Age-related efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) and docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC): A subgroup analysis of ARASENS.
Authors: Joan Carles, Bertrand F. Tombal, Maha H. A. Hussain, Fred Saad, Karim Fizazi, Alvaro Montesa Pino, Maria Jose' Méndez-Vidal, Alejo Rodriguez-Vida, Daniel Castellano, Pablo Borrega, Patrick Adorjan, Cristina Moretones, Manjari Dissanayake, Matthew R Smith
Journal: Journal of Clinical Oncology (2025)

143 Background: In ARASENS, darolutamide (DARO) + ADT + docetaxel (DOC) significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P &lt;0.0001) vs placebo (PBO) + ADT + DOC with similar incidence of treatment-emergent adverse events (TEAEs) between groups in patients (pts) with mHSPC. DARO + ADT + DOC has become one of the standards of care in mHSPC. We report post-hoc efficacy and safety in pts by age subgroups (&lt;75 y, ≥75 y) in ARASENS. Methods: Pts were randomized to receive DARO 600 mg orally twice daily or PBO, with ADT + DOC. Age subgroups were analyzed for baseline characteristics including ongoing comorbidities, treatment duration, completion of DOC therapy, use of first subsequent therapy, key efficacy outcomes, and safety. Results: Of 1305 pts analyzed in ARASENS, ages ranged from 41–89 y, with 1086 pts &lt;75 y (83%; DARO n=546; PBO, n=540) and 219 pts ≥75 y (17%; DARO n=105; PBO n=114). Baseline characteristics were generally similar in the DARO and PBO groups by age subgroup. The most common comorbidities by system organ class in pts &lt;75 y and ≥75 y were vascular (55%, 67%), musculoskeletal/connective tissue (42%, 42%), and metabolism/nutrition (35%, 43%) disorders. Treatment duration was consistently longer with DARO vs PBO (&lt;75 y: 41.2 vs 16.8 mo; ≥75 y: 38.5 vs 15.0 mo). Most patients completed 6 cycles of DOC (&lt;75 y: 89%, 88%; ≥75 y: 80%, 76%). Among pts who entered follow-up, fewer DARO vs PBO pts initiated subsequent therapy independent of age (&lt;75 y: 57% vs 76%; ≥75 y: 54% vs 73%). The overall survival (OS) benefit of DARO vs PBO was consistent across age subgroups (&lt;75 y: HR 0.70, 95% CI 0.58–0.84; ≥75 y: HR 0.61, 95% CI 0.41–0.91). Time to metastatic castration-resistant prostate cancer (mCRPC) was longer with DARO vs PBO across age subgroups (&lt;75 y: HR 0.35, 95% CI 0.30–0.43; ≥75 y: HR 0.42, 95% CI 0.28–0.64) as was time to initiation of subsequent therapy (&lt;75 y: HR 0.40, 95% CI 0.34–0.48; ≥75 y: HR 0.35, 95% CI 0.22–0.54). TEAEs were generally similar between DARO and PBO, with slightly higher incidence rates in older pts. Few patients discontinued DARO or PBO due to TEAEs in both age subgroups (&lt;75 y: 13.2%, 9.1%; ≥75 y: 15.1%, 17.7%). The most common grade 3/4 TEAEs were generally similar between DARO and PBO across age subgroups and occurred most frequently during overlapping DOC treatment. TEAEs commonly associated with androgen receptor pathway inhibitors occurred at similar incidences between treatment groups in both age subgroups. Conclusions: Pts with mHSPC benefited from DARO + ADT + DOC irrespective of age (&lt;75 y and ≥75 y), with consistent improvements in OS, time to mCRPC, and time to initiation of subsequent therapy. DARO was well tolerated in both age subgroups, with similar incidences of TEAEs vs PBO. Clinical trial information: NCT02799602 .