The Phase III ARANOTE trial has revealed that darolutamide in combination with androgen deprivation therapy (ADT) significantly improves outcomes for patients with metastatic hormone-sensitive prostate cancer (mHSPC). The study, presented at the European Society for Medical Oncology (ESMO) 2024 Congress and published in the Journal of Clinical Oncology, indicates that this combination therapy could become a new standard of care, potentially replacing the need for docetaxel in certain patients.
The ARANOTE trial (NCT04736199) involved 669 patients with mHSPC who were randomized to receive either darolutamide 600 mg twice daily plus ADT (446 patients) or placebo plus ADT (223 patients). The primary endpoint was radiographic progression-free survival (rPFS), assessed by central blinded review. Key secondary endpoints included overall survival, time to metastatic castration-resistant prostate cancer (mCRPC), time to pain progression, and rates of undetectable PSA.
Significant Improvement in Radiographic Progression-Free Survival
At 24 months, the rPFS rate was 70.3% in the darolutamide arm compared to 52.1% in the placebo arm. The median rPFS was not reached in the darolutamide arm, while it was 25 months in the placebo arm. This translates to a 46% decreased risk for radiographic progression in patients treated with darolutamide (HR 0.54; 95% CI, 0.41-0.71; P<0.0001). According to Dr. Fred Saad from the Centre Hospitalier de l’Université de Montréal, the rPFS benefit was consistent across subgroups, including those with high- and low-volume disease.
Secondary Endpoints and Safety Profile
Beyond the primary endpoint, darolutamide also demonstrated significant benefits in secondary endpoints. The median time to mCRPC was not reached in the darolutamide arm but was 13.8 months in the placebo arm, representing a 60% decreased risk for castration-resistant disease (HR 0.40; 95% CI, 0.32–0.51). Similarly, the median time to pain progression was not reached in the darolutamide arm, compared to 29.9 months in the placebo arm (HR 0.72; 95% CI, 0.54–0.96).
Notably, 62.6% of darolutamide-treated patients achieved a PSA level below 0.2 ng/mL at any time during treatment, compared to only 18.5% in the placebo arm. The median time to PSA progression was also significantly delayed in the darolutamide group (HR 0.31; 95% CI, 0.23–0.41).
The safety profile of darolutamide was consistent with previous trials, with similar rates of treatment-related adverse events (TRAEs) between the study arms. The incidence of TRAEs leading to permanent discontinuation of the study drug was 6.1% in the darolutamide arm and 9.0% in the placebo arm.
Clinical Implications and Future Directions
The ARANOTE trial provides compelling evidence that darolutamide plus ADT is an effective treatment option for mHSPC, particularly for patients who may not be suitable candidates for docetaxel-based chemotherapy. “We believe that darolutamide and ADT without the need of docetaxel could become an additional standard of care for mHSPC,” said Dr. Saad.
Bayer plans to submit the data from the ARANOTE trial to health authorities globally to support the expanded use of darolutamide in patients with mHSPC. Darolutamide is already approved for the treatment of patients with mHSPC in combination with ADT and docetaxel in more than 80 markets, and for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in over 85 countries.
