(UroToday.com) The 2025 GU ASCO annual meeting featured a prostate cancer session and a presentation by Dr. Fred Saad discussing a subgroup analysis of the phase 3 ARANOTE trial assessing darolutamide + ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) by disease volume. Darolutamide + ADT significantly reduced the risk of radiological progression or death by 46% (HR 0.54, 95% CI 0.41–0.71; p < 0.0001) versus placebo plus ADT in patients with mHSPC in the ARANOTE trial.1 The incidence of treatment-emergent adverse events was low and similar between arms, with fewer patients discontinuing study drug due to treatment-emergent adverse events in the darolutamide versus placebo arm (6.1% versus 9.0%). It has been previously shown that disease volume is an established prognostic factor in mHSPC. As such, at GU ASCO 2025, Dr. Saad and colleagues reported the efficacy and safety by disease volume in both arms of ARANOTE.
Patients with mHSPC were randomized 2:1 to receive darolutamide 600 mg twice daily + ADT or placebo + ADT. High volume disease was defined by the presence of visceral metastases and/or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis based on the CHAARTED criteria. Low volume disease was defined as not meeting the high volume disease criteria. The primary endpoint was radiological progression free survival, and secondary endpoints included time to metastatic castration-resistant prostate cancer (mCRPC), time to PSA progression, and safety.
Of the 669 patients included in the full analysis set, 472 (71%; darolutamide n = 315; placebo n = 157) had high volume disease, and 197 (29%; darolutamide n = 131; placebo n = 66) had low-volume disease. Baseline demographics and patient characteristics were generally balanced between the treatment arms in high volume and low volume subgroups. Patients with low volume disease had better prognostic factors (ie. a higher proportion of patients with ECOG PS 0, Gleason <8, having received prior local therapy, and lower baseline median PSA levels):
Darolutamide + ADT improved radiological progression free survival versus placebo + ADT in both high volume and low volume subgroups. In the low volume subgroup, darolutamide + ADT reduced the risk of radiological progression or death by 70% (HR 0.30; 95% CI 0.15–0.60) with median radiological progression free survival not reached in either group. In the high volume subgroup, darolutamide + ADT reduced the risk of radiological progression or death by 40% (HR 0.60, 95% CI 0.44–0.80) with median radiological progression free survival of 30.2 months with darolutamide versus 19.2 months with placebo:
For the secondary endpoints, darolutamide delayed time to CRPC in both disease groups (high volume: HR 0.46, 95% CI 0.36–0.60; low volume: HR 0.21, 95% CI 0.12–0.37):
Darolutamide also delayed time to PSA progression (high volume: HR 0.34, 95% CI 0.25–0.46; low volume: HR 0.19, 95% CI 0.10–0.37) in both volume subgroups and there was benefit across other secondary efficacy endpoints, overall and by volume of disease:
A higher proportion of patients achieved PSA <0.2 ng/mL with darolutamide versus placebo versus placebo + ADT (high volume: 54.6% versus 15.5%; low volume: 82.6% versus 25.4%) in high volume and low volume subgroups:
Incidences of treatment-emergent adverse events were low and similar between treatment groups across the high volume and low volume subgroups and consistent with the overall population. Lower rates of fatigue and treatment discontinuations due to treatment-emergent adverse events with darolutamide versus placebo were observed in the low volume subgroup: 2.3% versus 13.8% and 3.1% versus 10.8%, respectively:
Dr. Saad concluded his presentation with a subgroup analysis of the phase 3 ARANOTE trial assessing darolutamide plus ADT in patients with mHSPC by disease volume with the following take-home points:
- In patients with mHSPC in the ARANOTE study, efficacy outcomes with darolutamide + ADT were improved versus placebo + ADT, regardless of disease volume
- Darolutamide + ADT was well-tolerated in both volume subgroups with low treatment discontinuation rates, consistent with the overall population and reconfirming the established tolerability of darolutamide as observed in the ARAMIS and ARASENS trials
- Patients with low volume mHSPC had marked treatment efficacy with minimal treatment burden
Presented by: Fred Saad, MD, FRCS, University of Montreal Hospital Center, Montreal, Canada
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.
Related content: ARANOTE Trial Explores Darolutamide’s Role in High and Low-Volume Metastatic Prostate Cancer - Fred Saad
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