Darolutamide plus androgen-deprivation therapy (ADT) in patients with high-risk biochemical recurrence (BCR) of prostate cancer: A phase 3, randomized, double-blind, placebo-controlled study (ARASTEP).

TPS432 Background: Patients with prostate cancer treated with radiotherapy (RT) or radical prostatectomy (RP) as primary therapy may develop BCR, defined by a prostate-specific antigen (PSA) increase with no evidence of metastases on conventional imaging. Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) may detect lesions in patients with BCR. Patients with BCR are at high risk of disease progression, and lesions identified by PSMA PET/CT need effective treatment to delay progression. Darolutamide, a structurally distinct and highly potent androgen receptor inhibitor, significantly improved metastasis-free survival (MFS) and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (CRPC). ARASTEP (NCT05794906) will evaluate whether darolutamide when added to ADT improves radiologic progression-free survival (rPFS) by PSMA PET/CT vs placebo plus ADT in patients with BCR following primary therapy and PSMA PET/CT-positive lesions. Methods: Eligible patients were treated by primary RT or RP +/- adjuvant RT (ART) or salvage RT (SRT), present with high-risk BCR (PSA doubling time [PSADT] <12 months and PSA ≥0.2 ng/mL after primary RP [± ART/SRT] or PSA ≥2 ng/mL above nadir after primary RT only), and must have ≥1 PSMA PET/CT-positive lesion of prostate cancer without visible lesions on conventional imaging, and serum testosterone ≥150 ng/dL. Approximately 750 patients from 221 global sites will be randomized 1:1 to oral darolutamide 600 mg twice daily or placebo, both with ADT, for 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent. Patients with detectable PSA values (≥0.2 ng/mL) after 24 months will continue study treatment until PSMA PET/CT progression by blinded independent central review (BICR). Stratification factors are PSADT <6 vs ≥6–<12 months, intent to treat baseline PSMA PET/CT lesions with image-guided RT/surgery (Yes vs No) and distant ± locoregional vs locoregional-only lesions. The primary endpoint is rPFS by PSMA PET/CT assessed by BICR. Secondary endpoints include MFS on conventional imaging by BICR, time to CRPC, OS, quality of life, and safety. As of October 2024, 248 patients have been randomized. Clinical trial information: NCT05794906 .