The FDA has accepted a supplemental new drug application (sNDA) for darolutamide (Nubeqa) in combination with androgen deprivation therapy (ADT) for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC). This regulatory milestone brings darolutamide closer to potentially becoming a new treatment option for a broader population of prostate cancer patients.
The sNDA is supported by data from the phase 3 ARANOTE trial (NCT04736199), a global, randomized, double-blind, placebo-controlled study. Findings presented at the 2024 ESMO Congress demonstrated a statistically significant improvement in radiographic progression-free survival (rPFS) for patients treated with darolutamide plus ADT compared to placebo plus ADT.
ARANOTE Trial Results
The ARANOTE trial enrolled patients with mHSPC who had an ECOG performance status of 0 to 2. Patients were randomly assigned 2:1 to receive darolutamide at 600 mg twice per day plus ADT or placebo plus ADT. The primary endpoint was rPFS per central blinded review. Key secondary endpoints included overall survival (OS), time to subsequent anticancer therapy, and time to metastatic castration-resistant prostate cancer (mCRPC).
The median rPFS was not reached (NR; 95% CI, NR-NR) in the darolutamide plus ADT arm compared with 25.0 months (95% CI, 19.0-NR) in the placebo plus ADT arm (HR, 0.54; 95% CI, 0.41-0.71; P< .0001). The 24-month rPFS rates were 70.3% and 52.1%, respectively, demonstrating a clinically meaningful benefit.
Christine Roth, executive vice president of Global Product Strategy and Commercialization at Bayer, stated that the acceptance of the sNDA brings them closer to providing an additional treatment option for darolutamide to benefit those living with mHSPC. She also noted that, if approved, this would expand the indication for darolutamide in patients with mHSPC to include darolutamide both with and without chemotherapy.
Additional Efficacy Data
Additional data from the ARANOTE trial showed that the rPFS benefit associated with the darolutamide regimen was consistent across all subgroups. While overall survival (OS) data were immature at the data cutoff, the median OS was NR in both the darolutamide and placebo arms (HR, 0.81; 95% CI, 0.59-1.12). The median time to mCRPC was NR in the darolutamide arm vs 13.8 months in the placebo arm (HR, 0.40; 95% CI, 0.32-0.51).
The median time to PSA progression was NR in the darolutamide arm vs 16.8 months in the placebo arm (HR, 0.31; 95% CI, 0.23-0.41). The time to subsequent systemic therapy was NR in both groups (HR, 0.40; 95% CI, 0.29-0.56), and the median time to pain progression was NR in the darolutamide group vs 29.9 months in the placebo group (HR, 0.72; 95% CI, 0.54-0.96).
Safety Profile
The median treatment duration was 24.2 months for the darolutamide regimen vs 17.3 months for the placebo regimen. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 91.0% of patients in the experimental arm vs 90.0% of patients in the placebo arm. The rates of grade 3 or 4 TEAEs were 30.8% and 30.3%, respectively. Grade 5 TEAEs were reported in 4.7% of patients in the darolutamide arm vs 5.4% of patients in the placebo arm. The rates of serious TEAEs were 23.6% for darolutamide vs 23.5% for placebo, and TEAEs led to treatment discontinuation in 6.1% of patients in the experimental arm vs 9.0% of patients in the control arm.
Specific TEAEs associated with androgen receptor pathway inhibitors included fatigue, mental impairment disorder, hypertension, cardiac arrhythmias, coronary artery disorders, heart failure, falls, bone fracture, vasodilatation and flushing, diabetes mellitus and hyperglycemia, and rash. These were generally comparable between the darolutamide and placebo arms.
