This is a Phase III, international, multicentre, randomised, double-blinded placebo controlled trial, evaluating the efficacy and safety of ADT +/- darolutamide in castration-naïve de novo metastatic prostate cancer patients with vulnerable functional ability who have not elected for docetaxel or other androgen receptor pathway inhibitors.

This is a Phase III, international, multicentre, randomised, double-blinded placebo controlled trial, evaluating the efficacy and safety of ADT +/- darolutamide in castration-naïve de novo metastatic prostate cancer patients with vulnerable functional ability who have not elected for docetaxel or other androgen receptor pathway inhibitors. The study plans to enroll 300 patients who will be randomized (1:1) to receive either: (i) Experimental arm: ADT + darolutamide 600 mg po bid, or (ii) Control arm: ADT + placebo po bid. Response to treatment will be assessed according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria (Scher, 2016). Treatment will be continued until radiographic disease progression. Treatment may also be terminated at the initiative of either the patient or the investigator for any reason that would be beneficial to the patient, including: unacceptable toxicity, intercurrent conditions that preclude continuation of treatment, or patient request. Following treatment discontinuation patients will enter the follow-up period and will be monitored for up to 10 years with regards to survival status, subsequent antineoplastic treatments and the status of ongoing adverse events (AEs) and/or new investigational product related AEs.

Inclusion Criteria:

1. Signed a written informed consent form prior to any trial specific procedures.

2. Men with histologically or cytologically confirmed adenocarcinoma of the prostate.

3. Aged ≥18 years old at the time of signing informed consent.

4. De novo metastatic disease defined by clinical or radiological evidence of metastases.

   Note: For patients with nodal metastases only, only patients with extra-pelvic enlarged lymph nodes (lymph nodes located above the iliac bifurcation) can be included if they have either:

   • At least one extra-pelvic lymph node ≥2 cm
   • At least one extra-pelvic lymph node ≥1 cm if the patients also have at least one pelvic lymph node ≥2 cm

5. Measurable disease or bone lesions that are evaluable according to PCWG3 criteria.

6. Ineligible for treatment with all of the following drugs: docetaxel, abiraterone, enzalutamide, apalutamide; AND meets at least one of the following frailty criteria:

   1. Activities of daily living (ADL) assessment (excluding urinary incontinence question) score 3 or 4/5, or;
   2. 4-Instrumental activities of daily living (4-IADL) assessment score 2 or 3/4, or;
   3. A Grade 3 event on the Cumulative Illness Score Rating-Geriatrics (CISR-G) questionnaire, or;
   4. Body mass index (BMI) ≤21 kg/m² and/or >5% weight loss in the last 6 months, or;
   5. Timed up and go test (TUG) >14 sec. Nota Bene: Regarding CISR-G assessment, more specifically genitourinary scoring, score N°4 is not applicable.

7. Adequate bone marrow function: haemoglobin ≥80 g/L, white blood cells ≥3.0 x10⁹/L and platelets ≥80 x10⁹/L.

8. Adequate liver function: alanine aminotransferase (ALT) <2 x upper limit of normal (ULN) and bilirubin <1.5 x ULN, (or if bilirubin is between 1.5-2 x ULN, they must have a normal conjugated bilirubin). For patients with documented liver metastasis, ALT <5 x ULN is acceptable.

9. Adequate renal function: calculated creatinine clearance >30 ml/min (using the Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD EPI) method).

10. For sexually active men, agreement to use adequate contraception for the duration of trial participation and up to 2 weeks after completing study treatment.

11. Affiliated to the social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials).

12. Willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.

Exclusion Criteria:

1. Three or more Grade 3, or any Grade 4 events on the CISR-G questionnaire. Nota Bene: (Regarding CISR-G assessment, more specifically genitourinary scoring, score N°4 is not applicable).
2. Eastern Cooperative Oncology Group (ECOG) performance status score ≥3.
3. Hypertension not controlled by an anti-hypertensive treatment (systolic blood pressure [BP] ≥160 mmHg or diastolic BP ≥95 mmHg; 3 consecutive measures taken 5 minutes apart).
4. Acute toxicities of prior treatments and procedures not resolved to grade ≤1 or baseline before randomisation, with the exception of hot flushes and erectile dysfunction.
5. Previous systemic treatment for prostate cancer, except less than 12 weeks of ADT and/or an old-generation AR inhibitor.
6. Severe or uncontrolled concurrent disease, infection or co-morbidity.
7. Known hypersensitivity to the study treatment or any of its ingredients.
8. Major surgery within 28 days before randomisation.
9. Any of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV.
10. Prior malignancy ≤3 years before study enrolment. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e., pTis, pTa, and pT1) is allowed, as well as any localized cancer for which treatment has been completed ≥6 months before randomisation and from which the subject has been disease-free, or for which the risk of relapse is less than 30%, as well as early stage chronic lymphocytic leukaemia that does not require any specific treatment.
11. Inability to swallow oral medications.
12. Gastrointestinal disorder or procedure that can be expected to interfere significantly with the absorption of study treatment.
13. Known to have active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease at screening.
14. Treatment with any investigational product within 28 days before randomisation.
15. Concurrent participation in another clinical trial involving an investigational product (patients enrolled in non-experimental trials with no modification of the standard of care can be included).
16. Individual deprived of liberty or placed under the authority of a tutor.
17. Significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule or any condition that, in the opinion of the investigator, would preclude participation in this trial.](streamdown:incomplete-link)

IPD can be shared upon request to the sponsor

After primary analysis until end of trial

Steering committee approval

double-blinded placebo controlled trial