mHSPC: Adding darolutamide to ADT and docetaxel ups OS in most disease volume and risk subgroups

Triplet therapy with darolutamide, androgen-deprivation therapy (ADT) and docetaxel improves overall survival (OS) by approximately 30 percent vs ADT plus docetaxel in most disease volume and risk subgroups of patients with metastatic hormone-sensitive prostate cancer (mHSPC), a post hoc analysis of the phase III ARASENS trial has shown.

Significant improvements in OS were seen with the triplet vs doublet regimen in the high-volume, high-risk and low-risk disease subgroups, while results in the low-volume disease subgroup suggested a trend for OS benefit. The adverse event (AE) profile of the triplet regimen was similar across all subgroups, with many of the most common AEs being known to be related to docetaxel. [Hussain MHA, et al, ASCO GU 2023, abstract 15; J Clin Oncol 2023;doi:10.1200/JCO.23.00041]

The ARASENS trial (n=1,305) previously demonstrated significantly improved OS with darolutamide + ADT + docetaxel vs placebo + ADT + docetaxel in patients with mHSPC (hazard ratio [HR], 0.68; 95 percent confidence interval [CI], 0.57–0.80; p<0.0001). The incidence of treatment-emergent AEs (TEAEs) was similar between the darolutamide and placebo groups. [N Engl J Med 2022;386:1132-1142]

“The current post hoc analysis investigated the impact of disease burden and risk on efficacy and safety outcomes,” said Dr Maha Hussain of Northwestern University Feinberg School of Medicine, Chicago, Illinois, US, at ASCO GU 2023.

High-volume disease was defined as visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral column or pelvis. [N Engl J Med 2015;373:737-746] High-risk disease was defined as presence of ≥2 risk factors, including Gleason score ≥8, ≥3 bone metastases, and visceral metastases. [N Engl J Med 2017;377:352-360]

At ARASENS baseline, 77 percent of patients had high-volume disease, while 70 percent had high-risk disease.

“Median OS was not reached [NR] among darolutamide recipients, regardless of disease volume or risk,” Hussain pointed out.

Significant improvement in OS was observed in the darolutamide vs placebo group in patients with high-volume (median, NR vs 42.4 months; HR, 0.69; 95 percent CI, 0.57–0.82), high-risk (median, NR vs 43.2 months; HR, 0.71; 95 percent CI, 0.58–0.86), and low-risk (median, NR in both groups; HR, 0.62; 95 percent CI, 0.42–0.90) disease. In patients with low-volume disease, results showed a trend for OS benefit, which did not reach statistical significance (median, NR in both groups; HR, 0.68; 95 percent CI, 0.41–1.13).

Time to castration resistance (a secondary efficacy endpoint) was significantly prolonged with darolutamide vs placebo in patients with high-volume (median, NR vs 16.4 months; HR, 0.41; 95 percent CI, 0.34–0.49), low-volume (median, NR vs 25.8 months; HR, 0.21; 95 percent CI, 0.14–0.33), high-risk (median, NR vs 16.1 months; HR, 0.38; 95 percent CI, 0.32–0.46) and low-risk (median, NR vs 25.1 months; HR, 0.32; 95 percent CI, 0.23–0.45) disease.

“Other key secondary efficacy endpoints, including time to pain progression, time to first symptomatic skeletal event, and time to initiation of subsequent systemic antineoplastic therapy, also favoured the darolutamide group irrespective of disease volume or risk,” said Hussain.

“The favourable safety profile of darolutamide was confirmed in all disease volume and risk subgroups, consistent with the overall ARASENS population,” she continued. “TEAEs were similar between treatment groups across these subgroups.”

“Based on these results, darolutamide plus ADT and docetaxel should be considered a new standard of care for patients with mHSPC,” Hussain concluded.