Meet the Trialist: Prof. Fred Saad shares insights from the ARANOTE trial

The phase 3 ARANOTE trial investigated the efficacy and safety of combining darolutamide, an androgen receptor inhibitor, with androgen-deprivation therapy (ADT) in 669 patients with metastatic hormone-sensitive prostate cancer (mHSPC). Presented at the ESMO Congress 2024, the study's results offer valuable insights into improving treatment strategies for this patient population [1,2]. We interviewed lead investigator Prof. Fred Saad (Montreal Cancer Institute; University of Montreal Hospital Center Research Center, Canada) to discuss the impact of this study.

The ARANOTE study (NCT04736199) randomised 669 participants in a 2:1 ratio to receive either darolutamide (600 mg twice daily) plus ADT or placebo plus ADT. The primary endpoint was radiological progression-free survival (PFS), while secondary endpoints included overall survival (OS), time to castration-resistant prostate cancer (CRPC), and time to pain progression.

Darolutamide combined with ADT significantly reduced the risk of radiological progression or death by 46% compared with placebo (HR 0.54; 95% CI 0.41–0.71; P<0.0001). The positive effects were seen across patient subgroups, including those with high- and low-volume disease. While the OS data favoured darolutamide, it was not statistically significant at the time of analysis (HR 0.81; 95% CI 0.59–1.12). Importantly, the combination therapy delayed the onset of CRPC (HR 0.40; 95% CI 0.32–0.51) and reduced the time to pain progression (HR 0.72; 95% CI 0.54–0.96).

Adverse events (AEs) were comparable between the 2 groups, with 5.6% of patients in the darolutamide group experiencing fatigue, compared with 8.1% in the placebo group. Fewer patients on darolutamide discontinued treatment due to AEs (6.1% vs 9.0%).

Clinical implications

According to Prof. Saad, this study “confirms the efficacy and tolerability of darolutamide combined with ADT in patients with mHSPC, demonstrating a statistically significant improvement in radiological PFS and a favourable safety profile. The ARANOTE trial establishes darolutamide plus ADT as a highly effective and well-tolerated treatment option for men with mHSPC.”

Given the growing landscape of therapeutic options, he continued, “the findings from ARANOTE suggest that darolutamide can be a viable option for delaying disease progression in mHSPC without the need for chemotherapy. This is especially important as it offers patients a treatment pathway that may delay progression to castration-resistant prostate cancer, improving clinical outcomes as well as quality-of-life.”

Potential impact on standard-of-care

Prof. Saad said “I believe the findings could lead to darolutamide becoming a new standard-of-care for patients with mHSPC. What we hope is that this will become another standard-of-care for patients using what we now consider the best baseline standard-of-care, which means ADT plus an ARPI [androgen receptor pathway inhibitor],” he explains. “Darolutamide adds to the therapeutic arsenal, providing a flexible treatment approach that can be tailored to patients' individual needs and profiles.”

Additionally, the study opens the door to potential combinations with other agents, such as docetaxel. Prof. Saad notes that "we'll be able to consider patients for ADT plus darolutamide, with or without docetaxel, based on patient needs and preferences."

Future directions

“The safety and efficacy of darolutamide also make it a promising candidate for earlier stages of prostate cancer. Ongoing trials are exploring its use in non-metastatic and earlier settings. The encouraging safety profile and low likelihood of drug-drug interactions mean that darolutamide can be combined with other therapies without significantly increasing the risk of adverse effects. I think it's a very interesting drug to be able to look at combinations, since we're able to safely administer this with many drugs with little fear of worsening the side effect profiles of combinations, and the drug-drug interactions are really quite encouraging.”

Prof. Saad concluded, “the ARANOTE trial demonstrates that darolutamide plus ADT is a highly effective and well-tolerated treatment for mHSPC, significantly delaying disease progression while maintaining a favourable safety profile. These results mark an important step forward in optimising treatment strategies for patients with mHSPC and highlight darolutamide’s potential role in further improving outcomes for this population.”

1. 
   
   1. Saad F, et al. Efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase III ARANOTE trial. Abstract LBA68, ESMO Congress 2024, 13–17 September, Barcelona, Spain.
   2. Saad F, et al. J Clin Oncol. 2024;Sep 16. DOI:10.1200/JCO-24-01798.

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Posted on 25 September 202425 September 2024