Best Salvage Treatment for High-risk Relapsing Prostate Cancer (PEACE-9 - ESCALATE-RT)

The goal of this clinical trial is to learn if adding metastasis-directed radiotherapy with or without pelvic salvage radiotherapy, to intermittent prostate cancer drugs (intensified hormone therapy) can delay the need to restart these drugs in men with oligometastactic prostate cancer recurrence. In practice, this study is open to men whose PSA level (a blood marker of cancer activity) is rising as defined by biochemical recurrence, and who have 1 to 5 areas of cancer spread (1 to 5 metastases defining oligometastatic status) found on a specialized scan (PSMA PET/CT). Since intensified hormone therapy, including androgen deprivation therapy combined with a next-generation hormone therapy, represents the standard treatment strategy for these patients, researchers want to find out if adding radiation therapy can help patients to spend more time off cancer drugs while keeping their cancer under control. The main questions this trial aims to answer are: * Does adding radiation therapy to each metastases with or without pelvic area, lengthen the time before participants need to restart drug treatment? * Does adding radiation therapy increase the number of participants whose PSA drops to a very low level (0.2 ng/mL or lower)? * Does adding radiation therapy affect participants' quality of life? Researchers will randomly assign participants (chosen by chance) to receive either enzalutamide (next-generation hormone therapy) plus androgen-deprivation therapy (first-generation hormone therapy ) alone, or the same association of these drugs combined with radiation therapy aimed at each metastases with or without pelvic area. This comparison will show whether adding radiation therapy helps participants reach a deeper PSA response and go longer without needing cancer drugs. Participants will: * Take enzalutamide and androgen-deprivation therapy for 9 months * Have an equal chance of also receiving radiation therapy to each metastases with or without pelvic area * Stop drug treatment after 9 months if their PSA drops below 0.2 ng/mL, a level showing the cancer is well controlled * Restart drug treatment if their PSA rises again during the treatment-free period * Have regular blood tests and clinic visits to check their PSA, testosterone, and overall health * Complete short quality-of-life questionnaires during the study * Take part in a study conducted at several hospitals in Switzerland, Belgium, and France.

Inclusion Criteria: * Histologically proven initial diagnosis of adenocarcinoma of the prostate * Rising PSA after local therapy as defined by PSA ≥ 0.2 ng/mL after RP +/- adjuvant/salvage prostate bed RT and at least 2 ng/mL above nadir for primary RT, with a PSADT ≤ 9 months * Serum Testosterone ≥ 150 ng/dl (6.9343 nM/L) * On PSMA PET/CT restaging presence of: 1 to 5 distant metastases that are amenable to MDT ± N1 patients (no limit in the number of nodes) * ECOG performance status 0 - 2 * Age \> or =18 years * Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial * Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations Exclusion Criteria: * More than 5 distant PSMA positive metastases and/or brain or leptomeningeal metastases. * Prostate recurrence (positive PSMA disease) after primary prostate irradiation * Prostate bed recurrence (positive PSMA disease) after salvage/adjuvant irradiation * Pelvic nodal recurrence (positive PSMA disease) after primary WPRT irradiation * Contraindications to pelvic RT and/or MDT * Prior evidence of distant metastatic disease * Contraindications to ADT * Contraindication for treatment with enzalutamide * Prior hormonal therapy (Neoadjuvant/adjuvant therapy to treat PCa ≤ 36 months in duration and ≥ 9 months before randomization is allowed) * Previous treatment with cytotoxic agent for PCa * Any active malignancies (i.e., progressing or requiring any treatment in the previous 36 months) other than prostate cancer (except non-muscle invasive bladder cancer; non-melanomatous skin cancer or a malignancy that is considered cured with minimal risk of recurrence