Open-label study of androgen receptor inhibition with darolutamide plus androgen-deprivation therapy (ADT) versus ADT in men with metastatic hormone-sensitive prostate cancer using an external control arm (ARASEC).
Authors: Shore Neal D. , Preston Mark A. , Gregg Justin R. , Salami Simpa Samuel , Ross Ashley , Bruno Amanda , Srinivasan Shankar , Constantinovici Niculae , Ortiz Jorge A. , Verholen Frank , McKay Rana R. 
Published: June 2022

TPS5111 Background: Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor (ARI) that significantly improved metastasis-free survival by ̃2 years and reduced the risk of death by 31% vs placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC). Darolutamide has a favorable safety and tolerability profile, with only ≤2% difference vs placebo for most adverse events (AEs) of interest (falls, fractures, hypertension, mental impairment). Fatigue was the only AE with > 10% incidence in the darolutamide arm (13.2%; placebo, 8.3%). Darolutamide has shown lower blood–brain barrier penetration than other ARIs in preclinical models (supported by human neuroimaging studies), which may lead to a lower risk of central nervous system-related AEs and has a low potential for drug–drug interactions. For patients with metastatic hormone-sensitive prostate cancer (mHSPC), the combination of darolutamide and ADT is expected to offer a favorable benefit–risk profile. ARASEC will evaluate the efficacy and safety of darolutamide plus ADT in mHSPC in the US (NCT05059236) and complement the data in the ongoing ARANOTE study (NCT04736199). Methods: ARASEC is a US-based, phase 2, open-label, single-arm study with an external control arm. Eligible patients will have confirmed adenocarcinoma of the prostate, radiologic evidence of metastatic disease by conventional imaging, and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Patients with mHSPC will receive darolutamide 600 mg twice daily plus ADT (luteinizing hormone-releasing hormone agonist/antagonist or orchiectomy). The control arm for ARASEC will be derived from the 393 patients with mHSPC treated with ADT alone in the CHAARTED trial. Patients in the active arm will be matched 1:1 to patients in the control arm using important baseline characteristics such as age, ECOG PS, extent of disease defined as low or high volume according to CHAARTED, and presence of bone and visceral metastases. Study duration was defined as the time from the first patient’s first visit until either the event count threshold triggering the primary endpoint analysis has been met or all patients have been followed for ≥2 years after enrollment, whichever occurs later. The primary endpoint is progression-free survival (PFS), defined in CHAARTED as the time from enrollment to prostate-specific antigen (PSA) progression, clinical progression (including radiological or symptomatic progression or clinical deterioration), or death, whichever occurs first. Secondary endpoints are overall survival, radiographic PFS, time to CRPC, complete PSA response rate at 6 months, and safety. Patient recruitment is in progress. Clinical trial information: NCT05059236.