Darolutamide (Nubeqa) combined with standard treatment significantly improved survival in patients with metastatic hormone-sensitive prostate cancer (mHSPC), the phase III ARASENS trial found.

At data cutoff, patients who received darolutamide plus androgen deprivation therapy (ADT) and docetaxel had a 32.5% lower risk of death compared with the group who received placebo plus the standard (HR 0.68, 95% CI 0.57-0.80, P<0.001), reported Matthew Smith, MD, PhD, of Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, during the Genitourinary Cancers Symposium.

The overall survival (OS) rate at 4 years was 62.7% in the darolutamide group versus 50.4% in the placebo group, with a treatment effect that was favorable across most subgroups.

“Based on the results of ARASENS, darolutamide in combination with ADT and docetaxel should become a new standard of care for treatment of patients with mHSPC,” Smith said.

This OS benefit was observed despite the fact that a high percentage of patients in the placebo group received subsequent life-prolonging systemic therapy during follow-up, as noted in the New England Journal of Medicine, where the study was simultaneously published.

Darolutamide was also associated with consistent benefits in secondary endpoints, including:

• Longer time to development of castration-resistant disease (HR 0.36, 95% CI 0.30-0.42, P<0.001)
• Longer time to pain progression (HR 0.79, 95% CI 0.66-0.95, P=0.01)
• Longer symptomatic skeletal event-free survival (HR 0.61, 95% CI 0.52-0.72, P<0.001)
• Longer time to a first symptomatic skeletal event (HR 0.71, 95% CI 0.54-0.94, P=0.02)
• Longer time to the initiation of subsequent systemic antineoplastic therapy (HR 0.39, 95% CI 0.33-0.46, P<0.001)

Darolutamide is an androgen-receptor inhibitor that demonstrated efficacy in patients with nonmetastatic castration-resistant prostate cancer in the phase III ARAMIS trial. Median metastasis-free survival was almost 2 years longer and risk of death was 31% lower among patients who received darolutamide with ADT versus those who received placebo with ADT.

Since 2015, “the narrative in mHSPC has continued to evolve,” noted discussant Elizabeth Heath, MD, of the Karmanos Cancer Institute at Wayne State University in Detroit.

“We went from standard ADT as a singlet, to now doublets with docetaxel, abiraterone, and apalutamide, to the narrative now changing to triple therapy with the discussion and report of PEACE-1 last year, and now today with ARASENS,” she said. “It’s important to our patients, because treatment intensification prolongs overall survival, period, full stop.”

However, Health also pointed out that real-world intensification patterns show that many men are not receiving treatment intensification. “Even with all this great level 1 evidence, we’re still getting this lost in translation,” she said. “How can we move on to triplets, if we’re not getting the doublets? This is going to take the entire community to understand that we’re not getting the messaging across.”

The international ARASENS trial included 1,306 patients with mHSPC cancer (86% with metastatic disease at the time of initial diagnosis) who were randomly assigned 1:1 to darolutamide 600 mg twice daily or matching placebo, both in combination with ADT and docetaxel, at 286 centers in 23 countries from November 2016 to June 2018.

Of the patients in both groups, median age was 67 years, 71.1% had an Eastern Cooperative Oncology Group performance status score of 0, and 78.2% had a Gleason score of 8 or higher.

At data cutoff, median duration of treatment was longer in the darolutamide group (41.0 months) than in the placebo group (16.7 months), and a higher percentage of patients in the darolutamide group were still receiving the assigned trial treatment (45.9% vs 19.1% in the placebo group).

Adverse events were similar between the two groups, and the incidence of the most common adverse events was highest during the overlapping docetaxel treatment period in both groups. Grade 3 or 4 adverse events occurred in 66.1% of the darolutamide group and 63.5% of the placebo group, with neutropenia being the most common grade 3 or 4 adverse event (33.7% and 34.2%, respectively).

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