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

TPS5122 Background: Up to half of patients (pts) whose prostate cancer (PC) has been treated with radiotherapy (RT) or radical prostatectomy (RP) as primary therapy will develop biochemical recurrence (BCR), defined as a prostate-specific antigen (PSA) increase without evidence of metastases on conventional imaging (e.g., CT/MRI). Compared with conventional imaging, prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is a more precise imaging method that may detect small PC lesions in pts with BCR. Effective treatment is needed for pts with BCR at high risk of metastatic progression, and who have lesions identified by PSMA PET/CT, to delay progression. Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor with low blood–brain barrier penetration and limited potential for drug–drug interactions. In ARAMIS (phase 3; NCT02200614), DARO significantly improved metastasis-free survival (MFS) and reduced risk of death in pts with nonmetastatic castration-resistant prostate cancer (nmCRPC). ARASTEP (NCT05794906) is evaluating whether DARO plus androgen-deprivation therapy (ADT) improves radiological progression-free survival (rPFS) by PSMA PET/CT vs placebo (PBO) plus ADT in pts with BCR following primary therapy and PSMA PET/CT-positive lesions. Methods: ARASTEP is a global, phase 3, double-blind, placebo-controlled study in which ~750 pts from 192 sites will be randomized to receive oral DARO 600 mg twice daily or PBO, both with ADT, for 24 months. Eligible pts have PC previously treated with primary RT or RP followed by adjuvant RT (ART) or salvage RT (SRT) or RP alone if unfit for ART/SRT, ECOG PS 0/1, serum testosterone >150 ng/dL, and high-risk BCR. High-risk BCR is defined as PSA doubling time (PSADT) <12 months, PSA ≥0.2 ng/mL above the nadir after primary RP followed by ART or SRT or ≥2 ng/mL after primary RT only, and ≥1 PSMA PET/CT-positive lesion with no evidence of metastasis on conventional imaging. Image-guided RT (IGRT) or surgery of baseline (BL) PSMA PET lesions assessed by blinded independent central review (BICR) is allowed ≤12 weeks from randomization. Stratification factors are PSADT (<6 vs ≥6–<12 months), intent to treat BL PSMA PET/CT lesions by BICR with IGRT/surgery (Yes vs No), and distant ± locoregional vs locoregional-only metastases. The primary endpoint is rPFS by PSMA PET/CT assessed by BICR. Secondary endpoints are MFS by BICR, time to CRPC, time to first subsequent systemic antineoplastic therapy, time to locoregional progression by PSMA PET/CT, time to first symptomatic skeletal event, overall survival, PSA <0.2 ng/mL at 12 months, time to deterioration in FACT-P score, safety, and time to symptomatic progression. Enrollment for ARASTEP began in April 2023. Currently 18 patients have been enrolled. Clinical trial information: NCT05794906 .