— Adding darolutamide to ADT and RT improved metastasis-free survival, but questions persist
October 26, 2026 • 4 min read
Men with very high-risk prostate cancer had a significantly lower risk of metastasis when they received darolutamide (Nubeqa) in addition to androgen deprivation therapy (ADT) and radiation therapy (RT), a randomized trial showed.
Metastasis-free survival by conventional imaging (MFS-CI) at 4 years improved from 88% with RT and ADT to 95% when darolutamide was added. Freedom from prostate-specific antigen (PSA) progression, progression to castration-resistant prostate cancer (CRPC), and need for subsequent hormonal therapy all favored the addition of darolutamide.
The safety profile did not change appreciably in patients randomized to darolutamide, reported Tamim Niazi, MD, of McGill University in Montreal, at the European Society for Medical Oncologyopens in a new tab or window congress in Madrid.
"The take-home point is that 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," said Niazi. "MFS-CI is a strong surrogate for overall survival [OS] in this setting, and this benefit was pretty consistent across all subgroups."
"Our conclusion is that darolutamide reduces the risk of relapse to a clinically meaningful degree, and as such, it does define a new paradigm for the care of prostate cancer patients at very high risk of recurrence, patients who are planned for curative-intent radiation therapy," Niazi added.
The DASL-HiCaP randomized trial met the primary endpoint and clearly is a positive study, but a number of questions remain unanswered, said ESMO invited discussant Silke Gillessen, MD, of the Oncology Institute of Southern Switzerland in Bellinzona. The trial added to evidence that treatment intensification in high-risk prostate cancer can improve MFS, but that pertains only to conventional imaging, not prostate-specific membrane antigen (PSMA)-PET imaging.
"I think MFS by conventional imaging is a valid endpoint, but we do not know how much of an improvement in MFS by conventional imaging is needed in 2026 to be a surrogate for OS, since we have made progress in the treatment of patients with prostate cancer," she said.
Second, the definition of "very high risk" continues to be a moving target.
Two previous randomized trials addressed the issue of treatment intensification for high-risk localized or relapsed prostate cancer but yielded different results. The STAMPEDEopens in a new tab or window trial showed that abiraterone (Zytiga), with or without enzalutamide (Xtandi), significantly improved MFS-CI versus ADT alone. On the other hand, the ENZARADopens in a new tab or window trial failed to show an improvement in MFS-CI when enzalutamide was added to ADT and RT.
Collectively, three randomized trials have addressed the same question and produced two answers, said Gillessen. How the investigators in the trials defined high risk likely influenced the results. Almost 40% of the STAMPEDE population had N1 disease versus 11% in ENZARAD and 24% in DASL-HiCaP. DASL-HiCaP had substantially more patients with Gleason 9/10 pathology, whereas almost all of the STAMPEDE patients had cT3/4 versus about half of the patients in the other two studies. The median PSA value was two to three times higher in STAMPEDE, and the RT protocols varied somewhat.
"[DASL-HiCaP] data does help to resolve the difference between the other two trials, which is based around the proportion of patients at risk," said Gillessen. "The ARPI [androgen receptor pathway inhibitor] benefit seems to appear when the risk of metastasis is high and disappears in lower-risk N0 patients. The role of pelvic radiotherapy in very high risk N0 patients has yet to be resolved."
"We need to redefine very high risk, incorporating modern imaging and biomarkers," she said. "In the future, we should evaluate not only intensification but biomarker-driven de-escalation to avoid overtreatment in this group of patients, ideally with non-testosterone-suppressing strategies."
By way of introduction to DASL-HiCaP, Niazi noted that the STAMPEDE and ENZARAD trials reported that a subset of patients with high-risk localized/locally-advanced prostate cancer benefit from the addition of an ARPI to standard long-course ADT plus RT. In the aftermath of those trials, uncertainty persisted about which patients that received standard-of-care RT and ADT are most likely to benefit from intensification of systemic treatment.
To address the uncertainty, investigators in the multinational DASL-HiCaP trial enrolled and randomized 1,106 patients with very high-risk features and planned definitive RT or salvage RT after radical prostatectomy. For patients scheduled for radical radiation therapy, very high risk was defined as grade group 5 or grade group 4 associated with cT2b-T4 or rT3a-T4 disease, a PSA level >20 ng/mL, or cN1 disease. For patients undergoing salvage RT, very high risk comprised pN1 or cN1, grade group 5, or grade group 4 with pT3a-pT4 disease.
The patients were randomized to standard RT and long-course ADT with or without darolutamide continued. The primary endpoint was MFS-CI. The study population included 935 patients scheduled for primary RT and 171 with planned salvage RT.
The primary analysis showed that the darolutamide group had a 58% lower hazard for MFS-CI as compared with the control group (95% CI 0.27-0.66, P=0.0001). The darolutamide arm had a total of nine metastases and 18 deaths without metastasis versus 46 metastases and 17 deaths without metastasis in the other arm.
Key secondary endpoints favored the darolutamide group, including PSA progression-free survival (91% vs 83%; HR 0.47, 95% CI 0.33-0.67), freedom from CRPC (99% vs 95%; HR 0.22, 95% CI 0.09-0.52), and freedom from subsequent hormonal therapy (96% vs 90%; HR 0.36, 95% 0.21-0.60). Prostate cancer-specific survival (99% in both groups) and OS (97% vs 95%) did not differ significantly.