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Treatment intensification in very high-risk prostate cancer patients is an ongoing area of investigation. The STAMPEDE trial demonstrated improved metastasis-free survival and overall survival with two years of abiraterone-based therapy in high-risk nonmetastatic prostate cancer, setting the benchmark for further treatment intensification trials such as DASL-HiCaP.

The much-anticipated interim analysis was presented Oct. 24 at ESMO 2026. It will be important for physicians to consider the trial’s findings within the broader context of high-risk prostate cancer treatment.

“These results are exciting, because they suggest that more patients with very high-risk, non-metastatic prostate cancer may benefit from the addition of an androgen receptor inhibitor to radiation therapy and androgen deprivation,” says Dr. Timothy Showalter, a radiation oncologist at UVA Health.

Positive Interim Results

DASL-HiCaP, the phase 3 trial, found that adding darolutamide to androgen-deprivation therapy (ADT) and radiation significantly improved metastasis-free survival in men with very high-risk prostate cancer. At four years, 95% of men receiving darolutamide were alive without metastasis, compared with 88% with placebo (HR, 0.42; 95% CI, 0.27-0.66; P = .0001).

The results are promising, but an overall survival benefit has not yet been demonstrated. PSA progression-free survival also improved (91% vs. 83% at four years; HR, 0.47). Overall survival and prostate cancer-specific survival data are immature (OS HR, 0.88; 95% CI, 0.49-1.59).

While no new safety signals were reported, the overall rate of severe adverse events was higher in the darolutamide arm. The more detailed adverse-event breakdown also suggests that fatigue and some androgen-receptor-inhibitor-associated effects deserve attention.

The most commonly reported side effects include hot flashes/flushing (66% vs. 64%) and fatigue (64% vs. 57%). Fatigue was more frequent with darolutamide, and the overall incidence of grade 3 or higher adverse events was 7 percentage points higher (43% vs. 36%).

“Although prior studies have demonstrated clinical benefits to adding other androgen receptor inhibitors for high-risk, localized prostate cancer, the DASL-HiCaP trial extends the eligible population to include high-grade tumors with relatively low PSA levels,” Dr. Showalter tells SurvivorNet.

While the results are promising, the MFS benefit must be weighed against the added treatment burden, particularly fatigue, over 96 weeks of therapy.

DASL-HiCaP: What Physicians Need to Know

1. STAMPEDE sets the benchmark for treatment intensification.

STAMPEDE demonstrated improved metastasis-free survival and overall survival with two years of abiraterone-based therapy in high-risk nonmetastatic prostate cancer. In the relevant analysis, metastasis-free survival improved with a hazard ratio of 0.53, while overall survival improved with a hazard ratio of 0.60. These results establish an important benchmark against which new intensification strategies should be considered.

2. DASL-HiCaP tests darolutamide in a different clinical setting.

The phase 3 trial evaluates darolutamide vs. placebo alongside ADT and definitive or salvage radiation in 1,106 patients with very high-risk localized prostate cancer. Its findings should be interpreted according to the trial’s eligibility criteria, treatment schedule, endpoint definitions, and follow-up. Darolutamide should not be assumed to replace abiraterone or to provide additional benefit when combined with it without comparative evidence.

3. PSMA PET complicates the definition of localized disease.

Modern molecular imaging can identify nodal or distant disease that conventional CT and bone scans do not detect. This creates a potential stage-migration problem when applying older nonmetastatic trial results to patients staged with PSMA PET. DASL-HiCaP defined nonmetastatic disease by conventional imaging, so its results apply most directly to that population. Whether they extend to patients with metastases detected only on PSMA PET is not yet known.

4. Tolerability matters, but comparative claims require evidence.

Darolutamide has pharmacologic characteristics and a tolerability profile that may be relevant when selecting an androgen-receptor pathway inhibitor. The practical assessment should include adverse events, treatment discontinuation, drug interactions, quality of life, and the burden of prolonged therapy. A favorable profile in another disease setting does not establish superior tolerability in this population.

Who Was Eligible for the Trial?

The trial enrolled two clinically distinct groups.

A. Primary definitive radiation

Men with very high-risk localized disease, defined by criteria including:

B. Post-prostatectomy radiation

• Men within one year of radical prostatectomy with persistent or rising PSA and very high-risk features, including Grade Group 5 disease, Grade Group 4 with pT3a or higher disease, or qualifying pelvic nodal involvement.
• Patients with distant metastases on conventional staging were excluded. The protocol specified CT or MRI and bone-scan assessment. Importantly, a pelvic node detected only by PSMA PET that measured 10 mm or less was not, by itself, sufficient to establish nodal eligibility.

What Is the Primary Endpoint?

The primary endpoint was metastasis-free survival (MFS), using an ICECaP-validated definition. The protocol defined the endpoint around metastasis on conventional imaging or death from any cause.

Secondary endpoints included:

• Overall survival.

• Prostate cancer-specific survival.

• PSA progression-free survival.

• Time to subsequent hormonal therapy.

• Time to castration-resistant prostate cancer.

• Adverse-event frequency and severity.

• Health-related quality of life and fear of cancer recurrence.

Questions That Should Drive the Clinical Discussion

• Does darolutamide replace abiraterone? No direct equivalence or superiority should be inferred without a head-to-head comparison.
• Should darolutamide be added to abiraterone? The trial does not establish the safety or efficacy of combining the two agents simply because each targets the androgen-signaling pathway.
• How long should treatment continue? Do not automatically apply STAMPEDE’s two-year abiraterone regimen.
• Will the MFS benefit justify the increased rate of adverse events? This becomes an individualized discussion between the patient and clinician about potential declines in overall quality of life vs. the expected benefits of treatment.
• How should PSMA PET affect treatment decisions? Patients staged with PSMA PET may have more advanced disease than the conventional-imaging trial population, which limits direct comparison.
• Will cost and access affect adoption? Consider coverage, out-of-pocket costs, treatment duration, and the practical burden of adding another oral anticancer agent.