Darolutamide in Combination with Androgen-Deprivation Therapy in Patients with Metastatic Hormone-Sensitive Prostate Cancer from the Phase III ARANOTE Trial

Academic Background

Metastatic hormone-sensitive prostate cancer (mHSPC) is a common type of prostate cancer. Patients typically respond to androgen-deprivation therapy (ADT) for a period of time. However, most patients eventually develop metastatic castration-resistant prostate cancer (mCRPC), which has a poor prognosis and significantly reduces the quality of life. Therefore, delaying the progression of mHSPC to mCRPC is crucial not only for overall survival (OS) but also for improving patients’ quality of life.

In recent years, several Phase III clinical trials have shown that combining ADT with androgen receptor pathway inhibitors (such as abiraterone, enzalutamide, or apalutamide) can significantly extend OS in mHSPC patients and delay the progression to mCRPC. However, the application of these combination therapies in clinical practice still faces many challenges, including drug accessibility, tolerability, safety, drug interactions, and healthcare provider education. Thus, finding a treatment that effectively delays disease progression while maintaining good tolerability has become a significant need in the field of mHSPC treatment.

Darolutamide is a structurally unique and potent androgen receptor inhibitor with low blood-brain barrier penetration and limited potential for drug interactions, making it particularly suitable for elderly patients and those requiring multiple medications. Previously, darolutamide has demonstrated significant efficacy and favorable safety in Phase III trials for non-metastatic castration-resistant prostate cancer (nmCRPC) and mHSPC. Based on these positive results, the ARANOTE trial aimed to evaluate the efficacy and safety of darolutamide combined with ADT (without chemotherapy) in mHSPC patients.

Source of the Paper

The study was conducted by 18 authors, including Fred Saad, from renowned medical institutions across multiple countries, such as the University of Montreal Hospital in Canada, P. Stradiņš Clinical University Hospital in Latvia, and the Carolina Urologic Research Center in the United States. The paper was published on September 16, 2024, in the Journal of Clinical Oncology (JCO), with the DOI: https://doi.org/10.1200/JCO-24-01798.

Research Process

Trial Design

The ARANOTE trial was a global, randomized, double-blind, placebo-controlled Phase III clinical trial sponsored by Bayer and Orion Pharma. The trial was conducted at 133 centers across 15 countries, including Asia, Latin America, Europe, Australia, New Zealand, Canada, and South Africa. The trial design was developed by the first author and Bayer, and all participating centers obtained ethical committee approval for the study protocol and related documents. The trial adhered to the principles of the Declaration of Helsinki and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines. All patients provided written informed consent before enrollment.

Patients and Interventions

Eligible patients were men aged 18 years or older with histologically or cytologically confirmed prostate adenocarcinoma and metastatic disease confirmed by conventional imaging. Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and had to have started ADT within 12 weeks before randomization. Patients were randomized in a 2:1 ratio to receive either darolutamide 600 mg twice daily or placebo, along with continued ADT. Treatment continued until radiographic disease progression, unacceptable toxicity, initiation of new anticancer therapy, patient or physician decision to discontinue, or study drug interruption for more than 28 consecutive days.

Study Assessments

During treatment and follow-up, patients were evaluated at clinic visits every 12 weeks. The primary endpoint was radiographic progression-free survival (rPFS) based on imaging assessments. Secondary endpoints included OS, time to initiation of subsequent systemic anticancer therapy, time to mCRPC, time to prostate-specific antigen (PSA) progression, proportion of patients with PSA <0.2 ng/mL, and time to pain progression. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Statistical Analysis

Sample size calculations were based on the primary endpoint of rPFS, with an estimated 665 patients required to observe 214 progression events, ensuring 90% statistical power. The primary analysis used a stratified log-rank test, and secondary endpoints were analyzed using a stratified Cox regression model.

Main Results

Patient Characteristics

From March 2021 to August 2022, 669 patients were randomized, with 446 patients receiving darolutamide plus ADT and 223 patients receiving placebo plus ADT. The median age of patients was 70 years, with 31.2% being Asian and 9.7% Black. Most patients had an ECOG performance status of 0 (49.8%) or 1 (47.2%), and 68.3% had a Gleason score ≥8. De novo metastatic disease was present in 72.5% of patients, and 12.0% had visceral metastases.

Primary Endpoint

At the primary analysis cutoff date (June 7, 2024), darolutamide plus ADT significantly improved rPFS, reducing the risk of radiographic progression or death by 46% compared with placebo plus ADT (HR=0.54, 95% CI: 0.41-0.71, p<0.0001). The median rPFS was not reached in the darolutamide group, while it was 25.0 months in the placebo group. The benefit of darolutamide on rPFS was consistent across all subgroups, including patients with high- and low-volume disease.

Secondary Endpoints

At the primary analysis cutoff date, OS results suggested a benefit with darolutamide versus placebo (HR=0.81, 95% CI: 0.59-1.12), and clinical benefits were observed across all other secondary endpoints. Darolutamide significantly prolonged the time to mCRPC (HR=0.40, 95% CI: 0.32-0.51) and time to pain progression (HR=0.72, 95% CI: 0.54-0.96). Additionally, a higher proportion of patients in the darolutamide group achieved PSA <0.2 ng/mL compared with the placebo group (62.6% vs 18.5%).

Safety

The incidence of adverse events was similar between the darolutamide and placebo groups, with most AEs being grade 1 or 2. Fatigue was less frequent in the darolutamide group (5.6%) than in the placebo group (8.1%), and fewer patients in the darolutamide group discontinued treatment due to AEs (6.1% vs 9.0%).

Conclusion

The results of the ARANOTE trial confirm the efficacy and tolerability of darolutamide plus ADT in mHSPC patients, significantly improving rPFS and demonstrating a favorable safety profile. These findings provide a new treatment option for mHSPC patients, particularly those who are not suitable for chemotherapy.

Research Highlights

1. Significant Improvement in rPFS: Darolutamide plus ADT significantly reduced the risk of radiographic progression or death, with consistent benefits across all subgroups.
2. Favorable Safety Profile: Darolutamide had a low incidence of adverse events, with fatigue being less frequent than in the placebo group.
3. Broad Applicability: The trial included patients from multiple regions worldwide, including elderly patients and diverse racial groups, making the results widely representative.

Research Significance

The results of the ARANOTE trial further support the use of darolutamide in the treatment of mHSPC, particularly in the absence of chemotherapy. The efficacy and safety of darolutamide make it an important treatment option for mHSPC patients, especially those who are not suitable for chemotherapy or have poor tolerance to it. Additionally, this study provides valuable insights for future clinical trials, helping to further optimize treatment strategies for mHSPC.