The investigators propose redefining this concept by focusing on volume rather than the number of metastases. To achieve this, the investigators aim to determine the Maximum Tolerated Volume (MTV) of metastatic lesions treatable with SRT (Stereotaxic radiotherapy) in a phase 1 study. In this study, the investigators will recruit patients with high-volume metastatic disease in bones or lymph nodes and progressively irradiate a volume-escalated subset of the total lesions. The selection will prioritize lesions at higher risk of causing pain or complications, such as fractures, spinal compression, or vascular compression. The investigators hypothesis is that SRT targeting multiple metastases (with a total volume ≤ MTV) will extend the duration without refractory pain and/or tumor-related complications in patients with castration-resistant and chemo-refractory prostate cancer.

Inclusion Criteria:

• Metastatic prostate cancer with clinical progression after the use of androgen-receptor pathway inhibitor, chemotherapy or any other life-prolonging therapy. Patient could have been treated previously by RadioLigand Therapy (RLT).

• Performance Status < 3

• Bone and/or lymph node metastases based on conventional (CT and bone scan) or metabolic imaging

• Bone and/or lymph node metastases suitable for SRT, according to the investigator

• Adequate organ function:

  1. Absolute Neutrophil Count (ANC) ≥ 1000/mm3 or
  2. Platelet Count ≥ 50 000/mm3 or
  3. Haemoglobin ≥ 8 g/dL (allowing transfusion or other intervention to achieve this minimum haemoglobin)

• Age ≥ 18 years at time of study entry

• Written informed consent obtained from the patient prior to performing any protocol-related

• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

• Patient has valid health insurance

• Life time expected > 3 months

Exclusion Criteria:

• Evidence of symptomatic metastases to the lungs, brain, peritoneum or liver

• Evidence of diffuse metastatic spread to the bone marrow (e.g. positive super bone scan) or the cerebral spinal fluid as per bone scan (no lumbar puncture required).

• Evidence of presence of symptomatic spinal cord compression with indication of neurosurgical decompression.

• Patient with symptomatic and/or high-risk tumor volume-to-bone marrow reserve ratio > 50%

• Concurrent enrolment in another clinical study, unless it is a non-therapeutic clinical study

• Mental impairment (psychiatric illness/social situations) that may compromise the ability of the patient to give informed consent and comply with the requirements of the study;

• Patient who has forfeited his/her freedom by administrative or legal award or who is under guardianship;

• Patients unable to undergo medical follow-up in the study for geographical, social or psychological reasons.

• History of another primary malignancy except for

  1. Malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of SRT and of low potential risk for recurrence
  2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  3. Adequately treated carcinoma in situ without evidence of disease

• Uncontrolled pain that contraindicates patient positioning on the radiotherapy table according to investigator

• Patient indicated to or currently treated by cytopenic treatment as chemotherapy or RadioLigand Therapy

• Patient under concomitant treatment that may generate severe gastro-intestinal disorder or genito-urinary disorder