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

Background In patients with metastatic hormone-sensitive prostate cancer (mHSPC), darolutamide significantly improved radiological progression-free survival versus placebo (hazard ratio [HR] 0·54, 95% CI 0·41–0·71) in the phase 3 ARANOTE study. In addition to survival, symptom control and health-related quality of life (HRQoL) are important factors in treatment decision making; we therefore report pain, HRQoL, and safety outcomes from the ARANOTE trial. Methods ARANOTE is an international, randomised, double-blind, placebo-controlled, phase 3 trial involving men aged 18 years or older, with Eastern Cooperative Oncology Group performance status 0–2 and recurrent or de novo mHSPC, treated at 133 cancer centres in 15 countries. Participants were randomly assigned (2:1) to 600 mg darolutamide or matching placebo orally twice daily, both with investigator&apos;s choice of androgen deprivation therapy (ADT; luteinising hormone-releasing hormone agonist or antagonist, or orchiectomy) starting within 12 weeks before randomisation. Randomisation was stratified by presence versus absence of visceral metastases and by previous versus no previous local therapy. Treatment was assigned centrally using an interactive web response system based on a computer-generated permuted block randomisation list with block sizes of six. The investigators, the participants, and the sponsor remained masked to treatment assignment throughout the study. The primary endpoint (reported previously) was radiological progression-free survival. Here, we assessed time to pain progression (≥2-point increase in Brief Pain Inventory—Short Form worst pain score or initiation of opioid for ≥7 days; secondary endpoint) and time to deterioration of overall wellbeing (≥10-point decrease in Functional Assessment of Cancer Therapy—Prostate [FACT-P] total score; prespecified exploratory endpoint). Pain and HRQoL outcomes were analysed in the intention to treat population; safety was analysed in all treated patients according to treatment actually received. The trial, registered at ClinicalTrials.gov , NCT04736199 , is ongoing, but no longer recruiting. Findings Between Feb 23, 2021, and June 14, 2022, 669 patients (all male; 376 [56%] White, 209 [31%] Asian, 65 [10%] Black, 19 [3%] other race) were randomly assigned to receive darolutamide (n=446) or placebo (n=223). At the data cutoff date for the primary analysis (June 7, 2024), the median follow-up duration for the analyses presented here was 22·8 months (IQR 12·3–27·4) in the darolutamide group and 20·3 months (11·4–25·2) in the placebo group. Darolutamide delayed time to pain progression (HR 0·72; 95% CI 0·54–0·96) and extended time to deterioration in FACT-P total score (HR 0·76; 0·61–0·94) versus placebo. The most common grade 3–4 adverse events were hypertension (19 [4%] of 445 patients who received darolutamide vs eight [4%] of 221 patients who received placebo), anaemia (14 [3%] vs eight [4%]), and aspartate aminotransferase increase (ten [2%] vs one [<1%]). Serious adverse events occurred in 105 (24%) versus 52 (24%) patients, respectively. One treatment-related grade 5 event occurred, reported as death (not otherwise specified). Interpretation Along with the known survival benefits, the clinically meaningful delays in pain progression and time to deterioration of overall wellbeing support consideration of darolutamide plus ADT as a standard-of-care treatment option in patients with mHSPC. Funding Bayer and Orion Pharma.