The DARO-flare trial: evaluating the impact of darolutamide on prostate-specific membrane antigen (PSMA) flare and its implications for imaging and staging of hormone-sensitive prostate cancer - study protocol.

INTRODUCTION: Prostate cancer (PCa) represents a major global health concern due to biological heterogeneity and the complexity of its underlying molecular pathways, which contribute to substantial morbidity and mortality. Ongoing research continues to elucidate distinct molecular mechanisms that may inform diagnostic and therapeutic strategies. Among these, the prostate-specific membrane antigen (PSMA) has emerged as a pivotal biomarker and therapeutic target in PCa. PSMA is indirectly modulated by androgen signalling through the androgen receptor (AR) pathway and has been observed to undergo transient upregulation following treatment with AR targeting agents, such as darolutamide, particularly in patients with castration-resistant PCa. This transient increase in PSMA expression-termed the 'PSMA flare phenomenon'-may enhance the sensitivity and accuracy of PSMA-based molecular imaging and disease staging.

METHODS AND ANALYSIS: The DARO-flare trials are a prospective, single-centre, interventional, phase I-II proof-of-concept study evaluating whether short-term administration of darolutamide induces a PSMA-flare in patients with hormone-sensitive PCa. The cohort being investigated comprises patients with oligometastatic recurrence following prior therapy with curative intent.Within the cohort, participants are randomised (1:1) to receive darolutamide 600 mg two times a day for either 7 or 14 days. All participants undergo baseline PSMA positron emission tomography (PET)/CT imaging as standard-of-care and two follow-up scans on days 7 and 14.The primary endpoint was the change in the number of PSMA-expressing PCa lesions and/or PSMA expression per lesion maximum standardised uptake value on repeated PSMA PET/CT, indicative of a darolutamide flare response. Secondary endpoints included the impact on clinical management decisions, defined as a treatment change following short-course darolutamide, tolerability and toxicity as assessed by adverse event reporting, and patient-reported outcomes related to quality of life.

ETHICS AND DISSEMINATION: The study protocol has been approved by the Medical Ethics Committee (METC) Amsterdam UMC and adheres to the Declaration of Helsinki. Written informed consent is obtained from all participants. Study findings will be disseminated through peer-reviewed publications and conference presentations.

TRIAL REGISTRATION NUMBER: 2025-520482-52-03 (https://euclinicaltrials.eu/ctis-public/view/2025-520482-52-03?lang=en, protocol nr 6.0).