Overview
The study is an open label, multi-centre, randomized phase III study. The patients will be randomised in a 1:1 ratio to treatment consisting of
- Arm A: MD-SBRT in addition to standard treatment
- Arm B: Standard treatment
Study population: Patients with hormone sensitive prostate cancer (HSPC) with oligometastatic disease detected by PSMA-PET/DT. This includes patients with de novo oligometastatic HSPC and recurrent HSPC after primary RT or prostatectomy.
Primary endpoint: Failure free survival
Secondary endpoints:
- Predictive value of investigated biomarkers in blood and imaging
- Acute and late toxicity after MD-SBRT
- PROM at 3 months, 1, 3 and 5 years
- Castration resistant prostate cancer, CRPC
- Overall survival
- Differences in outcome between patients by strata
Stratification: To avoid imbalance between treatment arms the minimisation method will be used to achieve balance between de novo oligo-metastatic and oligo-recurrent patients, as well as treatment site.
Safety evaluation: Adverse events and side effects graded according to CTCAE v5.0 will be collected every 6th month. Serious Adverse Events are to be reported within 24 hours throughout the study duration.
Statistical methods: Survival endpoints will be calculated using the Kaplan-Meier method with differences compared using the stratified log-rank test. Randomization time is set as baseline time. Pre-planned subgroup analysis will occur based on pre-specified stratification variables. A Cox multivariable regression model will be used to determine factors predictive of survival. Safety analysis will be performed with Mann-Whitney U-test or Fishers exact test.
Criteria for evaluation: Per protocol (patients that have started study treatment) and Intention to treat (all included patients).
Planned sample size: 118 patients
Analysis plan:
The primary end point will be analysed after pre-specified number of events have occurred. All patients randomised to SBRT will be followed minimum 60 months for toxicity. Safety analysis of acute toxicity will take place after median follow up of 6 months. Safety analysis of late toxicity will be analysed after study closure.
Duration of the study:
Three to five years inclusion. 72 months of follow-up after randomization of the last patient.
Description
Standard treatment (arm A and B): For patients without metastatic disease in conventional imaging 3 years of ADT with the addition of abiraterone+prednisolone for two years is considered the gold standard. For patients with M1 disease in conventional imaging, lifelong ADT is permitted. If the patient is de novo oligo-metastatic, RT to the prostate is considered as standard treatment.
Study intervention (arm A): MD-SBRT to all PSMA-PET/CT positive metastatic target volume(s) with 30 Gy in 3 fractions or 40 Gy in 5 fractions in addition to standard treatment. For recurrent patients post prostatectomy with PSMA-PET-positive finding at prostate bed (without prior local RT) salvage RT with SIB to the PSMA+ GTV is to be delivered. Concurrent PSMA-PET-positive regional lymph nodes are to be treated for all patients in the intervention arm (sum of SBRT-targets maximum 3).
Screening procedure:Inclusion/exclusion criteria evaluation including evaluation of feasibility of SBRT to all positive lesions on PSMA-PET/CT performed within approx. 30 days of randomization.
Study specific procedure: Recording/collecting of baseline data including baseline PROM and pre-ADT testosterone and PSA. Standard treatment with ADT administered at randomization to all study patients. Abiraterone is initiated within 8 weeks of study entry. Start of MD-SBRT within approx. 28 days of randomization to patients in arm A. Additional RT as specified in study intervention started within 90 days. Follow up according to protocol, minimum 60 months.
Eligibility
Inclusion Criteria:
- Histologically confirmed prostate cancer (ICD-O-3 C61)
- WHO/ECOG performance status 0-1
- 1-3 skeletal or extra pelvic lymph node metastases detected by PSMA-PET/CT in i. de novo prostate cancer or ii. PSA-relapse after definitive RT or prostatectomy
- Willing and able to provide informed consent-
Exclusion Criteria:
- Castration resistant prostate cancer (progression with castrate levels of testosterone <20ng/dL)
- Any treatment known to affect PSA (including ADT) for prostate cancer within 6 months (exception: ADT started due to oligometastatic disease within 2 weeks of study entry)
- Patient eligible for other treatment (e.g., early docetaxel) than standard treatment described in the protocol as judged by treating physician
- Life expectancy <3 years by any reason, including concomitant or previous malignancies
- Previous radiotherapy or surgery that may interfere with the planned treatment (including intra-prostatic recurrence if previous RT to the prostate)
- > 3 PSMA-PET/CT positive target lesions (excluding the prostate in de novo patients or prostate bed post radical prostatectomy)
- PSMA-PET verified metastases other than skeletal or lymph nodes
- Metastases in base of scull and/or calotte
- Any target lesions not treatable with image guided RT (IGRT) due to overlap with previous RT fields or exceeded dose constraint to OAR(s) as specified in study protocol