Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor. In the phase 3 ARAMIS study (NCT02200614) in nonmetastatic castration-resistant prostate cancer (CRPC), DARO + ADT significantly improved metastasis-free survival and overall survival (OS) vs placebo + ADT, with a favorable tolerability and safety profile. In the phase 3 ARASENS study (NCT02799602) in metastatic hormone-sensitive prostate cancer (mHSPC), DARO + ADT + docetaxel significantly reduced the risk of death by 32.5% vs ADT + docetaxel (hazard ratio 0.68; 95% confidence interval 0.57–0.80; P<0.0001), with no additional adverse events. DARO + ADT vs ADT alone in patients (pts) with mHSPC is being evaluated in the ongoing, global (ex-US), phase 3 ARANOTE study (NCT04736199). The phase 2 ARASEC study (NCT05059236) will complement ARANOTE by evaluating DARO + ADT in US pts with mHSPC. Given that ADT alone is no longer an acceptable comparator in the US, an external control arm will be derived from a historical study. Methods: To participate in ARASEC, pts must have confirmed adenocarcinoma of the prostate, metastatic disease on conventional imaging for which they have not received prior systemic therapy, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2. Pts will receive DARO 600 mg twice daily + ADT (luteinizing hormone-releasing hormone agonist/antagonist or orchiectomy). ADT can be started ≤4 months before DARO, and there must be no evidence of progression on ADT before DARO initiation. The external control arm will be derived from 394 pts with mHSPC treated with ADT alone in CHAARTED (NCT00309985). Pts in the active and control arms will be matched 1:1 on baseline characteristics such as age, ECOG PS, CHAARTED-defined extent of disease, prior therapy, and Gleason score. The propensity score (ie, the assessed probability that a pt is allocated to the DARO + ADT arm based on baseline profile) will be used to address bias in estimating differential effects, by matching pts with scores within a narrow window across the cohorts. The primary endpoint is progression-free survival (PFS), defined as the time from enrollment to prostate-specific antigen (PSA) progression, radiologic or symptomatic progression, clinical deterioration, or death, whichever occurs first, as defined in CHAARTED. Secondary endpoints are OS, radiographic PFS, time to CRPC, 6-month PSA response (<0.2 ng/mL), and safety. The study will continue until either the event count threshold triggering the primary endpoint analysis (161 PFS events) has been met or all pts have been followed for ≥2 years after enrollment, whichever occurs later. ARASEC is enrolling, with the first pt enrolled in November 2021. As of September 10, 2022, 59 pts have been enrolled. The target total enrollment is 200 pts at 30 sites. Clinical trial information: NCT05059236.