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

Prostate Cancer Clinical Trial

— ARACOG  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04335682
• Other study ID #: AFT-47
• Status: Recruiting
• Phase: Phase 2
• Start date: August 17, 2021
• Est. completion date: August 2024

Study information

• Verified date: November 2023
• Source: Alliance Foundation Trials, LLC.
• Contact: Director Quality Management and Compliance
• Phone: 617-732-8727
• Email: ClinicalTrials.Queries[@]alliancefoundationtrials.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 132
• Est. completion date: August 2024
• Est. primary completion date: August 1, 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Castrate Resistant Prostate Cancer
• Metastatic Prostate Cancer
• Prostate Cancer
• Prostate Cancer Metastatic
• Prostatic Neoplasms

Intervention

Drug:
• Darolutamide
Patients randomized to darolutamide.
• Enzalutamide
Patients randomized to enzalutamide.

Locations

Country	Name	City	State
United States	Dana Farber Cancer Institute	Boston	Massachusetts
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	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	University of California - San Francisco at Mount Zion	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
Alliance Foundation Trials, LLC.	Bayer

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: N Engl J Med. 2022 Sep 1;387(9):860. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

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