For patients with metastatic castration-sensitive prostate cancer (mCSPC), combining androgen-deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARis) has been shown to extend the time to disease progression and improve survival compared with ADT alone.1
In the following interview, Rana R. McKay, MD, Medical Oncologist and Professor of Medicine, Urology, and Radiation Medicine and Applied Sciences, discusses the purpose and findings of the Phase 3 ARANOTE trial, which investigated the efficacy and safety of ADT combined with NUBEQA® (darolutamide) versus ADT alone.
NUBEQA® is a prescription medicine used to treat adults with prostate cancer:
- that has not spread to other parts of the body and no longer responds to a medical or surgical treatment that lowers testosterone
- that has spread to other parts of the body and responds to a medical or surgical treatment that lowers testosterone
- that has spread to other parts of the body and responds to a medical or surgical treatment that lowers testosterone in combination with docetaxel.
It is not known if NUBEQA is safe and effective in females or children.
NUBEQA may cause serious side effects including: Heart disease which can lead to death. Seizure, avoid activities where a sudden loss of consciousness could cause serious harm to yourself or others. Tell your doctor right away if you have chest pain or discomfort or shortness of breath, loss of consciousness or seizure. NUBEQA can harm unborn babies and cause loss of pregnancy. Use effective birth control during treatment and for one week after the last dose of NUBEQA. Common side effects of NUBEQA were increase in liver function tests, decreased white blood cells and feeling more tired than usual. Common side effects of NUBEQA in combination with docetaxel were constipation, rash, decreased appetite, bleeding, weight gain, high blood pressure, decreased red blood cells (anemia), high blood sugar levels, decreased white blood cells, increase in liver function tests and low blood calcium levels. See additional Important Safety Information and full Prescribing Information for NUBEQA below.
What questions was the ARANOTE trial designed to answer?
The ARANOTE trial investigated the efficacy and safety of the combination of ADT plus NUBEQA (darolutamide) versus ADT alone in patients with mCSPC outside the U.S.
At the time that the trial was designed, there was emerging data that supported the use of the ADT-ARi combination over ADT alone.
One important thing to note is that, in the U.S. population, the standard of care has evolved, with most treatment approaches now incorporating a combination approach for mCSPC versus ADT monotherapy. This is why, for the ARANOTE trial, to ensure we had a clear comparator to evaluate ADT+ARi versus ADT alone, we conducted the trial in different jurisdictions outside the U.S. This allowed for a robust evaluation of the efficacy and safety of NUBEQA when added to the backbone of ADT.
In your opinion, what were the most compelling findings from the ARANOTE trial, and what are some of the key takeaways for a clinician?
The ARANOTE study met its primary endpoint, which was to evaluate radiographic progression-free survival (rPFS) of the combination of ADT plus NUBEQA over ADT alone. Other key secondary endpoints — such as overall survival and prostate-specific antigen (PSA) response were also evaluated. Additionally, the study evaluated safety, with results consistent with the established safety profile, providing further insight into the risk-benefit profile. 3
While this was a smaller study, the key takeaway is that we demonstrated efficacy of the combination over ADT alone based on the primary endpoint rPFS.3
How did these results help position NUBEQA within the current treatment landscape?
These results supported the most recent FDA approval for NUBEQA, with results from the ARANOTE trial providing data that support NUBEQA as an effective ARi to use in the mCSPC setting.3 We know about the tolerability profile of NUBEQA and the limited drug-drug interactions associated with it.* The data from the ARANOTE trial added to the body of evidence for NUBEQA in the metastatic hormone-sensitive setting and provided the basis for the approval, expanding access to this medication for physicians and patients in this setting.
*Please see the prescribing information for more information on tolerability and drug interactions for concomitant use of NUBEQA. Among patients receiving NUBEQA + ADT, permanent discontinuation, dose interruption, and dose reduction due to adverse events occurred in 6%, 14%, and 3.6% of patients, respectively. Drug-drug interaction findings are based on in vitro, pharmacokinetic/pharmacodynamic (PK/PD) and dedicated drug interaction studies. Darolutamide has demonstrated limited clinically meaningful drug-drug interactions, including no clinically meaningful interactions with ADTs. In vitro activity may not correlate with clinical outcomes.
For which patients are the ARANOTE trial findings most relevant?
The ARANOTE trial included patients with mCSPC across a range of baseline clinical characteristics including both with high- and low-volume, de novo or metachronous disease — all sites of metastases — and enrolled patients up to an Eastern Cooperative Oncology Group score (ECOG) of 2. This study really sought and targeted a broad population of patients with mCSPC and the results show that NUBEQA plus ADT can provide statistically significant benefits to patients with mCSPC, regardless of chemotherapy use.3
From a clinical perspective, how have you found treating patients with NUBEQA since the ARANOTE data became available and following the FDA approval?
NUBEQA is a pill given twice a day which offers an FDA approved option to treat patients with mCSPC, and most importantly, it has been shown to be an effective treatment option.
About NUBEQA® (darolutamide)4
NUBEQA® (darolutamide) is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription.
NUBEQA was developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company.
NUBEQA is an androgen receptor inhibitor indicated for the treatment of adult patients with:
- Non-metastatic castration-resistant prostate cancer (nmCRPC)
- Metastatic castration-sensitive prostate cancer (mCSPC)
- Metastatic castration-sensitive prostate cancer (mCSPC) in combination with docetaxel
IMPORTANT SAFETY INFORMATION
Warnings & Precautions
Ischemic Heart Disease – Ischemic heart disease, including fatal cases, occurred in patients receiving NUBEQA.
In a pooled analysis of ARAMIS and ARANOTE, ischemic heart disease occurred in 3.4% of patients receiving NUBEQA and 2.2% receiving placebo, including Grade 3-4 events in 1.4% and 0.3%, respectively. Ischemic events led to death in 0.4% of patients receiving NUBEQA and 0.4% receiving placebo.
In ARASENS, ischemic heart disease occurred in 3.2% of patients receiving NUBEQA with docetaxel and 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% and 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel and 0% receiving placebo with docetaxel.
Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease.
Seizure – Seizure occurred in patients receiving NUBEQA.
In a pooled analysis of ARAMIS and ARANOTE, Grade 1-3 seizure occurred in 0.2% of patients receiving NUBEQA. Seizure occurred from 261 to 665 days after initiation of NUBEQA.
In ARASENS, seizure occurred in 0.8% of patients receiving NUBEQA with docetaxel, including two Grade 3 events. Seizure occurred from 38 to 1754 days after initiation of NUBEQA.
It is unknown whether anti-epileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment.
Embryo-Fetal Toxicity – The safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose.
Adverse Reactions
In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia, and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo. Fatal adverse reactions that occurred in ≥2 patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). The most common (>2% with a ≥2% increase compared to placebo) adverse reactions, including laboratory test abnormalities, were increased AST (23%), decreased neutrophil count (20%), fatigue (16%), increased bilirubin (16%), pain in extremity (6%), and rash (4%). Clinically relevant adverse reactions occurring in 2% or more of patients treated with NUBEQA included ischemic heart disease (4%) and heart failure (2.1%).
In ARANOTE, serious adverse reactions occurred in 24% of patients receiving NUBEQA. Serious adverse reactions in ≥1% of patients who received NUBEQA included pneumonia (2%), urinary tract infection (1.8%), musculoskeletal pain (1.6%), hemorrhage (1.6%), arrhythmias (1.3%), and spinal cord compression (1.1%). Fatal adverse reactions occurred in 4.7% of patients receiving NUBEQA and those that occurred in ≥2 patients included sepsis (1.1%), craniocerebral injury (0.4%), and myocardial infarction (0.4%). The most common (≥10% with a ≥2% increase compared to placebo) adverse reaction is urinary tract infection (12%). The most common laboratory test abnormalities (≥15% with a ≥5% increase over placebo) are increased AST (32%), increased ALT (28%), increased bilirubin (17%), and decreased neutrophil count (16%). Clinically relevant adverse reactions in <10% of patients who received NUBEQA included arrhythmia (8.8%), pneumonia (3.6%), and myocardial infarction (0.7%).
In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), neutrophil count decreased (2.8%), musculoskeletal pain (2.6%) and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel. Fatal adverse reactions in ≥2 patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common (≥10% with a ≥2% increase over placebo with docetaxel) adverse reactions are constipation (23%), rash (20%), decreased appetite (19%), hemorrhage (18%), increased weight (18%), and hypertension (14%). The most common laboratory test abnormalities (≥30%) are anemia (72%), hyperglycemia (57%), decreased lymphocyte count (52%), decreased neutrophil count (49%), increased AST (40%), increased ALT (37%), and hypocalcemia (31%). Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures (8%), ischemic heart disease (3.2%), seizures (0.6%), and drug-induced liver injury (0.3%).
Drug Interactions
Effect of Other Drugs on NUBEQA – Concomitant use of NUBEQA with a combined P-gp and strong or moderate CYP3A4 inducer decreases darolutamide exposure which may decrease NUBEQA activity. Avoid concomitant use of NUBEQA with combined P-gp and strong or moderate CYP3A4 inducers.
Concomitant use of NUBEQA with a combined P-gp and strong CYP3A4 inhibitor increases darolutamide exposure which may increase the risk of NUBEQA adverse reactions. Monitor patients more frequently for NUBEQA adverse reactions and modify NUBEQA dosage as needed.
Effects of NUBEQA on Other Drugs – NUBEQA is an inhibitor of BCRP transporter. Concomitant use of NUBEQA increases the AUC and Cmax of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions, and consider dose reduction of the BCRP substrate drug.
NUBEQA is an inhibitor of OATP1B1 and OATP1B3 transporters. Concomitant use of NUBEQA may increase the plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor patients more frequently for adverse reactions of these drugs and consider dose reduction while patients are taking NUBEQA.\
Review the Prescribing Information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA.
For important risk and use information about NUBEQA, please see the accompanying full Prescribing Information.
Please see the full Prescribing Information.
The editorial staff had no role in this post’s creation.
References
- Raval AD, Lunacsek O, Korn MJ, Littleton N, Constantinovici N, George DJ. Real-World Evidence of Combination Therapy Use in Metastatic Hormone-Sensitive Prostate Cancer in the United States From 2017 to 2023. JCO Oncol Pract. 2025;21(8):1174-1184. doi:10.1200/OP-24-00690.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer (Version 5.2026). https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Published January 23, 2026. Accessed June 9, 2026.
- Saad F, et al, 2024. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the Phase III ARANOTE Trial. J Clin Oncol., 42(36): 4271-4281. doi:10.1200/JCO-24-01798.
- NUBEQA® (darolutamide) [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; June 2025.
PP-NUB-US-5469-1