ARASEC and ARACOG: Darolutamide Data in Metastatic Hormone-Sensitive Prostate Cancer Are Reshaping Treatment Preferences

KEY FINDINGS

• ARASEC (NCT05059236): A phase 2 trial evaluating a prospectively collected US cohort of darolutamide plus ADT (n=223) against a propensity score-matched ADT monotherapy control arm from the CHAARTED trial (n=393).
• Progression: A 71% reduction in the risk of progression or death by CHAARTED criteria (HR 0.29; 95% CI 0.20-0.40; p<0.001).
• Overall survival: Significant superiority (HR 0.50; 95% CI 0.30-0.82; p=0.003); 24-month OS rate 89% versus 80%.
• ARACOG (AFT-47): At week 24, decline in the most changed cognitive domain (MCCD) was -15.8 with darolutamide and -36.1 with enzalutamide (p=0.009).
• The real-world gap: Approximately one third of mCSPC patients in the United States still receive ADT alone; although this rate has fallen from around 50% a few years ago, it points to a significant gap in treatment intensification.

Background

In metastatic hormone-sensitive prostate cancer (mCSPC/mHSPC), treatment intensification with an androgen receptor pathway inhibitor (ARPI) is a standard proven by numerous phase 3 trials. Nevertheless, in real-world practice a substantial proportion of patients are still managed with ADT monotherapy; the principal reason is concern about tolerability in patients of advanced age, with a high comorbidity burden and polypharmacy.

Assessing this picture, the Urology Times Clinical Forum series brought together urologists, oncology nurses and advanced practice providers at four separate centres (Chicago, Houston, Bloomfield Hills, Omaha) in August 2026; the ARASEC, ARANOTE and ARACOG trials were at the centre of the discussions.

Study Design

ARASEC - A pragmatic phase 2 design with an external control arm

Because ADT monotherapy is no longer accepted as an ethical comparator in the United States, ARASEC adopted a pragmatic solution: a prospectively enrolled cohort of darolutamide 600 mg twice daily plus ADT (n=223) was analysed against an external control arm derived from the ADT monotherapy arm of the CHAARTED trial (n=393). Propensity score matching was performed on age, ECOG performance status, CHAARTED-defined disease volume, prior treatment, Gleason score and baseline PSA.

ARACOG (AFT-47) - A randomized comparison with cognitive endpoints

ARACOG (NCT04335682), conducted by the Alliance for Clinical Trials in Oncology, randomized 111 patients 1:1 to darolutamide or enzalutamide between 17 August 2021 and 11 March 2025. The population includes patients with mCRPC, non-metastatic CRPC and mHSPC. Cognitive assessment was performed objectively with five computer-based tests from the CANTAB battery before treatment and at weeks 12 and 24.

Key Results

Methodological note: ARASEC is not a randomized phase 3 trial; it is a phase 2 design using an external control arm. Although propensity score matching balances measured variables, it cannot exclude unmeasured confounders such as differences in supportive care and imaging between cohorts collected in different periods. The findings should be interpreted together with the randomized data from the phase 3 ARANOTE trial.

Implications for Clinical Practice

1. Treatment intensification should not be restricted by age

Subgroup analyses from ARANOTE and ARASEC show that the gain obtained is consistent regardless of age, comorbidity burden and the number of concomitant medications. "Advanced age" alone does not justify ADT monotherapy.

2. Drug-drug interactions are the most practical differentiator in choosing an agent

That darolutamide raises statin levels through inhibition of BCRP (Breast Cancer Resistance Protein) is frequently overlooked; a proactive review of lipid-lowering therapy is recommended. In patients on anticoagulants, darolutamide continues to be the preferred agent at many centres.

3. Cognitive endpoints are now a measurable selection criterion

ARACOG has for the first time demonstrated this difference under randomized conditions with an objective neuropsychological test battery. The investigators propose a difference in blood-brain barrier permeability as the mechanism; however, the study design does not provide evidence of a causal mechanism.

4. The definition of disease volume in the triplet therapy decision should be reconsidered

Volume thresholds determined by conventional imaging in the CHAARTED era can understate the true metastatic burden in the PSMA-PET age.

5. Side effects are most often reported not by the patient but by the family

This observation, prominent in the forums, suggests that interviewing the accompanying person should be systematically structured when screening for cognitive changes.

Conclusion

ARASEC provides evidence complementary to the phase 3 ARANOTE data on the efficacy of darolutamide plus ADT in mCSPC in the US population; ARACOG documents for the first time, with randomized and objective measurements, the difference in cognitive profile between ARPIs.

Clinical decisions increasingly rest less on comparing headline hazard ratios and more on matching the patient's comorbidity profile, drug interaction map, support system and self-stated life goals with the option on which they can remain in treatment longest. In metastatic hormone-sensitive disease, the real question is no longer "should we intensify?" but "with which agent, for which patient?"

References

• Urology Times. How ARASEC and ARACOG are reshaping mCSPC treatment choices. 24 August 2026.
• Urology Times. ARASEC: Darolutamide plus ADT reduces progression risk in mHSPC.
• UroToday. AUA 2026: Darolutamide + ADT in mHSPC - ARASEC, US Prospective, Open-Label Phase 2 Study with an External Control.
• Bobek O, Kwon DH, Berg SA, et al. Cognitive effects of darolutamide vs enzalutamide: results of ARACOG (AFT-47). J Clin Oncol. 2026;44(16 suppl):5005.
• The ASCO Post. Cognitive Effects of Darolutamide vs Enzalutamide in Advanced Prostate Cancer. May 2026.
• Saad F, Vjaters E, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer (ARANOTE). J Clin Oncol. 2024;42(36):4271-4281.