Metastasis Directed Stereotactic Body Radiotherapy for Oligo Metastatic Hormone Sensitive Prostate Cancer (METRO)

Metastasis Directed Stereotactic Body Radiotherapy for Oligo Metastatic Hormone Sensitive Prostate Cancer

Metastasis Directed Stereotactic Body Radiotherapy for Oligo Metastatic Hormone Sensitive Prostate Cancer

University Hospital, Umeå, Karolinska University Hospital, Region Örebro County, Region Jönköping County, Stockholm South General Hospital, Region Skane, Vastra Gotaland Region

The study is an open label, multi-centre, randomized phase III study. The patients will be randomised in a 2:1 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 (time to castration resistant prostate cancer, CRPC) 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 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: 114 patients Analysis plan: The primary end point will be analysed after pre-specified number of events have occurred or at 60 months of follow up. 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. 60 months of follow-up after randomization of the last patient.

Standard treatment (arm A and B): ADT is considered the gold standard for this patient group. This includes medical castration with GnRH-agonist and 30-day antiandrogen (flare protection) or GnRH-antagonist. 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 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. Start of study intervention with MD-SBRT within 21 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.

30 Gy in 3 fractions alternatively 40 Gy in 5 fractions delivered with stereotactic radiotherapy-principles

Time from randomisation to castation resistant prostate cancer (CRPC). CRPC is defined as 2 consecutive rises in blood PSA with castrate testosterone levels. PSA and testosterone will be collected every third month and registered in the electronic case report form.

Side effects according to Common Terminology Criteria for Adverse Events version 5, CTCAE v5 will be collected at baseline, 3 and 6 months after randomisation for all organs at risk within 3 cm from the SBRT-target in the electronic case report form. Adverse events are scored from 0 (none) to 5 (fatal) in the electronic case report form. We will report the number of patients with no reported side effects as well as the number of patients scoring 1, 2, 3, 4 and 5 assessed by CTCAE v5.

Side effects according to Common Terminology Criteria for Adverse Events version 5, CTCAE v5 will be collected every 6th months after randomisation for all organs at risk within 3 cm from the SBRT-target. Adverse events are scored from 0 (none) to 5 (fatal) are collected in the electronic case report form. We will report the number of patients with no reported side effects as well as the number of patients scoring 1, 2, 3, 4 and 5 assessed by CTCAE v5.

Blood samples will be collected to enable evaluation of circulating biomarkers in relation to patient response to treatment at baseline, 1 and 3 months after randomisation, and at progression. Specifically, plasma will be sampled and circulating tumor cells and platelets will be further isolated. Imaging parameters from the baseline PSMA-PET/CT will also be evaluated in relation to outcome.

Patients will fill out a cross validated self registration questionnaire; European Organistaion for Research and Treatment of Cancer Quality of Life Questionnaire, EORTC QLQ 30, at baseline, 3 months, year 1, 3 and 5. The questionnaire consists of 28 statements that are to be graded from 1 (not at all) to 4 (very well) according to how well they correspond to the patients perception. EORTC QLQ30 also ask for the patient to score their overall sense of 1)health and 2)quality of life on a scale from 1 (very poor) to 7 (excellent).

all outcomes 1-6 will be analysed by stata; primary or recurrent oligometastatic prostate cancer and study site (for inclusion)

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

SBRT-plans will be shared in detail for all treatment related adverse effects grade>3 according to CTCAE vers 5 in both final and interim analyses. Study protocol including Statistical Analysis Plan will be made public at study start through per review scientific publication