Adding darolutamide to ADT and radiation improves MFS in very high-risk localized prostate cancer

Adding darolutamide (Nubeqa) to 2 years of androgen deprivation therapy (ADT) and primary or salvage locoregional radiation therapy (RT) significantly improved metastasis-free survival by conventional imaging (MFS-CI) in patients with very high-risk prostate cancer, according to an interim analysis of the phase 3 DASL-HiCaP trial (ANZUP1801; NCT04136353).¹

At a median follow-up of 3.8 years, darolutamide plus ADT and radiation demonstrated a 58% reduction in risk of metastasis or death vs ADT and radiation alone. The results were presented by Tamim Niazi, MDCM, associate professor of the department of oncology, McGill University, at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain.

“In 2026, there is uncertainty of which patient populations will benefit from treatment intensification,” Niazi explained during the presentation. “To that end, we hypothesized that adding darolutamide for [patients with] prostate cancer with very high-risk disease who are planned to have either radical radiation therapy or salvage radiation therapy will improve metastasis-free survival by conventional imaging.”

Trial design

The randomized phase 3 trial enrolled 1,106 patients across 86 sites in Australia, Canada, New Zealand, Ireland, the United Kingdom, and the United States. Participants were randomly assigned 1:1 to darolutamide 600 mg twice daily or placebo for 96 weeks. All patients received 96 weeks of ADT plus RT to the prostate or prostate bed and pelvic lymph nodes. Enrollment ran from April 2020 to August 2023. Stratification factors were prior radical prostatectomy, planned docetaxel use, and clinical or pathologic pelvic N1 disease.

Eligibility required trial-defined very high-risk features. Patients receiving primary RT needed International Society of Urological Pathology (ISUP) grade group 5 disease, clinical N1 disease, or grade group 4 disease with at least 1 additional risk factor (clinical T2b-T4, radiologic T3a-T4, or a prostate-specific antigen [PSA] level >20 ng/mL). Patients receiving salvage RT needed prostate-specific antigen (PSA) persistence or a rise to 0.1 ng/mL or higher within 12 months, plus pathologic or clinical N1 disease, grade group 5 disease, or grade group 4 disease with pathologic T3a-T4 disease.

The primary RT cohort included 935 patients (84.5%), and the salvage cohort included 171 (15.5%). Median age was 70 years in the darolutamide arm and 71 years in the placebo arm. Further, 71% and 74% of patients had Gleason 9-10 disease, respectively, and 29% in each arm had clinical or pathologic pelvic nodal involvement. Overall, 79% of patients in the darolutamide arm and 78% in the placebo arm received at least 94 weeks of study drug at full dose. Pelvic nodal RT, which was mandated by protocol, was delivered to more than 90% of patients in both cohorts.

The primary end point was MFS-CI. Secondary end points included overall survival (OS), PSA-progression-free survival (PSA PFS), time to subsequent therapy, and time to castration resistance. The trial was powered at 80% to detect an HR of 0.60. The interim analysis was triggered after the 87th centrally confirmed MFS-CI event, or 67% of the 130 events planned for the final analysis.

Efficacy findings

At 4 years, MFS-CI was 95% in the darolutamide arm vs 88% in the placebo arm (HR, 0.42; 95% CI, 0.27 to 0.66; P = .0001). MFS-CI events occurred in 27 patients (5%) in the darolutamide arm and 63 (11%) in the placebo arm. The difference was driven by metastases (9 vs 46 events), whereas deaths without prior metastasis were balanced (18 vs 17).

The benefit was consistent across prespecified subgroups, including patients with pelvic nodal involvement (HR, 0.39; 95% CI, 0.19 to 0.81) and without it (HR, 0.44; 95% CI, 0.25 to 0.78), and patients who did (HR, 0.45; 95% CI, 0.24 to 0.85) or did not (HR, 0.39; 95% CI, 0.21 to 0.75) undergo discretionary prostate-specific membrane antigen (PSMA) PET at baseline.

Secondary end points also favored darolutamide. The 4-year PSA PFS rate was 91% with darolutamide compared with 83% with placebo (HR, 0.47; 95% CI, 0.33 to 0.67), and 99% vs 95% of patients remained free of castration-resistant prostate cancer (CRPC) at 4 years, respectively (HR, 0.22; 95% CI, 0.09 to 0.52). Darolutamide prolonged time to subsequent hormonal therapy (HR, 0.36; 95% CI, 0.21 to 0.60), and fewer patients in the darolutamide arm received any subsequent anticancer therapy (4% vs 10%). In a post hoc analysis censoring deaths from other causes, the HR for time to distant metastasis was 0.23 (95% CI, 0.12 to 0.45).

Survival end points remain immature. Prostate cancer-specific deaths occurred in 4 patients receiving darolutamide and 7 receiving placebo (HR, 0.58; 95% CI, 0.17 to 1.97). At the time of this analysis, OS was 97% in the darolutamide arm vs 95% in the placebo arm (HR, 0.88; 95% CI, 0.49 to 1.59).

Safety

“Adverse events were pretty similar across both arms,” Niazi noted during the presentation at ESMO. “Specifically, there was no new emergent toxicity by adding darolutamide to locoregional radiation therapy.”

The most common adverse events (AEs) of special interest were vasodilatation and flushing (66%, darolutamide and 64%, placebo) and fatigue or asthenic conditions (64% and 57%). Any grade 3 or higher AE occurred in 43% of patients in the darolutamide arm and 36% of patients in the placebo arm.²

Based on these results, Niazi concluded, “Darutamide reduces the risk of relapse to a clinically meaningful degree, and as such, it defines a new paradigm for the care of [patients with] prostate cancer at a very high risk of recurrence [and] who are planned for curative intent radiotherapy.”

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REFERENCES

1. Niazi T, Thomas H, Zhang A, et al. Darolutamide with androgen deprivation therapy (ADT) and definitive or salvage locoregional radiation therapy (RT) for localised, very high-risk prostate cancer: Interim analysis of an international, placebo-controlled, randomised phase 3 trial (DASL-HiCaP; ANZUP1801). Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026, Madrid, Spain. Abstract LBA4 https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2026_abstracts/LBA4.html.pdf

2. Darolutamide plus ADT and radiation therapy reduces risk of metastasis or death by 58% in prostate cancer patients at high risk of recurrence. News release. Orion Pharma. October 24, 2026. Accessed October 25, 2026. https://www.orionpharma.com/newsroom/all-news/releases/press-releases/2026/darolutamide-plus-adt-and-radiation-therapy-reduces-risk-of-metastasis-or-death-by-58-in-prostate-cancer-patients-at-high-risk-of-recurrence/