ADT +/- Darolutamide in de Novo Metastatic Prostate Cancer Patients With Vulnerable Functional Ability (PEACE6-Vulnerable)

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 ofmetastases. Note: For patients with nodal metastases only, only patients with extra-pelvicenlarged lymph nodes (lymph nodes located above the iliac bifurcation) can beincluded 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 leastone 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:

7. Activities of daily living (ADL) assessment (excluding urinary incontinencequestion) score 3 or 4/5, or;

8. 4-Instrumental activities of daily living (4-IADL) assessment score 2 or 3/4,or;

9. A Grade 3 event on the Cumulative Illness Score Rating-Geriatrics (CISR-G)questionnaire, or;

10. Body mass index (BMI) ≤21 kg/m² and/or >5% weight loss in the last 6 months,or;

11. Timed up and go test (TUG) >14 sec. Nota Bene: Regarding CISR-G assessment,more specifically genitourinary scoring, score N°4 is not applicable.

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

13. 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 musthave a normal conjugated bilirubin). For patients with documented liver metastasis,ALT <5 x ULN is acceptable.

14. Adequate renal function: calculated creatinine clearance >30 ml/min (using theModification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease EpidemiologyCollaboration [CKD EPI) method).

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

16. Affiliated to the social security system or in possession of equivalent privatehealth insurance (according to local regulations for participation in clinicaltrials).

17. Willing and able to comply with the protocol for the duration of the trial includingundergoing 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 isnot applicable).

2. Eastern Cooperative Oncology Group (ECOG) performance status score ≥3.

3. Hypertension not controlled by an anti-hypertensive treatment (systolic bloodpressure [BP] ≥160 mmHg or diastolic BP ≥95 mmHg; 3 consecutive measures taken 5minutes apart).

4. Acute toxicities of prior treatments and procedures not resolved to grade ≤1 orbaseline before randomisation, with the exception of hot flushes and erectiledysfunction.

5. Previous systemic treatment for prostate cancer, except less than 12 weeks of ADTand/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, myocardialinfarction, severe/unstable angina pectoris, coronary/peripheral artery bypassgraft; congestive heart failure New York Heart Association (NYHA) Class III or IV.

10. Prior malignancy ≤3 years before study enrolment. Adequately treated basal cell orsquamous cell carcinoma of skin or superficial bladder cancer that has not spreadbehind the connective tissue layer (i.e., pTis, pTa, and pT1) is allowed, as well asany localized cancer for which treatment has been completed ≥6 months beforerandomisation and from which the subject has been disease-free, or for which therisk of relapse is less than 30%, as well as early stage chronic lymphocyticleukaemia that does not require any specific treatment.

11. Inability to swallow oral medications.

12. Gastrointestinal disorder or procedure that can be expected to interferesignificantly with the absorption of study treatment.

13. Known to have active viral hepatitis, active human immunodeficiency virus (HIV) orchronic liver disease at screening.

14. Treatment with any investigational product within 28 days before randomisation.

15. Concurrent participation in another clinical trial involving an investigationalproduct (patients enrolled in non-experimental trials with no modification of thestandard 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 orwith psychological, familial, sociological or geographical condition potentiallyhampering compliance with the study protocol and follow-up schedule or any conditionthat, in the opinion of the investigator, would preclude participation in thistrial.