Randomised phase III trial of ADT +/- darolutamide in frail men with castration-naïve de novo metastatic prostate cancer

Prior treatment

• Inability to swallow oral medications
• Treatment with any investigational product within 28 days before randomisation.
• 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).
• 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.
• Previous systemic treatment for prostate cancer, except less than 12 weeks of ADT and/or an old-generation AR inhibitor.
• Severe or uncontrolled concurrent disease, infection or co-morbidity.
• Major surgery within 28 days before randomisation.
• 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.

Other illness

• Gastrointestinal disorder or procedure that can be expected to interfere significantly with the absorption of study treatment.
• Known to have active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease at screening.
• 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.
• 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).
• Known hypersensitivity to the study treatment or any of its ingredients.

Age

• 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.
• Individual of full age deprived of liberty or placed under a legal protection measure (tutorship/curatorship/temporary guardianship).

Other

• Three or more Grade 3, or any Grade 4 events on the CISR-G questionnaire.
• Eastern Cooperative Oncology Group (ECOG) performance status score ≥3

• Signed a written informed consent form prior to any trial specific procedures.
• For sexually active men, agreement to use adequate contraception for the duration of trial participation and up to 2 weeks after completing study treatment
• Affiliated to the social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials)
• 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.
• Men with histologically or cytologically confirmed adenocarcinoma of the prostate.
• Aged ≥18 years old at the time of signing informed consent
• De novo metastatic disease defined by clinical or radiographic evidence of metastases.
• Measurable disease or bone lesions that are evaluable according to PCWG3 criteria
• Ineligible for treatment with all of the following drugs: docetaxel, abiraterone, enzalutamide, apalutamide; AND meets at least one of the frailty criteria
• Adequate bone marrow function: haemoglobin ≥80g/L, white blood cells ≥ 3.0 x109/L and platelets ≥80 x109/L.
• Adequate liver function: alanine aminotransferase (ALT) < 2 xULN and bilirubin < 1.5 xULN, (or if bilirubin is between 1.5-2x ULN, they must have a normal conjugated bilirubin). For patients with documented liver metastasis ALT < 5 xULN is acceptable
• Adequate renal function: calculated creatinine clearance > 30 ml/min (using the MDRD or CKD EPI method)