ASCO GU: ARANOTE and ARASENS Trials Reinforce Darolutamide in Metastatic Hormone-Sensitive Prostate Cancer

In an interview with Pharmacy Times®, Fred Saad, MD, professor and chairman of the Department of Surgery at the University of Montreal, director of Genitourinary Oncology at the University of Montreal, discussed outcomes from phase 3 ARANOTE (NCT04736199) and ARASENS trials (NCT02799602) evaluating the efficacy of darolutamide in treatment of metastatic hormone-sensitive prostate cancer (mHSPC). The data were presented at the 2025 ASCO Genitourinary Symposium in San Francisco.^1,2

Prostate cancer cells dividing | Image Credit: © PRB ARTS - stock.adobe.com

Pharmacy Times: What is darolutamide?

Fred Saad, MD: Darolutamide is an androgen receptor pathway inhibitor (ARPI), one of the newest ARPIs with a unique molecular structure. We already had ARPIs like apalutamide and enzalutamide, which have very similar structures. Darolutamide has a unique structure quite different from the others, which likely explains why it does not penetrate the brain as much as the previous ones. This may also contribute to its lower potential for drug-drug interactions.

Pharmacy Times: Can you explain how darolutamide's efficacy and tolerability compare to other standard-of-care treatments for mHSPC?

Saad: In terms of efficacy, they are all very similar. There are no head-to-head trials to definitively say one is clearly more effective than the others. One distinguishing factor is tolerability. While we can’t claim with 100% certainty that one is better tolerated, a consistent theme emerging from placebo-controlled trials is that darolutamide has minimal additional side effects.

The ARANOTE study was particularly informative because it compared darolutamide directly to a placebo, with both groups receiving ADT [androgen deprivation therapy]. In this trial, we saw very little difference between darolutamide and placebo in terms of side effects. Adverse events like fatigue showed no significant increase—in fact, if anything, fatigue rates were slightly lower in the darolutamide arm, which is counterintuitive but reinforces that darolutamide does not appear to add much toxicity.

Pharmacy Times: Can you discuss the significance of progression-free survival (PFS) and overall survival (OS) improvements observed in these trials?

Saad: The real test of darolutamide in hormone-sensitive prostate cancer started with the ARASENS trial, which evaluated ADT plus docetaxel—a standard of care for newly diagnosed metastatic hormone-sensitive prostate cancer. This study demonstrated a 32% reduction in the risk of death with the addition of darolutamide, a statistically significant result. Since both arms received ADT and docetaxel, the survival benefit was clearly due to darolutamide. This trend was consistent across both low- and high-volume disease groups, with improvements in delaying metastatic castration-resistant disease, PSA progression, and achieving undetectable PSA levels.

This evidence led to the combination of ADT, docetaxel, and darolutamide becoming a standard of care for patients where docetaxel is indicated. A similar study, ARANOTE, compared ADT plus darolutamide to ADT plus placebo, reaching its primary endpoint with a 46% reduction in the risk of radiographic progression or death. Secondary endpoints, including PSA progression and undetectable PSA rates, also favored darolutamide.

Pharmacy Times: How do the ARANOTE and ARASENS trial results reinforce the role of darolutamide in the treatment of metastatic hormone-sensitive prostate cancer (mHSPC)?

Saad: At ASCO GU, we presented sub analyses from the ARANOTE study, focusing on high- and low-volume disease subgroups. A key question is whether these patients should be treated differently. The results showed that both high- and low-volume patients benefited from darolutamide, with a 70% reduction in the risk of radiographic progression or death in the low-volume group—an outstanding benefit. The high-volume group also saw strong results, with a 40% reduction in risk.

In terms of PSA response, 83% of low-volume patients achieved undetectable PSA levels, compared to 55% in the high-volume group. This suggests that while most low-volume patients are well-served with a doublet (ADT plus darolutamide), some high-volume patients may benefit from triplet therapy (ADT plus docetaxel and darolutamide).

Treatment decisions are not black and white. Even among low-volume patients, factors like age, disease aggressiveness, and tumor biology may justify triplet therapy in select cases. The goal is to personalize treatment to optimize outcomes based on individual patient characteristics.

Pharmacy Times: What challenges still remain in optimizing treatment strategies for mHSPC, and how might future research address them?

Saad: There is no question that the foundation of treatment for metastatic hormone-sensitive prostate cancer is ADT plus an ARPI, with darolutamide now being a key option. We now know that adding docetaxel further improves outcomes for certain patients, leading to the use of triplet therapy (ADT plus ARPI and docetaxel) in those who can tolerate it.

Despite this progress, some patients still do not respond optimally or progress more quickly, meaning there is more work to do. Future strategies may involve quadruplet or even quintuple therapy to address resistance mechanisms. A better understanding of tumor biology will help determine whether a patient needs doublet, triplet, or intensified therapy.

Conversely, some patients do very well with doublet or triplet therapy. A major research question now is whether treatment can be safely de-escalated in these cases. Unlike other cancers where therapy is often discontinued after remission, prostate cancer treatment has traditionally been lifelong. New trials are exploring whether patients who respond well could stop therapy after two to three years, which could significantly impact long-term treatment approaches.

REFERENCES

1. Darolutamide in addition to ADT Versus ADT in metastatic hormone-sensitive prostate cancer (ARANOTE). Updated January 24, 2025. Accessed February 14, 2025. https://clinicaltrials.gov/study/NCT04736199

2. Darolutamide in addition to standard androgen deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer (ARASENS). Updated Aptil 4, 2024. Accessed February 14, 2025. https://clinicaltrials.gov/study/NCT02799602