Nubeqa® (Darolutamide)
ARACOG Study
SUMMARY
ARACOG, a randomized open-label phase 2 study evaluated cognitive impact between darolutamide and enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC), metastatic hormone sensitive prostate cancer (mHSPC), and non-metastatic castration-resistant prostate cancer (nmCRPC). 1 Patients (N=111; randomized) received either darolutamide (n=55) or enzalutamide (n=56) for 12 or 24 weeks and could then crossover to the other treatment if eligible.
The primary endpoint was the maximally changed cognitive domain (MCCD) among the 5 Cambridge Neuropsychological Test Automated Battery (CANTAB) tests assessed from baseline to 24 weeks. These tests assess multiple cognitive domains, with individual tests measuring different combinations of executive function, working memory, visual memory, and attention. A statistically significant greater decline in MCCD from baseline to 24 weeks was observed with enzalutamide versus darolutamide (P=0.009):
Darolutamide: PALFAM (visual memory/executive function), median change -15.8%
Enzalutamide: SWM (working memory/executive function), median change -36.1%
This page is intended for US healthcare professionals and may contain information outside of the approved prescribing information. It is provided in response to an unsolicited request. It is not intended as an endorsement of any usage not contained in the Prescribing Information. This response should be reviewed together with the current full Prescribing Information (including Boxed Warning) and Medical Safety Summary. These materials contain the approved indications, contraindications, warnings and precautions, adverse reactions, and other important safety information for Nubeqa® (Darolutamide).
Nubeqa is an androgen receptor inhibitor indicated for the treatment of adult patients with non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-sensitive prostate cancer (mCSPC), and metastatic castration-sensitive prostate cancer (mCSPC) in combination with docetaxel.
At 24 weeks, statistically significant decreases of tests scores of enzalutamide compared to darolutamide were observed in 4 of 5 CANTAB tests assessed.
In the enzalutamide group, 16 of 31 patients who met criteria at week 12 crossed over to darolutamide, and 12 of 17 patients who met criteria at week 24 crossed over. In the darolutamide group, no patients who met crossover criteria at week 12 (n=24) or at week 24 (n=24) crossed over to enzalutamide.
CLINICAL DATA
ARACOG Study
Morgans, et al (2026)1 reported results from the phase 2 ARACOG study which compared cognitive function in US patients with advanced prostate cancer treated with darolutamide or enzalutamide.
Study Design/Methods
- ARACOG (AFT-47) was a randomized, open-label phase 2 study (NCT04335682).1,2
- Patients with mCRPC, nmCRPC, or mHSPC were enrolled from 17 August 2021 to 11 March 2025.1
- Patients were randomized 1:1 to receive either darolutamide or enzalutamide and remained on treatment for at least 12 weeks. 1,3 At 12 or 24 weeks, patients meeting any of the following criteria and with a preference to switch to the other treatment were allowed to crossover1:
- ≥30% decline in any CANTAB test
- ≥10-point decline in FACT-Cog score
- Fall or investigator-assessed increased risk of falls
- ≥Grade 2 neurologic toxicity event
- In case of severe neurocognitive AE, patients were allowed to crossover outside of week 12 or 24. Patients treated with darolutamide who experienced a fall, seizure, or posterior reversible encephalopathy syndrome (PRES) discontinued the study instead of crossing over to avoid similar events during treatment with enzalutamide.
- Neurocognitive function was assessed using 5 CANTAB tests which evaluated 4 cognitive domains (Table: Cognitive Domains Assessed by Each CANTAB Test):
- Executive function (eg, planning weekly schedule, breaking task into discrete steps)
- Working memory (eg, losing the plot when telling a story, forgetting name of an acquaintance mid-conversation)
- Visual memory (eg, placing keys in refrigerator and being unable to visualize location, lost in familiar place)
- Attention (eg, shifting from one task to another, unable to talk on phone and respond to timer when cooking dinner at the same time)
Table. Cognitive Domains Assessed by Each CANTAB Test1,3
Proportion of each test assessing each domain, % | SWM | PALFAM | OTS | SSP | RVP |
Executive function | 50 | 20 | 60 | - | - |
Working memory | 50 | - | 40 | 60 | 25 |
Visual memory | - | 80 | - | 40 | - |
Attention | - | - | - | - | 75 |
Key: CANTAB, Cambridge Neuropsychological Test Automated Battery; OTSMCC, executive function; PALFAM, memory recall; RVP, rapid visual processing; SSP, short-term visual memory, working memory; SWM, spatial working memory. aValues represent the percentage of each test attributable to the indicated cognitive domain. | |||||
- The primary endpoint was the MCCD from baseline to week 24 across the 5 CANTAB tests1. Patients who crossed over before week 24 were analyzed using their score at crossover.
- Other assessments included crossover criteria, patient reported outcome (FACT-Cog, FACT-P, PHQ-9, and sleep scale), functional status (timed up and go test), and AEs.
Results
Patient Characteristics
- A total of 55 patients were randomized to darolutamide and 56 patients to enzalutamide. Baseline characteristics are presented in Table: Baseline Characteristics.
Table. Baseline Characteristics1
| Characteristic | Darolutamide (n=55) | Enzalutamide (n=56) |
Age, median (IQR), years | 70.7 (48.6-86.2) | 71.3 (50.0-89.5) |
PSA, median (IQR), ng/mL | 1.0 (0.1-3.9) | 2.2 (0.2-8.3) |
Disease state at enrollment, n (%) | ||
| mHSPC | 30 (54.5) | 28 (50.0) |
| mCRPC | 19 (34.5) | 25 (44.6) |
| nmCRPC | 6 (10.9) | 3 (5.4) |
Race, n (%) | ||
| White | 51 (92.7) | 41 (73.2) |
| Black or African American/African heritage | 1 (1.8) | 7 (12.5) |
| Other (including not reported) | 3 (5.5) | 8 (14.5) |
Prior chemotherapy, n (%) | 5 (9.1) | 6 (10.7) |
Time from chemotherapy, median, months | 36.6 | 32.7 |
Education level, n (%) | ||
| Left school before 16 | 0 | 1 (1.9) |
| Left school at age 17-18 | 14 (28.6) | 9 (17.3) |
| Undergraduate degree | 28 (57.1) | 35 (67.3) |
| Master’s degree | 4 (8.2) | 5 (9.6) |
| Professional degree | 3 (6.1) | 2 (3.8) |
Key: IQR, interquartile range; mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone sensitive prostate cancer; nmCRPC, non-metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen. | ||
Table was adapted from Table. Baseline Characteristics in Morgans A, Bobek O, Kwon D, et al. Cognitive Effects of Darolutamide vs Enzalutamide – Results of ARACOG (AFT-47) a Randomized Clinical Trial from the Alliance for Clinical Trials in Oncology. Oral Presentation presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 29 - June 2, 2026; Chicago, IL. [downloaded 02 June 2026] Copyrights remain with the original source or as denoted therein.
Cognitive Assessments
- A statistically significant greater decline in MCCD from baseline to 24 weeks was observed with enzalutamide compared to darolutamide (P=0.009):
- Darolutamide (n=48): PALFAM (visual memory/executive function): median change, -15.8%
- Enzalutamide (n=47): SWM (working memory/executive function): median change, -36.1%
- At 24 weeks, statistically significant decreases of tests scores of enzalutamide compared to darolutamide were observed in 4 of 5 CANTAB tests assessed (Table: Change in Individual CANTAB Tests at 24 Weeks).
- The median % change shows the evidence of learning effect, as patients with stable cognitive function will have higher test scores over time by repeated testing. Between baseline and 24 weeks, patients treated with darolutamide showed increased median test scores across CANTAB cognitive domain modules, while patients treated with enzalutamide had stable to decreased median test scores.
Table. Change in Individual CANTAB Tests at 24 Weeks1,3
| CANTAB Module | Median darolutamide | Median enzalutamide | Median difference (95% CI) | Wilcoxon P-value | |
PALFAM | 5.6 | 0.0 | -20.8 (-40.0 to -1.3) | 0.0296 | |
OTSMCC | 5.8 | -7.8 | -11.5 (-21.8 to -1.4) | 0.0234 | |
SWM | 38.4 | -5.6 | -39.8 (-75.7 to -8.1) | 0.0080 | |
SSP | 6.3 | 0.0 | -2.3 (-16.7 to 0.0) | 0.1421 | |
RVP | 3.5 | 0.9 | -2.2 (-3.7 to -0.7) | 0.0043 | |
Key: CANTAB, Cambridge Neuropsychological Test Automated Battery; CI, confidence interval; OTSMCC, executive function;PALFAM, memory recall; RVP, rapid visual processing; SSP, short-term visual memory, working memory; SWM, spatial working memory. | |||||
Table was adapted from Table. CANTAB: Change in Individual Cognitive Domains in Morgans A, Bobek O, Kwon D, et al. Cognitive Effects of Darolutamide vs Enzalutamide – Results of ARACOG (AFT-47) a Randomized Clinical Trial from the Alliance for Clinical Trials in Oncology. Oral Presentation presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 29 - June 2, 2026; Chicago, IL. [downloaded 02 June 2026] Copyrights remain with the original source or as denoted therein.
- Treatment crossover was permitted for patients meeting predefined crossover criteria at weeks 12 and 24.
- In the enzalutamide group:
- At 12 weeks, among 31 patients who met crossover criteria, 16 crossed over to darolutamide.
- At 24 weeks, among 17 patients who met crossover criteria (3 for the first time, 14 after week 12), 12 crossed over to darolutamide.
- In the darolutamide group:
- At 12 weeks, among 24 patients who met crossover criteria, none crossed over to enzalutamide.
At 24 weeks, among 24 patients who met crossover criteria (10 for the first time, 14 after week 12), none crossed over to enzalutamide.
- In the enzalutamide group:
LITERATURE SEARCH
A literature search of Embase® , PubMed, and/or other resources, including internal/external databases, was conducted pertaining to this topic on 04 June 2026.
REFERENCES
All the references were accessed on the abovementioned literature search date
- Morgans A, Bobek O, Kwon D, et al. Cognitive Effects of Darolutamide vs Enzalutamide – Results of ARACOG (AFT-47) a Randomized Clinical Trial from the Alliance for Clinical Trials in Oncology. Oral Presentation presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 29 – June 2, 2026; Chicago, IL.
- NCT04335682. A Randomized Phase II Study of Androgen Receptor Directed Therapy on COGnitive Function in Patients Treated With Darolutamide or Enzalutamide (ARACOG). Active, not recruiting, Alliance Foundation Trials, LLC. Updated 2025–11– 04. Accessed via https://clinicaltrials.gov/study/NCT04335682
- Morgans A, Bobek O, Kwon D, et al. Cognitive effects of darolutamide vs enzalutamide: Results of ARACOG (AFT-47), a randomized clinical trial from the Alliance for Clinical Trials in Oncology. J Clin Oncol; 2026;44:suppl 16; abstr 5005. Accessed via https://www.doi.org/10.1200/JCO.2026.44.16_suppl.5005
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