DASL-HiCaP: Darolutamide Plus ADT and Radiation Therapy Improves MFS in Very High-Risk Localized Prostate Cancer

The addition of darolutamide (Nubeqa) to androgen deprivation therapy (ADT) and primary or salvage locoregional radiation therapy (RT) improved metastasis-free survival (MFS) by conventional imaging in patients with localized, very high-risk prostate cancer, according to an interim analysis of the phase 3 DASL-HiCaP trial (NCT04136353) presented at the 2026 ESMO Congress.¹

At 4 years, the MFS rate was 95% in the darolutamide arm (n = 553) vs 88% in the placebo arm (n = 553) (HR, 0.42; 95% CI, 0.27-0.66; P = .0001). The observed P value crossed the prespecified rejection boundary of .012. MFS events occurred in 27 patients (5%) in the darolutamide arm vs 63 patients (11%) in the placebo arm.

Metastases accounted for 9 of the 27 events in the darolutamide arm vs 46 of the 63 events in the placebo arm; deaths without prior metastasis accounted for 18 and 17 events, respectively. The planned interim analysis was triggered after the 87th MFS event was centrally confirmed.

"Our conclusion is that darolutamide 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 who are being treated with curative-intent radiation therapy," said Tamim Niazi, MDCM, of the Department of Oncology at McGill University and the Division of Radiation Oncology at the Jewish General Hospital in Montreal, Canada.

Niazi noted that the primary end point was assessed with conventional imaging rather than prostate-specific membrane antigen positron emission tomography (PET), which would detect metastatic disease earlier.

How was the phase 3 DASL-HiCaP trial of darolutamide in very high-risk prostate cancer designed?

DASL-HiCaP was 1 of 2 genitourinary trials selected for the meeting's Presidential Symposium.² The international, randomized, placebo-controlled trial enrolled 1,106 patients from April 2020 to August 2023.¹ Patients were randomly assigned 1:1 to receive darolutamide at 600 mg twice daily or placebo for 96 weeks, plus 96 weeks of ADT and RT to the prostate or prostate bed and pelvic lymph nodes. Stratification factors were previous radical prostatectomy, planned docetaxel use, and clinical or pathological pelvic N1 disease.

Patients undergoing primary RT were required to have International Society of Urological Pathology (ISUP) grade group 5 disease; ISUP grade group 4 disease with clinical T2b-T4 or radiologic T3a-T4 disease or a prostate-specific antigen (PSA) level above 20 ng/mL; or clinical N1 disease. Patients undergoing salvage RT were required to have PSA persistence or a rise of 0.1 ng/mL or higher within 12 months, plus pathological or clinical N1 disease, ISUP grade group 5 disease, or ISUP grade group 4 disease with pathological T3a-T4 disease.

The primary end point was MFS by conventional imaging. Secondary end points included overall survival (OS), prostate cancer–specific survival (PCSS), PSA progression-free survival (PSA-PFS), time to subsequent hormonal therapy, time to castration resistance, frequency and severity of adverse effects (AEs), and health-related quality of life. The trial was powered at 80% to detect an HR of 0.60, and the final analysis is planned at 130 MFS events.

The median age was 70 years in the darolutamide arm and 71 years in the placebo arm, and 29% of patients in each arm (n = 158) had pelvic nodal involvement. The primary RT cohort included 935 patients (84.5%), and the salvage RT cohort included 171 patients (15.5%). Overall, 79% of patients in the darolutamide arm and 78% in the placebo arm received study drug at full dose for at least 94 weeks. Pelvic nodal RT was delivered to 92% of patients in each arm of the primary RT cohort and to 95% vs 97% of patients in the salvage RT cohort.

Did darolutamide improve PSA-PFS and other secondary end points in DASL-HiCaP?

The MFS benefit with darolutamide was observed in patients with pelvic nodal involvement (n = 316; HR, 0.39; 95% CI, 0.19-0.81) and without it (n = 790; HR, 0.44; 95% CI, 0.25-0.78), as well as in those with previous radical prostatectomy (n = 171; HR, 0.1; 95% CI, 0.01-0.79). Results were similar in patients who did (n = 613; HR, 0.45; 95% CI, 0.24-0.85) and did not (n = 493; HR, 0.39; 95% CI, 0.21-0.75) undergo discretionary PET at baseline. Unadjusted interaction P values ranged from .08 to .80.

The 4-year PSA-PFS rate was 91% with darolutamide vs 83% with placebo (HR, 0.47; 95% CI, 0.33-0.67), with PSA progression events occurring in 18 vs 62 patients, respectively. At 4 years, 99% vs 95% of patients remained free of castration-resistant prostate cancer (HR, 0.22; 95% CI, 0.09-0.52). Darolutamide also prolonged time to subsequent hormonal therapy (HR, 0.36; 95% CI, 0.21-0.60).

In post hoc analyses that censored deaths from other causes, the 4-year rate free of distant metastasis was 98% vs 92% (HR, 0.23; 95% CI, 0.12-0.45), and the 4-year rate free of PSA progression was 94% vs 86% (HR, 0.37; 95% CI, 0.25-0.57).

PCSS and OS data are immature. Prostate cancer deaths occurred in 4 patients in the darolutamide arm vs 7 in the placebo arm (HR, 0.58; 95% CI, 0.17-1.97), and deaths from any cause occurred in 21 vs 24 patients (HR, 0.88; 95% CI, 0.49-1.59). Follow-up for these end points is ongoing.

What was the safety profile of darolutamide plus ADT and RT in DASL-HiCaP?

Rates of AEs of special interest of any grade were similar between the darolutamide and placebo arms, and no new safety signals emerged. The most common were vasodilatation and flushing (66% vs 64%) and fatigue or asthenic conditions (64% vs 57%). Other AEs of special interest included hypertension (8% vs 10%), mental impairment disorders (8% vs 7%), rash (8% vs 6%), diabetes mellitus and hyperglycemia (7% vs 8%), breast disorders or gynecomastia (6% vs 4%), falls (5% vs 6%), cardiac disorders (4% vs 3%), and bone fractures (3% in each arm).

Disclosures: Niazi reported receiving research funding from AbbVie, Astellas, Bayer, Sanofi, TerSera, and Tolmar; receiving honoraria from AbbVie, Astellas, Bayer, J&J, Knight Therapeutics, Pfizer, Novartis-AAA, TerSera, AstraZeneca, and Tolmar; receiving institutional funding from AbbVie, Bayer, and TerSera; and serving in non-remunerated roles as GUROC cochair (2021-2025), GROU-Q chair, and CCTG radiation oncology cochair and GU steering committee member.

References

1. Niazi T, Thomas H, Zhang AY, 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: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA4.
2. VOLGA, DASL-HiCaP data highlight key genitourinary cancer presentations arriving at ESMO 2026. OncLive. Published October 16, 2026. Accessed October 24, 2026. https://www.onclive.com/view/volga-dasl-hicap-data-highlight-key-genitourinary-cancer-presentations-arriving-at-esmo-2026