Phase III Randomized International Open Label Clinical Trial of Treatment Intensification With Docetaxel Plus Apalutamide in Patients With Metastatic Hormone-sensitive Prostate Cancer Who Did Not Achieve a Deep PSA Response After Initial Treatment With Apalutamide: REINFORCE Trial.

Approximately 320 patients will be randomized in a 1:1 ratio to the treatments as specified below:

• Arm A (experimental arm): docetaxel (75 mg/m2 every three weeks), for 6 planned cycles, plus apalutamide and ADT (240 mg, oral single daily dose).
• Arm B (control arm): continuation of SOC treatment with apalutamide and ADT (240 mg, oral single daily dose).

Randomization will be stratified by 3 factors:

• Metastasis timing (synchronous vs metachronous)
• Visceral metastasis at diagnosis (yes vs no)
• PSA at study inclusion (≤ 4 ng/ml vs >4 ng/ml) An IDMC will be established for regular safety monitoring, for the pre-planned interim analysis and the PK sub-study when available. The composition, role, responsibilities and procedures of the IDMC will be detailed in the IDMC Charter.

Inclusion criteria

• Written informed consent. Each patient must sign an informed consent form (ICF) indicating that he understands the purpose of and procedures, required for the study, and is willing to participate in the study.
• Patient must be a man ≥18 years of age.
• Histologically or cytologically confirmed adenocarcinoma of prostate.
• Metastatic hormone-sensitive prostate cancer.
• PSA >5 ng/ml at diagnosis of metastatic disease.
• Patients eligible to continue treatment with apalutamide and ADT and without contra-indication to receive docetaxel.
• Patients with at least 24 weeks and no more than 30 weeks of apalutamide.
• Patients with a maximum of 12 weeks ADT before apalutamide initiation.
• Lack of achievement of deep PSA response after 24 weeks and no more than 30 weeks of apalutamide. Deep PSA response is defined as PSA ≤ 0.2 ng/ml or PSA response ≥ 90% in combination with a PSA ≤4 ng/ml. Therefore, a non-deep PSA response is defined as PSA > 0.2 ng/ml in combination with a PSA response < 90%, or a PSA response ≥90% in combination with a PSA > 4 ng/ml.
• Patients who have not progressed to apalutamide.
• Patients that are tolerating adequately apalutamide 240 mg daily and with no toxicity higher than G1 at inclusion.
• Be able to swallow whole apalutamide film-coated tablets.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
• Clinical laboratory values at screening:

• hemoglobin ≥10.0 g/dL,
• absolute neutrophil count ≥1.5 × 10*9/L,
• platelet count ≥100 × 109/L, The patient must not have received any growth factor within 4 weeks or a blood transfusion within 7 days of the hematology laboratory sample obtained at screening
• serum alanine aminotransferase and/or aspartate transaminase ≤1.5 × the upper limit of normal (ULN),
• total bilirubin ≤ ULN,
• creatinine ≤2.0 × ULN
• Sexually active men must agree to use an external condom as an effective barrier method and refrain from sperm donation, and their female partners of childbearing potential must practice a highly effective method of contraception during and for 3 months after treatment with apalutamide and for 6 months after treatment with docetaxel.

Exclusion criteria

• Presence of neuroendocrine histology.
• Apalutamide treatment started more than 30 weeks before inclusion.
• Progression disease by any means, including radiographic, clinical or serological at inclusion.
• Patient who achieves deep PSA response on apalutamide treatment before randomization.
• Previous androgen-pathway receptor inhibitors, including enzalutamide, darolutamide, abiraterone or other ARPI. Previous treatment with first generation antiandrogens (i.e. bicalutamide) is allowed.
• Chemotherapy or immunotherapy for prostate cancer before randomization.
• Treatment with radiotherapy (external-beam radiation therapy, brachytherapy, or radiopharmaceuticals) within 2 weeks before randomization.
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs.
• Contraindication to both computed tomography and magnetic resonance imaging contrast agent.
• Prolonged QT interval defined as QTcF ≥ 480 ms at screening, based on the mean of triplicate 12-lead ECGs performed after at least 5 minutes of rest. Patients with congenital long QT syndrome will also be excluded.
• Any of the following within 6 months before randomization:

• stroke,
• myocardial infarction,
• severe or unstable angina pectoris,
• uncontrolled arrhythmia,
• coronary or peripheral artery bypass graft, or
• congestive heart failure (New York Heart Association class III or IV)
• Peripheral neuropathy ≥ grade 2.
• Uncontrolled hypertension, indicated by resting systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg despite medical management.
• Prior malignancy, except for adequately treated basal-cell or squamous-cell carcinoma of the skin or superficial bladder cancer that had not spread behind the connective-tissue layer (i.e., stage pTis, pTa, or pT1) or any cancer for which treatment had been completed ≥5 years before randomization and from which the patient was disease-free.
• A gastrointestinal disorder or procedure that was expected to interfere significantly with absorption of study drug.
• Active viral hepatitis, known human immunodeficiency virus infection with detectable viral load, or chronic liver disease requiring treatment.
• Previous (within 28 days before the start of study drug or 5 half-lives of the investigational treatment of the previous study, whichever was longer) or concomitant participation in another clinical study with investigational medicinal products.
• Any other serious or unstable illness or medical, social, or psychological condition that could jeopardize the safety of the patient and/or their compliance with study procedures or might interfere with their participation in the study or evaluation of the study results.