Darolutamide in Addition to ADT Versus ADT in Metastatic Hormone-sensitive Prostate Cancer

• Darolutamide (Nubeqa, BAY1841788) (Drug): Coated tablet, oral administration
• Placebo (Drug): Coated tablet matching Darolutamide in appearance, oral administration
• Androgen deprivation therapy (ADT) (Other): Luteinizing hormone-releasing hormone (LHRH) agonist/antagonists or orchiectomy

Primary outcomes

• Radiological Progression-free Survival (rPFS) Assessed by Central Review [From randomization to the date when 222 rPFS events were observed, approximately 36 months]: rPFS used conventional imaging method (99mTc-phosphonate bone scan, CT/MRI scan). rPFS was defined as the time from the date of randomization to the date of progressive disease in malignant soft tissue lesions, progressive disease in malignant bone lesions, or death due to any cause, whichever occurs first. Malignant soft tissue lesions were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and malignant bone lesions were assessed by Prostate Cancer Clinical Trials Working Group (PCWG3) criteria.

Secondary outcomes

• Overall Survival (OS) [From randomization to the final analysis date, approximately 47 months]: Time from the date of randomization to the date of death from any cause.
• Time to Castration-Resistant Prostate Cancer (CRPC) [From randomization to the date when 222 rPFS events were observed, approximately 36 months]: Time from the date of randomization to the date of first castration resistant event (radiological progression, Prostate-specific antigen (PSA) progression or symptomatic skeletal events, whichever occurs first).
• Time to Initiation of Subsequent Anti-cancer Therapy [From randomization to the date when 222 rPFS events were observed, approximately 36 months]: Time from the date of randomization to initiation of first subsequent anti-cancer therapy for prostate cancer.
• Time to PSA Progression [From randomization to the date when 222 rPFS events were observed, approximately 36 months]: Time from the date of randomization to the date of first prostate-specific antigen (PSA) progression. PSA progression with serum testosterone being at castrate level <0.50 ng/mL, is defined as a ≥25% increase above the nadir (lowest at or after baseline) value and an increase in absolute value of ≥2 ng/mL above nadir, and is at least 12 weeks from randomization date, which is confirmed by a second value 3 or more weeks later. All PSA values between the initial assessment meeting the PSA progression criteria and confirmation assessment must be ≥2 ng/mL and ≥25% increase above nadir, serum testosterone at castrate levels <0.50 ng/mL is requested at initial assessment.
• PSA Undetectable Rates (<0.2 ng/mL) [From randomization to the date when 222 rPFS events were observed, approximately 36 months]: Percentage of subjects with detectable PSA values of ≥0.2 ng/mL at baseline which became undetectable with any PSA values <0.2 ng/mL during the period between randomization and 30 days after last dose of study drug or start of new anti-cancer therapy whichever occurred earliest, based on the subjects had detectable PSA value at baseline.
• Time to Pain Progression [From randomization to the date when 222 rPFS events were observed, approximately 36 months]: Pain progression was assessed by Question 3 (Q3) of the BPI-SF questionnaire related to the worst pain in the last 24 hours (worst pain subscale \[WPS\]) taken as an average for post baseline score, or initiation of short or long-acting opioids for malignant disease for ≥7 consecutive days after randomization. Pain progression was defined as: (1) for asymptomatic subjects with WPS=0 at baseline, an increase of 2 or more points in the WPS score from nadir observed at 2 consecutive evaluations ≥4 weeks apart, or initiation of short- or long-acting opioid use for malignant disease for ≥7 consecutive days after randomization; (2) for symptomatic subjects with WPS >0 at baseline, an increase of 2 or more points in the WPS score from nadir observed at 2 consecutive evaluations ≥4 weeks apart and a WPS ≥5, or initiation of short- or long-acting opioid use for malignant disease for ≥7 consecutive days after randomization.
• Number of Participants With Adverse Events as a Measure of Safety [From start of study drug administration until 30 days after the last administration]: An AE is any untoward medical occurrence in a patient or clinical study participant, after providing written IC for participation in the study, may or may not be temporally associated with the use of study drug, whether or not considered related to the study drug. Treatment-emergent AE (TEAE) is defined as any event arising or worsening after the first dose of study drug until 30 days after the last dose of study drug.

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

* Histologically or cytologically confirmed adenocarcinoma of prostate
* Metastatic disease
* Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation anti-androgen, but not earlier than 12 weeks before randomization
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2
* Adequate bone marrow, liver and renal function

Exclusion Criteria:

* Prior treatment with: LHRH agonist/antagonists except neoadjuvant and /or adjuvant therapy; Second-generation androgen receptor (AR) inhibitors such as enzalutamide, darolutamide, apalutamide or other investigational AR inhibitors; Cytochrome P17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as anti-cancer treatment for prostate cancer; Chemotherapy including docetaxel or immunotherapy for prostate cancer; Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days prior to randomization; Radiopharmaceuticals; Any other anti-cancer treatment for prostate cancer, excluding local therapies and ADT.
* Treatment with radiotherapy within 2 weeks before randomization
* Contraindication to iodinated CT and gadolinium chelate MRI intravenous contrast agent(s)
* Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV)
* Uncontrolled hypertension as indicated by a resting systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite medical management
* A gastrointestinal (GI) disorder or procedure which is expected to interfere significantly with absorption of study drug
* Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 5 years prior to randomization
* Inability to swallow oral medications

Participant flow

Outcome results

• Radiological Progression-free Survival (rPFS) Assessed by Central Review (Primary), Median, Months: Darolutamide+ADT NA (NA to NA); Placebo+ADT 25.0 (19.0 to NA) (p <0.0001)
• Overall Survival (OS) (Secondary), Median, Months: Darolutamide+ADT NA (NA to NA); Placebo+ADT NA (33.8 to NA) (p 0.1007)
• Time to Castration-Resistant Prostate Cancer (CRPC) (Secondary), Median, Months: Darolutamide+ADT NA (NA to NA); Placebo+ADT 13.8 (12.0 to 16.8)
• Time to Initiation of Subsequent Anti-cancer Therapy (Secondary), Median, Months: Darolutamide+ADT NA (NA to NA); Placebo+ADT NA (27.7 to NA)
• Time to PSA Progression (Secondary), Median, Months: Darolutamide+ADT NA (NA to NA); Placebo+ADT 16.8 (13.9 to 20.1)
• PSA Undetectable Rates (<0.2 ng/mL) (Secondary), Number, Percentage of participants: Darolutamide+ADT 62.6 (57.8 to 67.2); Placebo+ADT 18.5 (13.5 to 24.4)
• Time to Pain Progression (Secondary), Median, Months: Darolutamide+ADT NA (NA to NA); Placebo+ADT 29.9 (29.7 to NA)
• Number of Participants With Adverse Events as a Measure of Safety (Secondary), Count of participants, Participants: Darolutamide (DB) 407; Darolutamide (DB + OL) 409; Placebo (DB) 199; Placebo - Darolutamide (CO) 30

Adverse events

Time frame: From start of study drug administration until 30 days after the last administration. All-cause mortality death events at any time during the study (approximately 59 months).

Serious adverse events by term

130 more terms not shown.

Other adverse events by term

31 more sites not listed.

• Results publication: Saad F, Shore N, Vjaters E, Olmos D, Littleton N, Testa I, Mo M, Verholen F, Srinivasan S, Haresh KP. Darolutamide Plus Androgen-deprivation Therapy in Metastatic Hormone-sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase 3 ARANOTE Trial. Eur Urol. 2026 Aug 12:S0302-2838(26)02313-4. doi: 10.1016/j.eururo.2026.07.026. Online ahead of print. PMID 42586872
• Results publication: Morgans AK, Haresh KP, Jievaltas M, Olmos D, Shore ND, Vjaters E, Xing N, Mohamed AF, Littleton N, Srinivasan S, Verholen F, Saad F. Pain and health-related quality-of-life outcomes with darolutamide in metastatic hormone-sensitive prostate cancer (ARANOTE): secondary and exploratory analyses of a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2026 May;27(5):614-624. doi: 10.1016/S1470-2045(26)00014-8. Epub 2026 Apr 9. PMID 41969015
• Results publication: Saad F, Vjaters E, Shore N, Olmos D, Xing N, Pereira de Santana Gomes AJ, Cesar de Andrade Mota A, Salman P, Jievaltas M, Ulys A, Jakubovskis M, Kopyltsov E, Han W, Nevalaita L, Testa I, Le Berre MA, Kuss I, Haresh KP; ARANOTE Study Investigators. Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial. J Clin Oncol. 2024 Dec 20;42(36):4271-4281. doi: 10.1200/JCO-24-01798. Epub 2024 Sep 16. PMID 39279580

• Study Protocol (PDF, 2022-06-28)
• Statistical Analysis Plan (PDF, 2025-10-02)