This interventional prospective multicenter international study will include 54 patients with very high-risk localized (cN0 cM0) or regional (i.e. cN1 cM0) prostate cancer according the NCCN criteria.

Patients will be treated with weekly CT or MR-informed online adaptive SBRT of the prostate and elective pelvic lymph nodes with 5 x 5 Gy. In the case of regional lymph nodes, a simultaneous integrated boost (SIB) of involved lymph nodes will be performed with 5 x 6.5 Gy. In the case of up to 2 dominant intraprostatic lesion (DIL) a SIB of the DIL with 5 x 9 Gy can be performed (optional). Importantly, coverage of these DIL volumes must be compromised as needed to respect OAR constraints.

This study is classified as risk category A according to ClinO, Art. 61, as stereotactic radiotherapy (SBRT) for localized or regional prostate cancer has been extensively evaluated in prospective interventional trials and is considered an established therapeutic modality.

Weekly CT- or MR-guided online adaptive SBRT to the prostate and elective pelvic lymph nodes with 5 × 5 Gy is, however, not yet routinely implemented for this specific patient population.

A diagnostic high field MRI during radiotherapy, e.g. week 3 is optional.

Follow-up is also according to standard of care (except for patient reported outcome measure using QLQ-C30 and QLQ-PR25 and a diagnostic MRI at 9 months after SBRT (optional), and 12 months in the case of an image non-complete response at 9 months (optional).

Inclusion criteria include:

• Very high risk localized defined (cN0) according to NCCN guidelines consisting of ≥2 of the following:

  • cT3 disease and/or
  • Gleason 8-10 and/or
  • PSA ≥40 (the baseline PSA value should be doubled for PSAs taken while on 5-alpha reductase inhibitors) OR

• Regionally metastatic prostate cancer (cN1, any T, any Gleason, any PSA) according to NCCN guidelines consisting of ≤3 lymph node metastases of any of the following:

  • Obturator
  • Internal iliac (hypogastric)
  • External iliac nodes
  • Presacral nodes
  • Common iliac (below iliac bifurcation)
  • Periprostatic/Perivesical AND

• Good to moderate performance status (WHO 0-2)

• Written informed consent.

• A PSMA PET and multiparametric MRI is mandatory according to staging guidelines.

• Age ≥ 18 years

Exclusion criteria include:

• ≥4 regional lymph nodes

• Patients with cT4 disease (tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall)

• Previous RT to the pelvis or prostate

• Previous radical prostatectomy

• Large body size that would not fit into the MRI-simulator bore

• Presence of distant metastases (i.e. cM1)

  • Non-regional lymph nodes (M1a):
  • Common iliac
  • Para-aortic / retroperitoneal
  • Inguinal
  • Mediastinal or supraclavicular
  • Mesorectal
  • Other
  • Bone metastases (M1b)
  • Other sites (M1c)

• Contraindications to CT or MR-adaptive SBRT (e.g., pacemakers, severe claustrophobia).

• Severe comorbidities that may interfere with treatment or follow-up (e.g. inflammatory bowel disease)

• Significant concomitant diseases (e.g. hepatic dysfunction, cardiovascular disease, etc.);

• Inability to follow procedures or insufficient knowledge of project language, inability to give consent.

• Participation in a clinical trial, which might influence the results of this project.

• Enrolment of the investigator, his/her family members, employees and other dependent persons.

• Severe GU or GI symptoms (e.g., recent urinary retention or diarrhea ≥ grade 3 or obstipation to CTCAE v.5.0).

• Severe urinary symptoms (prostate volume >60mL and/or IPSS >12)

This study will include male patients only since male patients only are able to get prostate cancer.