DASL-HiCaP: A randomized, phase 3, double-blind trial of darolutamide with androgen-deprivation therapy and definitive or salvage radiation for localized very high-risk prostate cancer.

Abstract

TPS396 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analogue (LHRHA), is a standard of care for patients with very high-risk localized prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of patients with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile, and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT used either as primary definitive therapy, or as salvage therapy, for very high-risk PC. Methods: This study is a randomized (1:1), phase 3, placebo-controlled, double-blind, international trial for patients planned for RT who have very high-risk localized PC on conventional imaging; or very high-risk features with PSA persistence or rise within one year following RP. The trial is stratified by previous RP; planned use of adjuvant docetaxel; clinical or pathological pelvic nodal involvement. 1100 participants will be randomized to receive darolutamide 600 mg or placebo twice daily for 96 weeks in combination with SOC (LHRHA for 96 weeks, plus RT starting week 8-24 from randomization). Participants are allowed nonsteroidal antiandrogen in addition to LHRHA for up to 90 days prior to randomization. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival, with secondary endpoints of overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety, and resistance to study treatment. Clinical trial information: NCT04136353 .