The aim is to define the postponement of next line systemic treatment (NEST), by the use of metastasis-directed therapy in patients with oligoprogressive castration-refractory prostate cancer. This will be defined by the NEST-free survival.

Furthermore the investigators will use 18F PSMA PET-CT as investigational imaging, to assess the predictive value and impact on treatment policy.

When treatment with pADT is initiated in case of mHSPC, the sensitivity to castration will eventually disappear due to the out-selection of castration-refractory clones. At that moment, the stage of mCRPC is attained. In the setting of mCRPC, clinical and iconographic progression (and to a lesser extent biochemical progression) traditionally implies a switch to a next-line systemic treatment (NEST). However, within the group of these progressive patients, there is a subgroup showing oligoprogressive disease, which is defined as the progression of a limited number of metastatic spots, whereas the majority of metastases is controlled by the systemic therapy the patient is receiving at that time. This heterogeneous response to treatment reflects the heterogeneity of the clonogenic cells that give rise to mCRPC. The hypothesis of this trial is that treatment with MDT of these oligoprogressive lesions allow patients to remain on their current systemic therapy, thereby delaying the need for NEST.

A multicentric retrospective chart analysis on MDT for oligoprogressive CRPC has been conductedat previously the UZ Leuven together with UZ Gent (doi: 10.1016/j.euo.2019.08.012.). A total of 30 patients with oligoprogressive CRPC were selected for further analysis. In this population, after a median follow-up of 17 months (IQR 9;25), the median NEST-FS in the MDT group was 16 months (95% CI: 10-22 months). The median progression free survival (PFS) was 10 months (95% CI: 6-15 months). Subsequently, the investigators selected within the MDT group those cases who received SBRT or surgery (metastasectomy), as these patients will be the subjects in this phase 2 trial. There was a median NEST-free survival of 21 months (CI 95% 12-21 months) and a median PFS of 10 months (95% CI: 6-14 months). SBRT or surgery-related toxicity was minor, with limited grade 1 and 2 toxicity and only one patient experiencing late grade 3 GU/GI toxicity after treatment for local relapse in the prostate.

These findings of this retrospective analysis clearly show the need for further prospective investigation. Therefore, this prospective phase 2 trial was initiated in patients with oligoprogressive mCRPC who will receive MDT. If the primary tumor has not been treated yet, local treatment will be added. Ongoing systemic treatment will be continued until progression. The trial is explorative and still hypothesis generating. The results from this trial will serve as a guidance for a randomized phase 3 trial in the near future.

Inclusion Criteria:

• Histologically proven initial diagnosis of adenocarcinoma of the prostate
• mCRPC setting, with testosterone level < 50 ng/dl or 1.7 nmol/l
• Oligoprogressive disease, defined as a maximum of 3 extracranial metastases in any organ system OR local recurrence, diagnosed on conventional imaging with CT and bone scan. This may present as either the progression of pre-existing disease, and/or the appearance of new metastases. (defined according to the PCWG 3 criteria (20), see section 6. Trial Procedures)
• Patients currently treated with ADT, whether or not combined with another systemic treatment such as abiraterone acetate, enzalutamide, docetaxel and radium-223. Denosumab is allowed but not considered as second-line systemic treatment.
• Priory treated primary tumor by radiotherapy or surgery. If the primary tumour is not treated, local therapy should be added to the treatment. Both radiotherapy as well as surgery are allowed.
• WHO performance status 0-1
• Age >= 18 years old
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and/or follow-up schedule. Those conditions should be discussed with the patient before registration in the trial.
• Patient presented at the multidisciplinary tumour board of the local hospital.
• Before patient registration/randomization, written informed consent must be given according to ICH/GCO and national/local regulations.

Exclusion Criteria:

• Serum testosterone level > 50 ng/ml or > 1.7 nmol/l.
• Presence of polyprogression, defined as more than 3 progressive/new metastatic lesions and/or local recurrence (which counts for 1 lesion).
• Active malignancy other than prostate cancer that can potentially interfere with the interpretation of the trial.
• Previous treatments (RT, surgery) or comorbidities rendering PDT impossible.
• Disorder precluding understanding of trial information or informed consent or signing informed consent.

Male -> prostate

Participant data will be coded and available for the involved researcher and PI only (dr. Charlien Berghen and prof. dr. De Meerleer Gert)