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Metastatic Prostate CancerPhase 2ARACOGNCT04335682

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

A Phase 2 study testing Darolutamide and Enzalutamide in people with Metastatic Prostate Cancer and Prostate Cancer Metastatic, run by Alliance Foundation Trials, LLC. at 8 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older, men only
What is being tested?
Darolutamide and Enzalutamide
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
111 participants
Where
8 sitesUnited States
Study dates
17 Aug 2021to 1 May 2026
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Men only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologically or cytologically confirmed adenocarcinoma of the prostate
  • Progressive disease per PCWG3 criteria with EITHER: Metastatic CRPC or non- metastatic CRPC (M0CRPC)
  • For mCRPC: metastatic disease documented by standard or novel imaging techniques
  • OR for M0CPRC: no evidence of metastatic disease on standard imaging.
  • OR mHSPC
  • Surgically or medically castrated, with testosterone levels of <50 ng/dL. If the patient is medically castrated, continuous dosing with GnRH agonist or antagonist must have been initiated at least 4 weeks prior to randomization and must be continued throughout the study.
Show all 10Show fewer
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤2
  • Able to complete cognitive testing and patient reported outcome surveys in English.
  • Ability to swallow study medications whole.
  • Able to provide informed consent.

Who cannot join

None listed.

Trial locations and contacts

8 sites in 1 country.

8 sites in 1 country

United States8 sites

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02115

  • Northwestern University Feinberg School of Medicine

    Chicago, Illinois, 60611

  • University of Chicago

    Chicago, Illinois, 60637

  • University of Kansas Cancer Center

    Fairway, Kansas, 66205

  • Froedtert and the Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

  • University of Minnesota

    Minneapolis, Minnesota, 55455

  • University of Oklahoma

    Oklahoma City, Oklahoma, 73104

  • University of California - San Francisco at Mount Zion

    San Francisco, California, 94115

Other trials in United States

About this study

Official title: 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 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.

Read the detailed description

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).

Being tested
Darolutamide, Enzalutamide
Medical subject headings
Prostatic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DarolutamideDrug

    Also called Nubeqa

    Patients randomized to darolutamide.

  • EnzalutamideDrug

    Also called Xtandi

    Patients randomized to enzalutamide.

Study groups in NCT04335682
Study groupRoleWhat they receive
Darolutamide (DARO)Active comparatorPatients 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.
Receives: Drug: Darolutamide
Enzalutamide (ENZ)Active comparatorPatients 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.
Receives: Drug: Enzalutamide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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).

    Measured: 24 weeks

Secondary outcomes (10)

  1. 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.

    Measured: 48 weeks

  2. 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.

    Measured: 48 weeks

  3. Proportion of Impaired Patients

    Cumulative proportion of impaired patients in each arm

    Measured: 24 weeks

  4. Proportion of Impaired Patients

    Cumulative proportion of impaired patients in each arm

    Measured: 48 weeks

  5. 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.

    Measured: 24 weeks

  6. 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.

    Measured: 48 weeks

  7. 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.

    Measured: 48 weeks

  8. Prostate-specific Antigen (PSA) Progression.

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

    Measured: 104 weeks

  9. Progression Free Survival

    Progression-free survival will be evaluated for each cohort.

    Measured: 104 weeks

  10. 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%)

    Measured: 24 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Apr 2020
  2. Study start17 Aug 2021
  3. Primary completion1 Sep 2025
  4. Study completion1 May 2026

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Other
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
111 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04335682
Sponsor's protocol ID
AFT-47
Acronym
ARACOG
Status last verified
Jun 2026
First submitted
13 Jan 2020
Last updated
21 Sep 2026
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2019 Mar 28;380(13):1235-1246. doi: 10.1056/NEJMoa1815671. Epub 2019 Feb 14.

    PubMed 30763142

  • Apple AC, Ryals AJ, Alpert KI, Wagner LI, Shih PA, Dokucu M, Cella D, Penedo FJ, Voss JL, Wang L. Subtle hippocampal deformities in breast cancer survivors with reduced episodic memory and self-reported cognitive concerns. Neuroimage Clin. 2017 Mar 16;14:685-691. doi: 10.1016/j.nicl.2017.03.004. eCollection 2017.

    PubMed 28377882

  • Podsiadlo D, Richardson S. The timed "Up & Go": a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991 Feb;39(2):142-8. doi: 10.1111/j.1532-5415.1991.tb01616.x.

    PubMed 1991946

  • Wang L, Apple AC, Schroeder MP, Ryals AJ, Voss JL, Gitelman D, Sweet JJ, Butt ZA, Cella D, Wagner LI. Reduced prefrontal activation during working and long-term memory tasks and impaired patient-reported cognition among cancer survivors postchemotherapy compared with healthy controls. Cancer. 2016 Jan 15;122(2):258-68. doi: 10.1002/cncr.29737. Epub 2015 Oct 20.

    PubMed 26484435

  • de Souza JA, Yap BJ, Wroblewski K, Blinder V, Araujo FS, Hlubocky FJ, Nicholas LH, O'Connor JM, Brockstein B, Ratain MJ, Daugherty CK, Cella D. Measuring financial toxicity as a clinically relevant patient-reported outcome: The validation of the COmprehensive Score for financial Toxicity (COST). Cancer. 2017 Feb 1;123(3):476-484. doi: 10.1002/cncr.30369. Epub 2016 Oct 7.

    PubMed 27716900

  • Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, Ivashchenko P, Demirhan E, Modelska K, Phung D, Krivoshik A, Sternberg CN. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474. doi: 10.1056/NEJMoa1800536.

    PubMed 29949494

  • Evans CP, Higano CS, Keane T, Andriole G, Saad F, Iversen P, Miller K, Kim CS, Kimura G, Armstrong AJ, Sternberg CN, Loriot Y, de Bono J, Noonberg SB, Mansbach H, Bhattacharya S, Perabo F, Beer TM, Tombal B. The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2016 Oct;70(4):675-683. doi: 10.1016/j.eururo.2016.03.017. Epub 2016 Mar 19.

    PubMed 27006332

  • Lim YY, Pietrzak RH, Ellis KA, Jaeger J, Harrington K, Ashwood T, Szoeke C, Martins RN, Bush AI, Masters CL, Rowe CC, Villemagne VL, Ames D, Darby D, Maruff P. Rapid decline in episodic memory in healthy older adults with high amyloid-beta. J Alzheimers Dis. 2013;33(3):675-9. doi: 10.3233/JAD-2012-121516.

    PubMed 23001710

  • Rosario ER, Carroll JC, Pike CJ. Evaluation of the effects of testosterone and luteinizing hormone on regulation of beta-amyloid in male 3xTg-AD mice. Brain Res. 2012 Jul 23;1466:137-45. doi: 10.1016/j.brainres.2012.05.011. Epub 2012 May 14.

    PubMed 22587890

  • Cherrier MM, Aubin S, Higano CS. Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer. Psychooncology. 2009 Mar;18(3):237-47. doi: 10.1002/pon.1401.

    PubMed 18636420

  • Nead KT, Gaskin G, Chester C, Swisher-McClure S, Leeper NJ, Shah NH. Association Between Androgen Deprivation Therapy and Risk of Dementia. JAMA Oncol. 2017 Jan 1;3(1):49-55. doi: 10.1001/jamaoncol.2016.3662.

    PubMed 27737437

  • Gonzalez BD, Jim HS, Booth-Jones M, Small BJ, Sutton SK, Lin HY, Park JY, Spiess PE, Fishman MN, Jacobsen PB. Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison. J Clin Oncol. 2015 Jun 20;33(18):2021-7. doi: 10.1200/JCO.2014.60.1963. Epub 2015 May 11.

    PubMed 25964245

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Darolutamide and Enzalutamide in people with Metastatic Prostate Cancer and Prostate Cancer Metastatic, run by Alliance Foundation Trials, LLC. at 8 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 21 Sep 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in the Maximally Changed Cognitive Domain (time frame: 24 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04335682, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2026.

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