota
Missouri Baptist Medical CenterRecruiting
New Hampshire Oncology and HematologyRecruiting
Ohio State University James Cancer Center
University of Oklahoma
Froedtert and the Medical College of WisconsinRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Darolutamide (DARO)

Enzalutamide (ENZ)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

Proportion of impaired patients

Cumulative proportion of impaired patients in each arm

Proportion of impaired patients

Cumulative proportion of impaired patients in each arm

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.

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.

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.

Prostate-specific antigen (PSA) progression.

Estimation of the probability of PSA progression over time using the cumulative incidence function.

Progression free survival

Progression-free survival will be evaluated for each cohort.

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%)

Full Information

NCT ID

NCT04335682

First Posted

January 13, 2020

Last Updated

November 28, 2022

Sponsor

Alliance Foundation Trials, LLC.

Collaborators

Bayer

1. Study Identification

Unique Protocol Identification Number

NCT04335682

Brief Title

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

Acronym

ARACOG

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Recruiting

Study Start Date

August 17, 2021 (Actual)

Primary Completion Date

August 1, 2024 (Anticipated)

Study Completion Date

August 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Alliance Foundation Trials, LLC.

Collaborators

Bayer

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Other

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

132 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Darolutamide (DARO)

Arm Type

Active Comparator

Arm Description

Arm Title

Enzalutamide (ENZ)

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Darolutamide

Other Intervention Name(s)

Nubeqa

Intervention Description

Patients randomized to darolutamide.

Intervention Type

Drug

Intervention Name(s)

Enzalutamide

Other Intervention Name(s)

Xtandi

Intervention Description

Patients randomized to enzalutamide.

Primary Outcome Measure Information:

Title

Change in the maximally changed cognitive domain

Description

Time Frame

24 weeks

Secondary Outcome Measure Information:

Title

Crossover from enzalutamide to darolutamide and darolutamide to enzalutamide

Description

Time Frame

52 weeks

Title

Maximally changed cognitive domain

Description

Time Frame

52 weeks

Title

Proportion of impaired patients

Description

Cumulative proportion of impaired patients in each arm

Time Frame

24 weeks

Title

Proportion of impaired patients

Description

Cumulative proportion of impaired patients in each arm

Time Frame

52 weeks

Title

Change in lowest ranking domain

Description

Time Frame

24 weeks

Title

Change in lowest ranking domain

Description

Time Frame

52 weeks

Title

Improve in cognitive function after crossover

Description

Time Frame

52 weeks

Title

Prostate-specific antigen (PSA) progression.

Description

Estimation of the probability of PSA progression over time using the cumulative incidence function.

Time Frame

104 weeks

Title

Progression free survival

Description

Progression-free survival will be evaluated for each cohort.

Time Frame

104 weeks

Title

Prostate-specific antigen (PSA) response rate

Description

Estimation or the proportion PSA responses at 24 weeks (on the basis of a decrease from baseline of ≥ 50%)

Time Frame

24 weeks

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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).

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Director Quality Management and Compliance

Phone

617-732-8727

ClinicalTrials.Queries@alliancefoundationtrials.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Monica Bertagnolli, MD

Organizational Affiliation

Alliance Foundation Trials

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of California - San Diego Moores Cancer Center

City

San Diego

State/Province

California

ZIP/Postal Code

92037

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Rana McKay, MD

Facility Name

University of California - San Francisco at Mount Zion

City

San Francisco

State/Province

California

ZIP/Postal Code

94115

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Daniel Kwon, MD

Facility Name

Northwestern University Feinberg School of Medicine

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

David Vanderweele, MD

Facility Name

University of Chicago

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60637

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Russell Szmulewitz, MD

Facility Name

University of Kansas Cancer Center

City

Fairway

State/Province

Kansas

ZIP/Postal Code

66205

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Elizabeth Wulff-Burchfield, MD

Facility Name

Dana Farber Cancer Institute

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Alicia Morgans, MD

Facility Name

University of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Charles Ryan, MD

Facility Name

Missouri Baptist Medical Center

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63131

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Paul Mehan, MD

Facility Name

New Hampshire Oncology and Hematology

City

Hooksett

State/Province

New Hampshire

ZIP/Postal Code

03106

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Douglas Weckstein, MD

Facility Name

Ohio State University James Cancer Center

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

J. Paul Monk, MD

Facility Name

University of Oklahoma

City

Oklahoma City

State/Province

Oklahoma

ZIP/Postal Code

73104

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kelly Stratton

Facility Name

Froedtert and the Medical College of Wisconsin

City

Milwaukee

State/Province

Wisconsin

ZIP/Postal Code

53226

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kathryn Bylow, MD

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

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