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In the randomized DASL-HiCaP trial, adding darolutamide to androgen deprivation therapy and radiation was associated with better metastasis-free survival in men with very high-risk prostate cancer. Four-year metastasis-free survival by conventional imaging was 95% with darolutamide versus 88% with standard treatment; questions remain about imaging, patient selection and longer-term survival.
Adding darolutamide to androgen deprivation therapy (ADT) and radiation therapy improved four-year metastasis-free survival for men with very high-risk prostate cancer in the randomized DASL-HiCaP trial, researchers reported at the European Society for Medical Oncology congress. By conventional imaging, the measure was 95% with darolutamide, compared with 88% with ADT and radiation alone, though the findings do not settle how the treatment should be used across different risk groups.
The multinational trial enrolled 1,106 patients with very high-risk features who were scheduled for definitive radiation or radiation after prostate removal. Of those, 935 were planned for primary radiation and 171 for salvage radiation. Patients were randomly assigned to standard radiation and long-course ADT, with or without darolutamide. The primary endpoint was metastasis-free survival by conventional imaging.
In the primary analysis, the darolutamide group had a 58% lower hazard of metastasis or death, compared with the control group (hazard ratio 0.42; 95% confidence interval 0.27-0.66; P=0.0001). The report counted nine metastases in the darolutamide arm and 46 in the control arm. Deaths without recorded metastasis were 18 and 17, respectively. These event counts are not the same as a direct comparison of overall survival.
Several secondary outcomes also favored darolutamide. Four-year freedom from prostate-specific antigen (PSA) progression was 91% versus 83%, and freedom from progression to castration-resistant prostate cancer was 99% versus 95%. The report said the safety profile did not change appreciably with darolutamide. It did not provide enough detail in the supplied results to assess specific side effects or treatment discontinuations.
What the Survival Results Show
Metastasis-free survival measures how long patients remain alive without cancer spreading to distant sites. For people treated with curative intent, delaying or preventing metastasis can be clinically meaningful and may affect later treatment needs. In DASL-HiCaP, the seven-percentage-point difference at four years and fewer recorded metastases support further consideration of treatment intensification for patients matching the trial’s very high-risk criteria.
The result does not establish that every patient with high-risk prostate cancer should receive darolutamide. The trial’s endpoint used conventional imaging, not PSMA-PET, and the reported analysis is not proof of an overall-survival benefit. The treatment decision also involves weighing potential benefit against side effects, duration and the patient’s individual risk. Those questions matter because broader use could expose some people to additional treatment without the same expected gain.
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How DASL-HiCaP Fits Earlier Trials
Earlier trials of androgen receptor pathway inhibitors alongside ADT and radiation did not produce identical results. The STAMPEDE trial found that abiraterone, with or without enzalutamide, improved metastasis-free survival by conventional imaging compared with ADT alone. ENZARAD did not show an improvement when enzalutamide was added to ADT and radiation. Those differences left uncertainty about which patients benefit from intensified systemic treatment.
At the congress, invited discussant Silke Gillessen pointed to differences in trial populations and treatment protocols. For example, the proportion with N1 disease was reported as nearly 40% in STAMPEDE, 11% in ENZARAD and 24% in DASL-HiCaP. The studies also differed in Gleason grade, tumor stage, PSA levels and radiation approaches. DASL-HiCaP’s definition of very high risk included features such as grade group 5 disease, certain combinations of grade group 4 with more advanced local disease, PSA above 20 ng/mL, or lymph-node involvement, with separate criteria for salvage radiation.
“The addition of darolutamide to 2 years of androgen deprivation therapy with salvage or primary radiation therapy and pelvic radiation therapy significantly improves metastasis-free survival by conventional imaging.”
— Tamim Niazi, MD, McGill University
Limits of the Current Evidence
The reported benefit is based on conventional imaging; how it compares with detection using PSMA-PET imaging was not established. The results also do not show whether darolutamide improves overall survival, and the supplied report does not give a follow-up duration beyond the four-year metastasis-free survival figure. Longer follow-up may clarify the durability and survival implications of the result.
Which patients should count as “very high risk” remains disputed, and trial populations varied. Gillessen said the role of pelvic radiation in very high-risk patients without detected nodal disease remains unresolved. The report also does not provide detailed subgroup estimates or enough safety data to compare specific adverse effects. The findings therefore support a benefit in the enrolled population, but do not settle individual treatment choices or the best definition of risk.
Questions for Longer Follow-Up
The next important evidence will be continued follow-up from DASL-HiCaP, particularly for overall survival, lasting disease control and fuller safety outcomes. Researchers and clinicians will also need to compare the trial’s risk criteria with modern imaging and biomarkers to determine whether the benefit is concentrated in particular groups.
Gillessen called for future work on both treatment intensification and biomarker-guided de-escalation, which could help avoid unnecessary treatment for patients less likely to benefit. Until those questions are answered, the reported findings describe a positive randomized trial result—not a universal treatment recommendation. The available report does not state when further analyses or guideline decisions are expected.
Key Questions
What did the DASL-HiCaP trial find?
It found better metastasis-free survival by conventional imaging when darolutamide was added to ADT and radiation for patients with very high-risk prostate cancer. The four-year result was 95%, compared with 88% for standard treatment alone.
Does the result prove darolutamide extends overall survival?
No. The primary endpoint was metastasis-free survival by conventional imaging. The report says this measure may be a surrogate for overall survival in this setting, but whether the observed improvement translates into longer life remains unclear.
Who took part in the trial?
The trial randomized 1,106 patients with very high-risk features who were planned for primary radiation or salvage radiation after prostate surgery. The eligibility criteria included combinations of tumor grade, stage, PSA level and lymph-node involvement.
How does this compare with earlier studies?
STAMPEDE found improved metastasis-free survival with abiraterone-based intensification, while ENZARAD did not find an improvement with enzalutamide. Differences in patient risk profiles and treatment protocols may help explain why the results varied.
Does this mean all high-risk patients should receive darolutamide?
No. The trial studied a defined very high-risk population, and questions remain about patient selection, imaging methods, overall survival and side effects. Treatment choices should be discussed with an oncology team familiar with the individual case.
Source: medpagetoday.com
