Data from the Phase III ARANOTE trial, presented at the 2024 European Society for Medical Oncology (ESMO) Congress, show that NUBEQA® (darolutamide) in combination with androgen deprivation therapy (ADT) significantly improved radiological progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). The study demonstrated a 46% reduction in the risk of radiological progression or death compared to placebo plus ADT (HR 0.54; 95% CI 0.41-0.71; P<0.0001). These findings, published simultaneously in The Journal of Clinical Oncology, suggest that darolutamide could broaden treatment options for mHSPC patients.
The ARANOTE trial, a randomized, double-blind, placebo-controlled study, involved 669 patients with mHSPC who were randomized in a 2:1 ratio to receive either 600 mg of NUBEQA (n=446) or placebo (n=223) twice daily in addition to ADT. The primary endpoint was rPFS, defined as the time from randomization to the first documented radiological disease progression or death from any cause. Secondary endpoints included overall survival (OS), time to castration-resistant prostate cancer (CRPC), time to initiation of subsequent anti-cancer therapy, time to prostate-specific antigen (PSA) progression, PSA undetectable rates, time to pain progression, and safety assessments.
Significant rPFS Improvement
The ARANOTE trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in rPFS with NUBEQA plus ADT compared to placebo plus ADT. The hazard ratio of 0.54 indicates a substantial benefit in delaying disease progression or death. Subgroup analyses showed consistent rPFS benefits, with a 40% risk reduction in patients with high-volume mHSPC (HR 0.60, 95% CI: 0.44-0.80) and a 70% risk reduction in patients with low-volume disease (HR 0.30, 95% CI: 0.15-0.60).
Additional Clinical Benefits
Beyond the primary endpoint, the ARANOTE data suggested clinical benefits across several secondary endpoints, including delaying the time to castration-resistant prostate cancer (CRPC) (HR 0.40; 95% CI, 0.32-0.51), time to PSA progression (HR 0.31; 95% CI 0.23-0.41), time to pain progression (HR 0.72; 95% CI 0.54-0.96), and time to initiation of subsequent systemic therapy (HR 0.40; 95% CI 0.29-0.56), compared to placebo plus ADT. An analysis of immature overall survival data (OS) showed an HR of 0.81 (95% CI 0.59-1.12) versus placebo plus ADT.
Safety Profile
The safety profile of NUBEQA plus ADT in the ARANOTE trial was consistent with previous findings. Rates of serious adverse events were similar between the treatment arms (23.6% for NUBEQA plus ADT compared to 23.5% for placebo plus ADT), while discontinuation due to treatment-emergent adverse events (TEAEs) was 6.1% in patients treated with NUBEQA plus ADT compared to 9% in patients receiving placebo plus ADT. Incidence rates for adverse events Grade 3 or higher were also similar between the two groups (35.5% and 35.7%, respectively). Notably, the incidence of fatigue was lower with NUBEQA plus ADT than with placebo plus ADT (5.6% and 8.1%, respectively).
Expert Commentary
"Each diagnosis of metastatic hormone-sensitive prostate cancer is unique, shaped by factors such as age, comorbidities and patient preferences. Each patient therefore requires a tailored treatment approach that thoughtfully addresses these key considerations," said Fred Saad, Professor and Chairman of Surgery and Director of Genitourinary Oncology at the University of Montreal Hospital Center (CHUM), and Principal Investigator of the ARANOTE trial. "With the positive results from ARANOTE, in addition to the ARASENS data, darolutamide has now demonstrated efficacy and safety data both with and without chemotherapy in mHSPC."
Neal Shore, M.D., FACS, Medical Director, Carolina Urologic Research Center, added, "The positive outcomes from the ARANOTE trial provide physicians with additional data that could broaden the use of NUBEQA as a treatment option for more patients with metastatic hormone-sensitive prostate cancer, which accounts for approximately 10% of prostate cancer diagnoses in the United States. These data demonstrate the potential of this therapy to provide significant benefits to patients with mHSPC, regardless of chemotherapy use."
Future Implications
Bayer plans to submit the data from the ARANOTE trial to the U.S. Food and Drug Administration (FDA) to support the expanded use of NUBEQA in patients with mHSPC. These findings, along with data from the ARASENS trial, reinforce the role of darolutamide as a valuable treatment option for men with mHSPC, both with and without the addition of docetaxel chemotherapy.
