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ARACOG — Darolutamide (Nubeqa) vs enzalutamide, advanced prostate cancer (cognition head-to-head; nmCRPC / mCRPC / mHSPC)

Abstract: 5005 (AFT-47) · Session: Genitourinary Cancer — Prostate, Testicular, and Penile, 2026 ASCO Annual Meeting · Presenter: Alicia K. Morgans, MD, MPH, FASCO (Dana-Farber Cancer Institute, Boston) · Embargo: ASCO 2026 (May 29 – Jun 2, 2026)

At a glance

  • Sponsor: Alliance Foundation Trials (AFT-47); funded by Prostate Cancer Foundation Challenge Award, Alliance Scholar Award, and Bayer
  • PI / presenter: Alicia K. Morgans, MD, MPH, FASCO (Dana-Farber Cancer Institute)
  • NCT ID: not stated in trade-press coverage
  • Phase: 2
  • Design: Randomized, head-to-head; patients randomized to darolutamide or enzalutamide, with protocol-defined crossover to the alternate agent for worsening cognition
  • N: 111 randomized; 95 evaluable (48 darolutamide, 47 enzalutamide)
  • Primary endpoint(s): Percent change in maximally changed cognitive domain (MCCD) from baseline to 24 weeks, via Cambridge Neuropsychological Test Automated Battery (CANTAB)
  • Comparator: Enzalutamide
  • Indication: Advanced prostate cancer — nmCRPC, mCRPC, or mHSPC
  • Line: Androgen receptor pathway inhibitor (ARPI) therapy

Headline result

ARACOG is the first randomized head-to-head comparison of cognitive effects between two androgen receptor pathway inhibitors. At 24 weeks, darolutamide patients had a median MCCD decline of −15.8% versus −36.1% for enzalutamide (P = .009) — i.e., significantly greater objective cognitive decline on enzalutamide. While similar proportions in each arm met protocol crossover criteria, all 30 observed crossovers moved from enzalutamide to darolutamide, and none from darolutamide to enzalutamide. The differential is attributed to enzalutamide's greater blood-brain barrier penetration relative to darolutamide.

Mechanism / class

Both agents are oral androgen receptor pathway inhibitors (ARPIs). Darolutamide (Nubeqa, Bayer) is a structurally distinct AR antagonist with low blood-brain barrier penetration, approved for nmCRPC and (with docetaxel + ADT) mHSPC. Enzalutamide (Xtandi) is an AR antagonist approved across nmCRPC, mCRPC, and mHSPC, with documented CNS effects (fatigue, cognitive impairment) linked to higher CNS exposure.

Discussant takeaway

Framed as the first prospective, randomized, objective (CANTAB-measured) head-to-head cognitive comparison of ARPIs — addressing a long-standing patient-reported concern ("brain fog") with quantitative endpoints rather than subjective report. Unidirectional crossover (all enzalutamide → darolutamide) reinforced the signal.

Practice-changing?

Pending. A 95-patient phase 2 will not by itself change labels, but it provides the first randomized objective evidence to inform ARPI selection where cognitive preservation matters (older patients, those with baseline cognitive concerns). Supports darolutamide as a cognition-sparing option; larger confirmation and hard oncologic outcomes still needed.

Sources

  • ASCO Meeting Library / J Clin Oncol 44, 2026 (suppl 16; abstr 5005): Morgans et al., ARACOG (AFT-47)
  • The ASCO Post: https://ascopost.com/news/may-2026/cognitive-effects-of-darolutamide-vs-enzalutamide-in-advanced-prostate-cancer/
  • ecancer: https://ecancer.org/en/news/28325-asco-2026-less-cognitive-decline-with-darolutamide-treatment-than-enzalutamide-in-people-with-advanced-prostate-cancer
  • Oncology Nursing News: https://www.oncnursingnews.com/view/darolutamide-shows-less-cognitive-decline-vs-enzalutamide-in-advanced-prostate-cancer
  • Targeted Oncology: https://www.targetedonc.com/view/darolutamide-associated-with-less-cognitive-decline-than-enzalutamide-in-advanced-prostate-cancer
  • Bayer press release: https://www.bayer.com/en/us/news-stories/new-findings-for-nubeqa