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

November 28, 2023 updated by: Karin Soderkvist, Umeå University

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Estimated)

118

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Histologically confirmed prostate cancer (ICD-O-3 C61)
  2. WHO/ECOG performance status 0-1
  3. 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
  4. Willing and able to provide informed consent-

Exclusion Criteria:

  1. Castration resistant prostate cancer (progression with castrate levels of testosterone <20ng/dL)
  2. 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)
  3. Patient eligible for other treatment (e.g., early docetaxel) than standard treatment described in the protocol as judged by treating physician
  4. Life expectancy <3 years by any reason, including concomitant or previous malignancies
  5. Previous radiotherapy or surgery that may interfere with the planned treatment (including intra-prostatic recurrence if previous RT to the prostate)
  6. > 3 PSMA-PET/CT positive target lesions (excluding the prostate in de novo patients or prostate bed post radical prostatectomy)
  7. PSMA-PET verified metastases other than skeletal or lymph nodes
  8. Metastases in base of scull and/or calotte
  9. 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Standard treatment
ADT and local RT to de novo patients
Drug: androgen deprivation therapy
Medical castration
Other Names:
  • gonadotropin releasing hormone-agonist
  • gonadotropin releasing hormone-antagonist
Radiation: Radiotherapy
RT to the prostate for de novo patients
Other Names:
  • external radiotherapy
Experimental: SBRT+Standard treatment
SBRT to all PSMA+ lesions in addition to ADT and local RT to de novo patients
Drug: androgen deprivation therapy
Medical castration
Other Names:
  • gonadotropin releasing hormone-agonist
  • gonadotropin releasing hormone-antagonist
Radiation: Radiotherapy
RT to the prostate for de novo patients
Other Names:
  • external radiotherapy
Radiation: stereotactic body radiotherapy
30 Gy in 3 fractions alternatively 40 Gy in 5 fractions delivered with stereotactic radiotherapy-principles
Other Names:
  • stereotactic ablative radiotherapy
  • image guided radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Failure free survival
Time Frame: Throughout the study duration (72 months of follow up for last patient included.)
Time from randomisation to progressive disease. Progression is defined as 2 consecutive rises in blood PSA. PSA will be collected every third month and registered in the electronic case report form.
Throughout the study duration (72 months of follow up for last patient included.)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v5.
Time Frame: Until 6 months after randomisation
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.
Until 6 months after randomisation
Number of participants with treatment-related serious adverse events as assessed by CTCAE v5.
Time Frame: Throughout the study duration (72 months of follow up for last patient included.)
Side effects grade 4 or higher 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.
Throughout the study duration (72 months of follow up for last patient included.)
Outcome prediction
Time Frame: Throughout the study duration (72 months of follow up for last patient included.)
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.
Throughout the study duration (72 months of follow up for last patient included.)
Patient reported quality of life assessed by EORTC-QLQ 30
Time Frame: Throughout the study duration (72 months of follow up for last patient included.)
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).
Throughout the study duration (72 months of follow up for last patient included.)
Overall survival
Time Frame: Throughout the study duration (72 months of follow up for last patient included.)
Death due to any cause
Throughout the study duration (72 months of follow up for last patient included.)
Castration resistent prostate cancer, CRPC
Time Frame: Throughout the study duration (72 months of follow up for last patient included.)
2 consecutive rises in blood PSA with castrate levels of testosterone. PSA will be collected every third month and registered in the electronic case report form. Testosterone will be collected if a rise in PSA level is detected.
Throughout the study duration (72 months of follow up for last patient included.)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
outcome according to strata
Time Frame: Throughout the study duration (72 months of follow up for last patient included.)
all outcomes 1-6 will be analysed by stata; primary or recurrent oligometastatic prostate cancer and study site (for inclusion)
Throughout the study duration (72 months of follow up for last patient included.)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Umeå University

Collaborators

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

Investigators

  • Principal Investigator: Karin Söderkvist, Region Västerbotten, Umeå University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 27, 2021

Primary Completion (Estimated)

December 1, 2025

Study Completion (Estimated)

December 1, 2031

Study Registration Dates

First Submitted

June 1, 2021

First Submitted That Met QC Criteria

July 27, 2021

First Posted (Actual)

July 30, 2021

Study Record Updates

Last Update Posted (Estimated)

December 5, 2023

Last Update Submitted That Met QC Criteria

November 28, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • METRO_vers1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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

IPD Sharing Time Frame

Planned publication of study at study start

IPD Sharing Access Criteria

Open access publication

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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