Pain and health-related quality-of-life outcomes with darolutamide in metastatic hormone-sensitive prostate cancer (ARANOTE): secondary and exploratory analyses of a multicentre, randomised, placebo-controlled, phase 3 trial.
A. Morgans, K. Haresh, et al. • The Lancet Oncology • 2026
Darolutamide plus ADT delayed time to pain progression (HR 0·72) and time to deterioration of overall wellbeing (HR 0·76) versus placebo plus ADT in patients with metastatic hormone-sensitive prostate cancer, supporting its consideration as a standard-of-care treatment option.
Key Findings
Results
Darolutamide significantly delayed time to pain progression compared to placebo in patients with metastatic hormone-sensitive prostate cancer.
Hazard ratio for time to pain progression was 0·72 (95% CI 0·54–0·96) in favor of darolutamide versus placebo.
Pain progression was defined as a ≥2-point increase in Brief Pain Inventory-Short Form worst pain score or initiation of opioid use for ≥7 days.
This was a secondary endpoint in the ARANOTE phase 3 trial.
Median follow-up was 22·8 months (IQR 12·3–27·4) in the darolutamide group and 20·3 months (IQR 11·4–25·2) in the placebo group at data cutoff (June 7, 2024).
Results
Darolutamide extended time to deterioration of overall wellbeing as measured by the FACT-P total score compared to placebo.
Hazard ratio for time to deterioration in FACT-P total score was 0·76 (95% CI 0·61–0·94) in favor of darolutamide.
Deterioration was defined as a ≥10-point decrease in Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score.
This was a prespecified exploratory endpoint.
Analysis was performed in the intention-to-treat population of 669 patients (darolutamide n=446, placebo n=223).
Background
The primary efficacy outcome of the ARANOTE trial showed darolutamide significantly improved radiological progression-free survival versus placebo.
Hazard ratio for radiological progression-free survival was 0·54 (95% CI 0·41–0·71) in favor of darolutamide.
This primary endpoint was reported previously and provides context for the pain and HRQoL secondary analyses presented in this paper.
Treatment was 600 mg darolutamide or matching placebo orally twice daily, both with androgen deprivation therapy (ADT).
Results
The safety profile of darolutamide plus ADT was broadly similar to placebo plus ADT, with comparable rates of serious adverse events.
Serious adverse events occurred in 105 (24%) of 445 patients receiving darolutamide versus 52 (24%) of 221 patients receiving placebo.
The most common grade 3–4 adverse event was hypertension: 19 (4%) in the darolutamide group versus 8 (4%) in the placebo group.
Grade 3–4 anaemia occurred in 14 (3%) darolutamide patients versus 8 (4%) placebo patients.
Grade 3–4 aspartate aminotransferase increase occurred in 10 (2%) darolutamide patients versus 1 (<1%) placebo patient.
One treatment-related grade 5 event (death, not otherwise specified) occurred in the study.
Methods
The ARANOTE trial enrolled 669 patients across 133 cancer centres in 15 countries between February 2021 and June 2022.
All participants were male; 376 (56%) were White, 209 (31%) Asian, 65 (10%) Black, and 19 (3%) other race.
Patients were randomly assigned 2:1 to darolutamide (n=446) or placebo (n=223).
Eligible patients were aged ≥18 years with ECOG performance status 0–2 and recurrent or de novo mHSPC.
Randomisation was stratified by presence versus absence of visceral metastases and by previous versus no previous local therapy.
What This Means
This research examined whether darolutamide, a prostate cancer drug, could help men with metastatic hormone-sensitive prostate cancer (mHSPC) maintain better quality of life and experience less pain, in addition to the already-known benefit of slowing cancer progression. The study involved 669 men who received either darolutamide or a placebo, both combined with standard hormone therapy (androgen deprivation therapy). Over a median follow-up of nearly two years, men taking darolutamide were significantly less likely to experience worsening pain (28% reduction in risk) and were significantly less likely to see their overall wellbeing decline as measured by a validated cancer quality-of-life questionnaire (24% reduction in risk).
The safety findings showed that serious side effects occurred at similar rates in both groups—about 24% in each—suggesting that adding darolutamide did not substantially increase the burden of severe adverse events. The most common serious side effects (high blood pressure, anaemia, and liver enzyme elevations) were seen at comparable or only slightly higher rates in the darolutamide group compared to placebo.
This research suggests that darolutamide combined with hormone therapy offers men with mHSPC not only a survival benefit but also meaningful protection against pain worsening and decline in day-to-day wellbeing. These findings may be relevant to treatment decision-making for patients and their clinicians, as quality of life is often a key priority alongside survival outcomes in this disease setting. The study was funded by Bayer and Orion Pharma, the manufacturers of darolutamide.
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A. Morgans, K. Haresh, M. Jievaltas, D. Olmos, N. Shore, E. Vjaters, et al.. (2026). Pain and health-related quality-of-life outcomes with darolutamide in metastatic hormone-sensitive prostate cancer (ARANOTE): secondary and exploratory analyses of a multicentre, randomised, placebo-controlled, phase 3 trial.. The Lancet Oncology. https://doi.org/10.1016/s1470-2045(26)00014-8