The FDA has approved darolutamide (Nubeqa) for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC), marking an expansion of the drug's approved indications. This regulatory decision was based on compelling data from the randomized, double-blind, placebo-controlled phase 3 ARANOTE trial, which demonstrated significant clinical benefits for patients receiving the androgen receptor inhibitor.
ARANOTE Trial Design and Patient Population
The ARANOTE trial (NCT04736199) enrolled 669 patients with mCSPC, randomly assigning them 2:1 to receive either darolutamide at 600 mg twice daily (n = 446) or matched placebo (n = 223), with all patients receiving concomitant androgen deprivation therapy (ADT). The study included adult patients at least 18 years of age with histologically or cytologically confirmed adenocarcinoma of the prostate and centrally confirmed metastatic disease by conventional imaging.
Eligible patients were required to have an ECOG performance status of 0 to 2, along with adequate liver, bone marrow, and renal function. All participants began ADT within 12 weeks prior to initiating study treatment, with patients stratified by use of prior local therapy and the presence of visceral metastases.
Primary Efficacy Results
Patients who received darolutamide achieved a statistically significant improvement in radiographic progression-free survival (rPFS) compared with those who received placebo. The median rPFS was not reached in the darolutamide arm versus 25.0 months (95% CI, 19.0-NR) in the placebo arm, representing a hazard ratio of 0.54 (95% CI, 0.41-0.71; P < 0.0001). The 24-month rPFS rates were 70.3% with darolutamide compared to 52.1% with placebo.
Consistent rPFS benefits were observed with darolutamide across patient subgroups, including patients with high-volume disease (HR, 0.60; 95% CI, 0.44-0.80) and low-volume disease (HR, 0.30; 95% CI, 0.15-0.60).
Secondary Endpoint Analysis
The final analysis revealed no statistically significant improvement in overall survival (OS) with darolutamide versus placebo (HR 0.78; 95% CI, 0.58-1.05). The 24-month OS rates were 79.8% with darolutamide versus 75.5% with placebo.
However, clear benefits with darolutamide versus placebo were demonstrated across multiple secondary endpoints. These included time to metastatic castration-resistant prostate cancer (mCRPC) with an HR of 0.40 (95% CI, 0.32-0.51), time to PSA progression (HR, 0.31; 95% CI, 0.23-0.41), time to initiation of subsequent systemic anticancer therapy (HR, 0.40; 95% CI, 0.29-0.56), and time to pain progression (HR, 0.72; 95% CI, 0.54-0.96).
Additionally, a higher proportion of patients in the darolutamide arm achieved a PSA level lower than 0.2 ng/mL at any time during the treatment period (62.6%) compared with those in the placebo arm (18.5%).
Safety Profile and Tolerability
The safety profile of darolutamide was consistent with previously observed toxicities associated with its use as monotherapy. The most common grade 3/4 adverse effects seen with darolutamide in ARANOTE were hypertension (3.6%) and anemia (3.6%), followed by pain in extremity (1.8%), and bone pain and increased alkaline phosphatase levels (1.4% each).
Other grade 3/4 adverse events occurring in less than 1% of patients included back pain, headache, and COVID-19 (0.9% each), as well as increased aspartate aminotransferase levels, increased alanine aminotransferase levels, increased weight, urinary tract infection, and fatigue (0.5% each).
Dosing and Administration
The recommended dose of darolutamide is 600 mg, administered as two 300-mg tablets taken orally twice daily with food until disease progression or unacceptable toxicity. The prescribing information includes precautions and warnings regarding ischemic heart disease, seizure, and embryo-fetal toxicity.
This approval represents an expansion of darolutamide's therapeutic applications, as the FDA had previously approved the drug in combination with docetaxel for mCSPC. The ARANOTE trial results provide clinicians with additional evidence supporting darolutamide's efficacy as part of combination therapy with ADT alone in the metastatic castration-sensitive setting.
