Among patients with hormone-sensitive prostate cancer, an alternative dosing regimen of docetaxel — 50 mg/m2 once every two weeks instead of 75 mg/m2 once every three weeks — plus Nubeqa (darolutamide) and androgen deprivation therapy (ADT) was associated with statistically significant and clinically meaningful improvements in severe, life-threatening and fatal side effect rates as well neutropenia and death of any reason, study results have shown.
The findings, from the phase 3 ARASAFE study, were presented at the 2025 European Society for Medical Oncology Congress in Berlin by Dr. Marc-Oliver Grimm, professor and chair of urology at Jena University Hospital in Jena, Germany.
By way of background, Grimm explained that the use of ADT, Nubeqa and docetaxel is FDA approved for patients with mHSPC based on findings from the phase 3 ARASENS trial. In that regimen, the docetaxel dosage is 75 mg/m2 once every three weeks. However, Grimm pointed out that toxicity such as neutropenic complications could limit the use of this regimen compared with androgen receptor pathway inhibitor/ADT doublet therapy. For ARASAFE, Grimm and his co-authors sought to evaluate toxicity in triplet therapy with Nubeqa/ADT/docetaxel with docetaxel dosages of 50 mg/m2 once every two weeks and 75 mg/m2 once every three weeks.
Glossary
Neutropenia: a condition where the number of neutrophils (a type of white blood cell that helps fight infections) is lower than normal. This can make it easier to get infections.
Overall Survival: the length of time from the start of treatment that patients are still alive. It’s a way doctors measure how well a treatment works.
Leukopenia: a condition where there are fewer white blood cells than normal. White blood cells help protect the body from infections.
Prostate-Specific Antigen (PSA): a protein made by the prostate gland. PSA levels are often checked with a blood test to help detect or monitor prostate cancer.
“We hypothesized that triplet therapy with [Nubeqa], ADT and 50 mg[/m2] every two weeks reduces grade 3 (severe) to 5 (fatal) adverse events compared to the standard 75-mg[/m2] schedule,” Grimm said. Grimm also pointed to previous research indicating that ADT plus docetaxel 50 mg/m2 once every two weeks was associated with better time to treatment failure and fewer grade 3 to 4 (life-threatening) side effects in patients with metastatic castration-resistant prostate cancer.
In ARASAFE, a total of 250 patients with mHSPC were randomly assigned to Nubeqa 600 mg twice daily plus ADT plus six cycles of docetaxel 75 mg/m2 once every three weeks (three-week cycle, 129 patients) or to Nubeqa 600 mg twice daily plus ADT plus six cycles of docetaxel 50 mg/m2 once every two weeks (four-week cycle, 121 patients). Total expected docetaxel dose was 450 mg/m2 in the 75 mg/m2 arm versus 600 mg/m2 in the 50 mg/m2 arm.
Primary end points included grade 3 to 5 side effects and grade 3 to 4 neutropenia or death of any reason. Secondary end points included time to castration-resistant prostate cancer, overall survival, time to pain progression, time to first symptomatic skeletal event, time to initiation of subsequent systemic antineoplastic therapy, time to worsening of disease-related physical symptoms and quality of life.
Median age at baseline was 68 years in the 75 mg/m2 arm versus 67 years in the 50 mg/m2 arm. High-volume disease was present in 108 (83.7%) patients in the 75 mg/m2 arm versus 104 (86%) patients in the 50 mg/m2 arm. Mean number of docetaxel doses was 5.6 in the 75 mg/m2 arm versus 10.7 in the 50 mg/m2 arm. Mean cumulative docetaxel dose was 842.8 mg in the 75 mg/m2 arm versus 1073.5 mg in the 50 mg/m2 arm.
Grimm reported that the study reached its primary end points: The grade 3 to 5 side effect rate was 78.9% in the 75 mg/m2 arm versus 61.2% in the 50 mg/m2 arm. Additionally, the grade 3 to 4 neutropenia/death of any reason rate was 64.1% in the 75 mg/m2 arm versus 24% in the 50 mg/m2 arm.
Grimm also reported that the rates of neutropenia, leukopenia and febrile neutropenia favored the 50 mg/m2 dosage over the 75 mg/m2 dosage.
The investigators utilized prostate-specific antigen (PSA) response at week 26 as a putative surrogate for oncologic outcome. Grimm reported that the median PSA level in the 75 mg/m2 arm was 0.16 ng/mL versus 0.26 ng/mL in the 50 mg/m2 arm. PSA levels of 0.2 ng/mL or lower were observed in 63 (48.8%) patients in the 75 mg/m2 arm versus 50 (41.3%) patients in the 50 mg/m2 arm.
“In summary, ARASAFE demonstrates a statistically highly significant and clinically meaningful reduction in the incidence of grade 3 to 5 [side effect] rate and the rate of grade 3 to 4 neutropenia or death regardless of reason for the experimental approach. This was achieved despite higher total doses of docetaxel in the experimental arm. Therefore, the ARASAFE approach may be considered a potential new standard of care,” Grimm said in his concluding remarks.
REFERENCES
- “3-weekly docetaxel 75 mg/m2 vs 2-weekly docetaxel 50 mg/m2 in combination with darolutamide + ADT in patients with mHSPC: Results from the randomised phase III ARASAFE trial,” by Dr. Marc-Oliver Grimm, et al. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA92.
- “FDA approves darolutamide tablets for metastatic hormone-sensitive prostate cancer,” FDA; https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-tablets-metastatic-hormone-sensitive-prostate-cancer
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