Evaluation of the impact of metastasis-directed therapy in patients with castration-refractory prostate cancer and a maximum of 5 progressive lesions.

MEDCARE phase 3 trial is approved by the central Ethics committee. It is a multicentric, randomized, prospective, open-label, two-arm, phase III trial. The aim is to evaluate the impact of progression-directed therapy (PDT) in patients presenting with oligoprogressive mCRPC on overall survival (OS). The study will employ a 1:1 randomization between arm A and arm B. Patients will be stratified according to number of metastases (1 versus > 1), initial localization (local recurrence, N or M1a vs. M1b or M1c) and systemic therapy (patient type 1 vs. type 2, see below) (Fig 1). Randomization will be carried out after approval in the multidisciplinary tumour board were the standard-of-care treatment and kind of PDT (metastasectomy or SBRT) will be decided before randomization.

Inclusion Criteria:

Participants eligible for inclusion in this Trial must meet all the following criteria:

• Written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures.
• Acinar adenocarcinoma (inclusive neuro-endocrine dedifferentiation).
• Oligoprogressive disease on conventional imagine within a maximum of 6 weeks prior to randomisation defined as: a maximum of 3 extracranial progressive lesions (pre-existing lesions, the development of new lesions, or both) in any organ. Nodal (N1) disease should be measured in the short axis. Nodes more than 1.5 cm in the short axis are considered pathologic and measurable. Oligoprogression on bone scan is defined as the occurrence of maximal 3 new and/or progressive lesions. In case of not unambiguously, additional imaging such as diagnostic magnetic resonance imaging (MRI) or dedicated CT-scan should be performed. Visceral disease reported separately (lung, liver, adrenal, or CNS) and is considered measurable if an individual lesions is more than 1 cm longest dimension.

In case of locally persistent/recurrent disease, a diagnostic MRI of the prostate (bed) and/or biopsy of the site is recommended. There are two different mCRPC patient groups who are eligible for inclusion in the trial:

1. Patients with oligoprogressive disease with pADT only as ongoing treatment (Type 1).

2. Patients with oligoprogressive disease with pADT +/- second line systemic therapy. This is both the combination of pADT + ARTA as ongoing treatment or patients who had received docetaxel in the past (Type 2).

   • Castration-refractory disease, defined as testosterone level < 50 ng/dL.
   • Prior treatment of the primary tumor by radiotherapy or surgery. If the primary tumor has not been treated previously, this treatment is obligatory within the trial.
   • WHO performance 0-2
   • Age >= 18 years old
   • Absence of psychological, sociological, or geographical condition potentially hampering compliance with study protocol.
   • Patients must be presented at the multidisciplinary board meeting and the inclusion in the trial needs approval by this board.

Exclusion Criteria:

• Ductal adenocarcinoma and small-cell prostate cancer.
• Serum testosterone level > 50 ng/ml.
• Presence of poly-progressive disease, defined as more than 3 progressive lesions on conventional imaging or nodal and/or metastatic lesions on conventional imaging
• Active malignancy other than prostate cancer that could potentially interfere with the interpretation of this trial.
• Previous treatments (RT, surgery) or comorbidities rendering new treatment with SBRT impossible.
• Spinal bone lesion that is highly symptomatic, neurologically threatening or at risk of fracture.
• Patients already treated with radionuclides, cabazitaxel or PARP-inhibitors in the past.
• Patients with progressive disease while receiving docetaxel.
• Not able to understand the treatment protocol or sign informed consent.