Adding darolutamide to radiotherapy in very high-risk prostate cancer cut the risk of metastasis or death by 58% — DASL-HiCaP at ESMO 2026
In this article
DASL-HiCaP: Does adding darolutamide to radiotherapy and ADT reduce metastasis in very high-risk prostate cancer?
Medical content reviewed by Prof. Dr. Mustafa Özdoğan · Last updated: October 2026
The DASL-HiCaP phase 3 trial, presented at ESMO 2026 (Presidential Symposium I, LBA4), compared adding darolutamide with placebo in men with very high-risk prostate cancer receiving radiotherapy and 96 weeks of androgen deprivation therapy (ADT). At a planned interim analysis the risk of metastasis or death fell by 58% (HR 0.42); 4-year metastasis-free survival was 95% and 88%. No overall survival difference has been shown yet, and this use is not approved.
- Primary endpoint (metastasis-free survival by conventional imaging, MFS): HR 0.42 (95% CI 0.27–0.66; p=0.0001); 4-year MFS 95% vs 88%, an absolute difference of 7 points (by simple arithmetic, about 1 in 14 patients was spared metastasis or death at 4 years). MFS events: 27 (5%) vs 63 (11%).
- Secondary endpoints: PSA progression-free survival HR 0.47 (0.33–0.67), 91% vs 83% at 4 years. Overall survival HR 0.88 (0.49–1.59; 21 vs 24 events) and prostate cancer-specific survival HR 0.58 (0.17–1.97; 4 vs 7 events): both immature and not significant.
- Safety: no new safety signal reported. Any grade ≥3 adverse event 43% vs 36%; grade ≥2 fatigue/asthenia 14% vs 10%; hypertension 7% vs 9%. Full-dose treatment for ≥94 weeks: 79% vs 78%.
- Limitations: interim analysis at 67% of the planned 130 MFS events; the primary endpoint was measured by conventional imaging, not PSMA PET; no quality-of-life data. Darolutamide is not yet approved in this setting.
Why does this matter?
In very high-risk prostate cancer (features such as a high ISUP grade, lymph node involvement or a PSA that fails to fall after surgery), the standard approach is radiotherapy plus prolonged androgen deprivation therapy. Even so, in the placebo arm of DASL-HiCaP (ADT + radiotherapy), 4-year metastasis-free survival was 88%: about 12% of patients developed metastasis or died within four years. Darolutamide is an androgen receptor inhibitor (ARTA), and the question was whether adding it to radiotherapy reduces recurrence.
Darolutamide is not a new drug: the FDA approved it on 30 July 2019 for non-metastatic castration-resistant prostate cancer (ARAMIS: median MFS 40.4 vs 18.4 months; HR 0.41), in August 2022 with docetaxel for metastatic hormone-sensitive prostate cancer (ARASENS: overall survival HR 0.68), and on 3 June 2025 without docetaxel for metastatic hormone-sensitive disease (ARANOTE: radiographic progression-free survival HR 0.54; no significant overall survival difference). None of these approvals covers localized disease. The companies describe DASL-HiCaP as the first phase 3 trial of darolutamide in early prostate cancer; the drug is not licensed for this indication. Comparable trials with other ARTAs have had mixed results (see the comparison table below).
How was darolutamide given with radiotherapy?
In DASL-HiCaP, men with very high-risk prostate cancer received radiotherapy (to the prostate or prostate bed and pelvic lymph nodes) and 96 weeks of LHRH-analogue ADT, plus either darolutamide 600 mg twice daily or placebo for 96 weeks. At 4 years the risk of metastasis or death fell by 58%; the use is not yet approved.
How was the DASL-HiCaP trial designed?
DASL-HiCaP (ANZUP1801; NCT04136353) is an investigator-initiated, international, randomized, placebo-controlled phase 3 trial run by the University of Sydney and the ANZUP Cancer Trials Group.
| Feature | Details |
|---|---|
| Design | Phase 3, 1:1 randomization, placebo-controlled; Australia, New Zealand, Canada, the United States, Ireland and the United Kingdom |
| Patients | 1,106 patients (April 2020–August 2023): 553 darolutamide, 553 placebo; median age 70 and 71* |
| Population | Very high-risk localized prostate cancer, or PSA that failed to fall or rose within a year after radical prostatectomy. Primary radiotherapy: ISUP grade group 5; or group 4 with clinical T2b–T4, radiologic T3a–T4 or PSA >20 ng/mL; or clinical N1*. Salvage radiotherapy: PSA persistence or a rise of ≥0.1 ng/mL plus an additional adverse feature* |
| Cohorts | Primary radiotherapy 935 patients (84.5%), salvage radiotherapy after surgery 171 patients (15.5%); pelvic lymph node involvement 29% in each arm |
| Treatment | Darolutamide 600 mg twice daily or matching placebo for 96 weeks; both arms received 96 weeks of LHRH analogue and radiotherapy to the prostate/prostate bed and pelvic lymph nodes |
| Stratification | Prior radical prostatectomy, planned docetaxel use, clinical or pathological pelvic N1 disease* |
| Primary endpoint | Metastasis-free survival by conventional imaging (CT and/or bone scan; MFS-CI): centrally confirmed metastasis or death from any cause |
| Secondary endpoints | PSA progression-free survival, prostate cancer-specific survival, overall survival, safety |
| Analysis | Planned interim analysis at the 87th centrally confirmed MFS event (67% of 130 planned events); the disclosure boundary (p<0.012) was crossed; designed with 80% power to detect HR 0.60; median follow-up 3.8 years. Reported event counts add up to 90* |
Figure 1 · How the two arms are built
DASL-HiCaP trial schema (simplified)
What were the metastasis-free survival and other results?
The comparisons below are between arms of the same trial, so they are direct. Colored bars are the darolutamide arm and gray bars the placebo arm; all values are 4-year rates.
4-year rates
DASL-HiCaP · interim analysis, median follow-up 3.8 years
Metastasis-free survival (MFS-CI) · year 4
PSA progression-free survival · year 4
Overall survival · year 4 (no significant difference)
Prostate cancer-specific survival · year 4 (no significant difference)
All values compare the arms of the same trial. Overall survival and prostate cancer-specific survival are immature and showed no statistically significant difference between arms. 3- and 5-year MFS rates and median MFS were not reported.
| Endpoint | Darolutamide + ADT + RT | Placebo + ADT + RT | Hazard ratio / difference |
|---|---|---|---|
| MFS-CI, 4 years (primary) | 95% | 88% | HR 0.42 (0.27–0.66); p=0.0001 |
| MFS events | 27 (5%) | 63 (11%) | Difference 7 points (4 years) |
| Metastasis events* | 9 | 46 | — |
| Deaths without metastasis* | 18 | 17 | — |
| PSA progression-free survival, 4 years | 91% | 83% | HR 0.47 (0.33–0.67) |
| Castration-resistance-free, 4 years | 99% | 95% | HR 0.22 (0.09–0.52) |
| Time to subsequent hormonal therapy | Not reported | Not reported | HR 0.36 (0.21–0.60) |
| Prostate cancer-specific survival, 4 years | 99% (4 events) | 99% (7 events) | HR 0.58 (0.17–1.97) |
| Overall survival, 4 years | 97% (21 events) | 95% (24 events) | HR 0.88 (0.49–1.59) |
This is a planned interim analysis: the trial was assessed at 67% of the 130 planned MFS events (the 87th event) and crossed the prespecified significance boundary (p=0.012). The primary endpoint was measured by conventional imaging, not PSMA PET. Follow-up continues for overall survival and prostate cancer-specific survival; no difference has been shown for these endpoints so far. CI = confidence interval.
What did the additional analyses and treatment adherence show?
The data below include post hoc (not prespecified) analyses and treatment adherence, and should be interpreted with less certainty than the primary finding.
| Measure | Darolutamide + ADT + RT | Placebo + ADT + RT | Hazard ratio |
|---|---|---|---|
| Distant metastasis-free survival, 4 years (post hoc, other-cause deaths censored)* | 98% | 92% | HR 0.23 (0.12–0.45) |
| PSA progression-free survival, 4 years (post hoc, other-cause deaths censored)* | 94% | 86% | HR 0.37 (0.25–0.57) |
| Full-dose treatment for ≥94 weeks* | 79% | 78% | — |
| Subsequent anticancer therapy* | 4% | 10% | — |
Was the result consistent across subgroups?
The MFS benefit pointed the same way across prespecified subgroups. Subgroup analyses are small, exploratory and not sufficient for decisions on their own.
| Subgroup | Patients | HR for MFS (95% CI) |
|---|---|---|
| Pelvic lymph node involvement* | 316 | 0.39 (0.19–0.81) |
| No pelvic lymph node involvement* | 790 | 0.44 (0.25–0.78) |
| Prior radical prostatectomy (salvage radiotherapy)* | 171 | 0.1 (0.01–0.79) |
| Baseline PET performed* | 613 | 0.45 (0.24–0.85) |
| Baseline PET not performed* | 493 | 0.39 (0.21–0.75) |
Unadjusted interaction p values ranged from 0.08 to 0.80. Separate HRs for the primary and salvage radiotherapy cohorts were not given; only cohort sizes were reported. ADT duration was fixed (96 weeks), so there is no subgroup by ADT duration. The confidence interval for the post-surgery group is very wide (0.01–0.79).
What are the most common side effects during treatment?
According to the sources, no new safety signal was seen and the safety profile was consistent with earlier darolutamide trials. Grade ≥3 adverse events were, however, somewhat more frequent in the darolutamide arm.
Adverse events
DASL-HiCaP · interim analysis
Any grade ≥3 adverse event
Vasodilatation / hot flushes (any grade)
Fatigue / asthenia (any grade)
Fatigue / asthenia (grade ≥2)
Red bars are the darolutamide arm and gray bars the placebo arm. Any-grade and grade ≥2 rates are different definitions and should not be confused. Comparisons are within the same trial.
| Measure | Darolutamide + ADT + RT | Placebo + ADT + RT |
|---|---|---|
| Any grade ≥3 adverse event | 43% | 36% |
| Vasodilatation / hot flushes, any grade | 66% | 64% |
| Fatigue / asthenia, any grade | 64% | 57% |
| Fatigue / asthenia, grade ≥2 | 14% | 10% |
| Hypertension, grade ≥2 | 7% | 9% |
| Fractures, grade ≥2 | 2% | 3% |
| Cardiac events, grade ≥2 | 3% | 3% |
| Hypertension, any grade* | 8% | 10% |
| Mental impairment, any grade* | 8% | 7% |
| Rash, any grade* | 8% | 6% |
| Diabetes / hyperglycemia, any grade* | 7% | 8% |
| Breast disorders / gynecomastia, any grade* | 6% | 4% |
| Falls, any grade* | 5% | 6% |
| Cardiac disorders, any grade* | 4% | 3% |
| Bone fractures, any grade* | 3% | 3% |
*Reported by a single secondary source (OncLive). Treatment discontinuation rates, details of grade ≥3 events and serious adverse event data were not reported in the sources. Grade ≥2 rates for fatigue, hypertension, fractures and cardiac events come from the company release (Orion/Bayer) and OncoDaily.
Why was the primary endpoint measured with conventional imaging, and what would PSMA PET change?
The primary endpoint relied on metastases detected by CT and/or bone scan. The presenter, Dr. Tamim Niazi, noted that PSMA PET would detect metastases earlier. The trial did not mandate baseline PET; about 613 patients had a discretionary baseline PET, and the MFS benefit was similar in those with (HR 0.45) and without (HR 0.39) PET*. The results may therefore not translate directly to patients staged with PSMA PET today.
How do these results compare with other ARTA trials?
The table sets three recent trials in high-risk localized prostate cancer treated with radiotherapy or surgery side by side, but patient groups, control arms and follow-up differ, so they cannot be compared directly.
| Trial | Setting and comparison | HR for MFS (95% CI) | Follow-up | Regulatory status |
|---|---|---|---|---|
| DASL-HiCaP (n=1,106) | Very high risk; radiotherapy + 96 weeks of ADT: darolutamide / placebo | 0.42 (0.27–0.66) | Median 3.8 years (interim) | Not approved in this setting |
| ENZARAD (n=802) | High-risk localized; ADT + radiotherapy: enzalutamide 24 months / conventional nonsteroidal antiandrogen 6 months | 0.88 (0.67–1.15); not significant | 8-year MFS 74% and 72% | Not stated in the sources |
| PROTEUS (n=2109) | Newly diagnosed high-risk localized/locally advanced; apalutamide + ADT before and after surgery / placebo + ADT | 0.80 (p=0.0169; CI not given in the source) | Median 61.7 months | Not stated in the sources |
The comparison is indirect. ENZARAD was negative; the reason for the difference is unresolved, and the control arm (short-course antiandrogen), follow-up and patient characteristics differ. In PROTEUS, MFS was amended to a composite that incorporates PSMA PET, and conventional imaging alone gave HR 0.84 (p=0.15). No trial compares these drugs with each other or with DASL-HiCaP, so no conclusion can be drawn about which drug is better.
Which results are established and which remain uncertain?
Figure 2 · Evidence map
DASL-HiCaP, ESMO 2026 LBA4
- Approval: According to the company release, darolutamide is not approved for this setting, and no filing plans were reported. In the US it is approved for non-metastatic castration-resistant prostate cancer and for metastatic hormone-sensitive prostate cancer (with or without docetaxel).
- Reimbursement and access: Availability and reimbursement vary by country and must be checked locally. The sources do not mention an access route for this use outside clinical trials.
- What should patients do? The radiotherapy and ADT plan for very high-risk prostate cancer is made with the oncology and radiation oncology team; using darolutamide for this purpose could only be considered within a clinical trial.
Frequently asked questions
- Can darolutamide be used with radiotherapy now?
- Not as an approved treatment. According to the company release, darolutamide is not approved in this setting and no filing plans were reported. It could only be considered within a clinical trial.
- Did it prolong life?
- Not yet shown. Overall survival HR was 0.88 (0.49–1.59); 97% vs 95% were alive at 4 years, but the number of events is very small (21 and 24) and follow-up continues. The benefit was shown in metastasis-free survival.
- What are the main side effects?
- Hot flushes (66% vs 64%) and fatigue (64% vs 57%) were the most common. Any grade ≥3 adverse event was 43% vs 36%. No new safety signal was reported.
- Do the results apply to patients staged with PSMA PET?
- Unknown. The primary endpoint was measured by conventional imaging; the benefit looks similar with and without baseline PET, but these subgroups are small.
Glossary
- Metastasis-free survival (MFS)
- The time a patient lives without metastasis and without death; here a metastasis or death from any cause counted as an event.
- ADT (androgen deprivation therapy)
- Hormone therapy that lowers testosterone, usually given as LHRH-analogue injections.
- ARTA
- Newer drugs that block the androgen receptor (darolutamide, apalutamide, enzalutamide).
- PSA progression-free survival
- The time until PSA rises to a predefined level.
- Salvage radiotherapy
- Radiotherapy given after surgery when PSA fails to fall or rises again.
- PSMA PET
- An advanced imaging method that labels the PSMA protein on prostate cells and can show small metastases too.
- Hazard ratio (HR)
- A value below 1 means a lower risk of the event in the experimental arm; 0.42 corresponds to about a 58% lower risk.
DROZDOGAN Academy Commentary
DASL-HiCaP shows that adding darolutamide to radiotherapy and ADT in very high-risk prostate cancer significantly reduces metastasis risk, but it is an interim analysis and the overall survival benefit is not yet known.
⚡ Why it matters
Even with radiotherapy and ADT, roughly one in eight of these patients develops metastasis or dies within four years. That adding darolutamide lowers this rate from 12% to 5% is the first positive phase 3 signal for this drug in localized disease, whereas enzalutamide, a drug of the same class, showed no MFS benefit in ENZARAD.
✅ Strengths
Randomized, placebo-controlled phase 3 design; 1,106 patients; the prespecified boundary was crossed; benefit in the same direction for PSA progression-free survival and castration resistance; similar benefit with and without pelvic lymph node involvement; no new safety signal and similar adherence to full-dose treatment in both arms.
⚠️ Limitations
Interim analysis (67% of planned events) and median follow-up of 3.8 years; overall survival and prostate cancer-specific survival are immature. The primary endpoint was measured without PSMA PET. Quality-of-life results and discontinuation rates were not reported. Grade ≥3 adverse events were somewhat more frequent in the darolutamide arm. Long-follow-up trials such as ENZARAD remind us that results can change over time. The post-surgery cohort comes from a small sample.
🩺 In practice
Darolutamide is not approved in this setting and is not a standard option today. People with very high-risk prostate cancer should plan treatment with their oncologist and radiation oncologist and ask about suitable clinical trials.
❓ Open questions
Will there be an overall survival benefit? Is the benefit the same in patients staged with PSMA PET? Are 96 weeks of ADT and darolutamide the optimal duration? What is the separate effect in primary and salvage radiotherapy patients? What are the long-term side effects and quality of life?
Conclusion: A strong and consistent reduction in metastasis risk; however, the interim analysis, the lack of overall survival data and the absence of approval call for caution.
- This article was prepared in October 2026.
- Figures come from the 24 October 2026 releases by Orion/Bayer and Bayer, and from OncLive, OncoDaily and Targeted Oncology reports; the full text and a peer-reviewed publication could not be accessed (the sources mention no publication). The data are from the interim analysis presented as ESMO 2026 LBA4.
- Metastasis event counts, subgroup HRs, post hoc analyses, cohort definitions, stratification, median age, full-dose adherence and detailed adverse event rates come from a single secondary source and are marked (*). The rate of subsequent anticancer therapy appeared only in Targeted Oncology.
- By protocol the interim analysis was triggered at the 87th event; the event counts reported in the sources add up to 90, and the difference is not explained.
- The trial is investigator-initiated (University of Sydney, ANZUP); Bayer states that it supports the research, but funding details were not reported. Darolutamide was developed jointly by Bayer and Orion. The "first phase 3" wording belongs to the company release; "new paradigm" is OncoDaily’s wording.
- ENZARAD and PROTEUS data come from secondary sources (ESMO Daily Reporter, ASCO Post) and the table is an indirect comparison. The earlier FDA approval dates of darolutamide rely on OncoDaily and the FDA page; for the August 2022 approval the sources give different days, so only the month and year are stated.
- The charts show only direct comparisons between the arms of the same trial.
- The schemas are derived from verified statements in the text and contain no new data. The Academy commentary is our own.
Sources
- Orion Corporation / Bayer. Darolutamide plus ADT and radiation therapy reduces risk of metastasis or death by 58% in prostate cancer patients at high risk of recurrence. Press release, 24 Oct 2026 (GlobeNewswire). https://www.globenewswire.com/news-release/2026/10/24/3387659/0/en/darolutamide-plus-adt-and-radiation-therapy-reduces-risk-of-metastasis-or-death-by-58-in-prostate-cancer-patients-at-high-risk-of-recurrence.html
- Bayer. ESMO 2026: NUBEQA (darolutamide) plus ADT and radiation therapy reduces risk of metastasis or death by 58% in prostate cancer patients at high risk of recurrence. Press release, 24 Oct 2026 (copy of the Business Wire release). https://www.financialcontent.com/article/bizwire-2026-10-24-esmo-2026-nubeqa-darolutamide-plus-adt-and-radiation-therapy-reduces-risk-of-metastasis-or-death-by-58-in-prostate-cancer-patients-at-high-risk-of-recurrence
- Niazi T, et al. DASL-HiCaP (ANZUP1801): darolutamide plus ADT and radiotherapy in very high-risk localized or persistent/recurrent prostate cancer. ESMO Congress 2026, Madrid, Presidential Symposium I, abstract LBA4, 24 Oct 2026 (interim analysis).
- OncLive. DASL-HiCaP: darolutamide plus ADT and radiation therapy improves MFS in very high-risk localized prostate cancer. Oct 2026. https://www.onclive.com/view/dasl-hicap-darolutamide-plus-adt-and-radiation-therapy-improves-mfs-in-very-high-risk-localized
- OncoDaily. DASL-HiCaP at ESMO 2026: darolutamide plus ADT and radiotherapy in very high-risk prostate cancer. 24 Oct 2026. https://oncodaily.com/genitourinary-oncology/dasl-hicap
- Targeted Oncology. Late-breaking phase 3 data headline ESMO 2026 Presidential Symposium I. Oct 2026. https://www.targetedonc.com/view/esmo-2026-presidential-symposium-i-late-breaking-recap
- ClinicalTrials.gov. DASL-HiCaP, darolutamide augments standard therapy for localised very high-risk cancer of the prostate (NCT04136353). https://clinicaltrials.gov/show/NCT04136353
- ESMO Daily Reporter. Mixed results with enzalutamide in non-metastatic prostate cancer (ENZARAD, EMBARK). ESMO Congress 2025. https://dailyreporter.esmo.org/esmo-congress-2025/genitourinary-cancers/mixed-results-with-enzalutamide-in-non-metastatic-prostate-cancer
- The ASCO Post. PROTEUS trial suggests perioperative apalutamide may improve outcomes in high-risk localized prostate cancer. 25 June 2026. https://ascopost.com/issues/june-25-2026/proteus-trial-suggests-perioperative-apalutamide-may-improve-outcomes-in-high-risk-localized-prostate-cancer/
- U.S. Food and Drug Administration. FDA approves darolutamide for metastatic castration-sensitive prostate cancer. 3 June 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-metastatic-castration-sensitive-prostate-cancer
- OncoDaily. Darolutamide (Nubeqa): uses, FDA approvals and key trials. https://oncodaily.com/drugs/darolutamide-nubeqa
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