Darolutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) by disease volume: Subgroup analysis of the phase 3 ARANOTE trial.
Authors: Fred Saad, Neal D. Shore, Egils Vjaters, David Olmos, Natasha Littleton, Anna Liu, Isabella Testa, Mindy Mo, Shankar Srinivasan, Kunhi Parambath Haresh
Journal: Journal of Clinical Oncology (2025)

151 Background: Darolutamide (DARO) plus ADT significantly reduced the risk of radiological progression or death by 46% (HR 0.54; 95% CI: 0.41–0.71; P &lt;0.0001) versus placebo (PBO) plus ADT in patients with mHSPC in the ARANOTE trial. The incidence of treatment-emergent adverse events (TEAEs) was low and similar between arms, with fewer patients discontinuing study drug due to TEAEs in the DARO vs PBO arm (6.1% vs 9.0%). Here, we report the efficacy and safety by disease volume in both arms of ARANOTE. Methods: Patients with mHSPC were randomized 2:1 to receive DARO 600 mg twice daily + ADT or PBO + ADT. High-volume (HV) disease was defined by the presence of visceral metastases and/or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis (CHAARTED criteria). The primary endpoint was radiological progression-free survival (rPFS). Secondary endpoints included time to metastatic castration-resistant prostate cancer (mCRPC), time to prostate-specific antigen (PSA) progression, and safety. Results: Of the 669 patients included in the full analysis set, 472 (71%; DARO n=315; PBO n=157) had HV disease and 197 (29%; DARO n=131; PBO n=66) had low-volume (LV) disease. Baseline demographics and patient characteristics were generally balanced between the treatment arms in HV and LV subgroups. Patients with LV disease had better prognostic factors (eg, a higher proportion of patients with ECOG PS 0, Gleason &lt;8, having received prior local therapy, and lower baseline median PSA levels). DARO + ADT improved rPFS vs PBO + ADT in both HV and LV subgroups. In the LV subgroup, DARO + ADT reduced the risk of radiological progression or death by 70% (HR 0.30; 95% CI: 0.15–0.60) with median rPFS not reached in either group. In the HV subgroup, DARO + ADT reduced the risk of radiological progression or death by 40% (HR 0.60; 95% CI: 0.44–0.80) with median rPFS of 30.2 months with DARO vs 19.2 months with PBO. For the secondary endpoints, DARO delayed time to CRPC (HV: HR 0.46; 95% CI: 0.36–0.60; LV: HR 0.21; 95% CI: 0.12–0.37) and time to PSA progression (HV: HR 0.34; 95% CI: 0.25–0.46; LV: HR 0.19; 95% CI: 0.10–0.37) and a higher proportion achieved PSA &lt;0.2 ng/mL with DARO vs PBO (HV: 54.6% vs 15.5%; LV: 82.6% vs 25.4%) in HV and LV subgroups. Incidences of TEAEs were low and similar between treatment groups across the HV and LV subgroups and consistent with the overall population. Lower rates of fatigue and treatment discontinuations due to TEAEs with DARO vs PBO were observed in the LV subgroup: 2.3% vs. 13.8% and 3.1% v 10.8%, respectively. Conclusions: Efficacy outcomes with DARO + ADT in patients with mHSPC were improved vs PBO + ADT regardless of disease volume. DARO + ADT was well-tolerated in both volume subgroups, consistent with the overall population. Patients with LV mHSPC had marked treatment efficacy with minimal treatment burden. Clinical trial information: NCT04736199 .