The ARANOTE trial demonstrated that darolutamide plus androgen-deprivation therapy (ADT) significantly improves radiological progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC), marking a significant advancement in treatment options for this condition. The study found that this combination therapy reduced the risk of radiological progression or death by 46% compared to ADT alone. These results are particularly encouraging given the limitations of existing treatment options. While combination therapies have shown promise in improving overall survival (OS) and delaying progression to metastatic castration-resistant prostate cancer (mCRPC), they remain underutilized due to concerns regarding accessibility, tolerability, safety, and drug interactions.
The ARANOTE trial addresses these concerns, highlighting darolutamide plus ADT as a well-tolerated treatment option. The trial showed low incidences of adverse events in both the darolutamide and placebo groups, with most adverse events being grade 1 or 2.

Additionally, the rate of fatigue was significantly lower in the darolutamide group compared to the placebo group, a notable finding considering fatigue is a common side effect associated with other androgen receptor pathway inhibitors. The low discontinuation rate due to adverse events further supports the favorable tolerability of this combination therapy. This is especially relevant given the continued global use of ADT alone due to concerns about adverse events associated with hormonal therapies. These findings, coupled with the significant improvement in rPFS and a favorable HR for OS, position darolutamide plus ADT as a valuable addition to the mHSPC treatment landscape.

In brief:

● Delayed Time to mCRPC: Darolutamide plus ADT significantly prolonged the time to mCRPC, a critical milestone in prostate cancer progression. The study reported a hazard ratio of 0.40 for time to mCRPC, indicating a substantial reduction in the risk of developing castration-resistant prostate cancer. This delay in mCRPC onset can translate into a longer period of responsiveness to hormonal therapies and potentially improved overall survival.
● Deep and Durable PSA Responses: A higher proportion of patients receiving darolutamide plus ADT achieved PSA levels below 0.2 ng/mL compared to those receiving ADT alone (62.6% vs. 18.5%). Achieving and maintaining low PSA levels is a strong indicator of treatment effectiveness and is associated with better prognosis in prostate cancer. The ARANOTE trial demonstrated darolutamide’s ability to induce deep and durable PSA responses, further supporting its clinical benefit.
● Increased Time to Pain Progression: The study also showed that darolutamide plus ADT delayed the time to pain progression, a key patient-relevant outcome. Pain is a common and often debilitating symptom experienced by men with mHSPC. By delaying the onset of pain, this combination therapy can contribute to maintaining patients’ quality of life for a longer duration.
● Favorable Safety and Tolerability: The ARANOTE trial confirmed the favorable safety and tolerability profile of darolutamide observed in previous trials. Notably, the incidence of fatigue, a common side effect associated with other androgen receptor pathway inhibitors, was lower in the darolutamide group compared to the placebo group. This finding is particularly relevant given that concerns about side effects are a major reason for the continued use of ADT alone in many patients with mHSPC.

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