Dose dE-eScalaTion IN prostATe radIOtherapy usiNg an MR-Linac in 2 Fractions (DESTINATION 2)

Dose dE-eScalaTion IN prostATe radIOtherapy usiNg an MR-Linac in 2 Fractions - a Randomised Trial

DESTINATION 2 is a multi-centre randomised trial treating intermediate risk localised prostate cancer with 2 fraction Stereotactic Body Radiotherapy (SBRT). All radiotherapy will be delivered in two fractions (sessions) on an MR Linac using daily adaptation. Men will either receive uniform dose radiotherapy or de-escalated dose radiotherapy. The primary endpoint is acute GU CTCAE v5 grade 2+ toxicity. It will also look at late toxicity, patient-reported outcome measures and PSA control.

Study Overview

• Status: Recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Radiation: Prostate radical radiotherapy

Detailed Description

54 patients meeting inclusion criteria will be randomised between two arms. Arm 1 (Uniform dose) will receive 27 Gy in 2 fractions to the whole prostate + seminal vesicles (SV), the CTV, with 0 mm CTV-PTV margin. Arm 2 (De-escalated dose) will use two dose levels: The benign prostate (on MRI) will receive 20 Gy in 2 fractions with a 0mm PTV margin. The intraprostatic tumour mass(es) as seen on MRI will receive 27 Gy in 2 fractions. A 4mm GTV-PTV margin will be added to the MR visible tumour to form PTV 27Gy. The primary endpoint is emergent acute GU CTCAE v5 Grade 2+ toxicity, recorded within 3 months of completing radiotherapy. Secondary endpoints are CT CAE v5 acute GI toxicity, late toxicity, patient-reported outcome measures (PROMs) (EPIC-26, IPSS, and IIEF-5) at 4 and 12 weeks, 6 months, 1 and 2 years post treatment, PSA control and kinetics

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sian Cooper; Email: sian.cooper@rmh.nhs.uk
• Study Contact Backup: Name: Francesca Mason; Phone Number: +44 20 3186 5157; Email: mrltrials@rmh.nhs.uk

Study Locations

• Canada
  • Toronto, Canada
    • Not yet recruiting
    • Sunnybrook Health Sciences Centre
    • Contact: Murtuza Saifuddin; Phone Number: 63094 416-480-5000; Email: murtuza.saifuddin@sunnybrook.ca
    • Contact: Andrea Deabreu; Phone Number: 61058 (416) 480-6100; Email: Andrea.Deabreu@sunnybrook.ca
    • Principal Investigator: Danny Vesprini
• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • Recruiting
    • The Christie NHS Foundation Trust
    • Contact: Roonak Nazari; Phone Number: +44(0)161 446 3422; Email: roonak.nazari@nhs.net
  • Sutton, United Kingdom
    • Recruiting
    • The Royal Marsden NHS Foundation Trust
    • Contact: Francesca Mason; Phone Number: 02031865157; Email: mrltrials@rmh.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Men aged ≥18 years
2. Histological confirmation of prostate adenocarcinoma requiring radical radiotherapy
3. Gleason score 3+3, 3+4 or 4+3 (Grade groups (GG) 1, 2 or 3)
4. MRI stage T3a or less (as staged by AJCC TNM 2018). MRI must be performed within a year of randomisation
5. MRI-visible tumour(s) of PIRADS v2 grade 3 or higher and able to be delineated on T2 and diffusion-weighted imaging +/- dynamic contrast-enhanced imaging. Tumour nodule visible on MRI should be considered able to be boosted by treating clinician and <2.5cm in maximal dimension
6. The MRI-defined lesion must be confirmed as malignant on biopsies (Gleason grade must be within the limits expressed in inclusion factor 3)
7. Patients can be concurrently treated with androgen deprivation therapy (ADT) if this would be standard of care. LHRH analogues, LHRH agonists or Bicalutamide are permitted. ADT is not mandatory where this would usually be omitted.
8. PSA <20 ng/ml prior to starting ADT, if used
9. WHO Performance status 0-2
10. Ability of the participant understand and the willingness to sign a written informed consent form.
11. Willing to consent to contraception during and for 1 year after treatment when applicable.
12. Ability/willingness to comply with the patient reported outcome questionnaires schedule throughout the study.

Exclusion Criteria:

1. Contraindications to MRI (e.g. pacemaker, potentially mobile metal implant, claustrophobia)
2. Severe GU symptoms that would preclude extreme hypofractionation per the discretion of the treating physician.
3. IPSS Score > 19
4. High grade disease (GG3) occult to MRI-defined lesion. As a guide, any pathology for which you would consider surveillance (eg GG1, low volume GG2) is allowed outside of the MRI-defined area.
5. Prostate volume >90cc
6. Comorbidities which predispose to significant toxicity (e.g. inflammatory bowel disease) or preclude long term follow up
7. Hip replacement, or other pelvic metalwork which causes significant artefact on diffusion-weighted imaging
8. Previous pelvic radiotherapy
9. Patients needing >6 months of ADT due to disease parameters.
10. Previous invasive malignancy within the last 2 years where this is likely to shorten lifespan the following will remain eligible: basal or squamous carcinomas of the skin, low risk non-muscle invasive bladder cancer (assuming cystoscopic follow up now negative) or small renal masses on surveillance.
11. Participating in another interventional trial for prostate cancer

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Uniform dose; Arm 1 (Uniform dose) will receive 27 Gy in 2 fractions to the whole prostate + seminal vesicles (SV), the CTV, with 0 mm CTV-PTV margin.	Radiation: Prostate radical radiotherapy; Radiation: De-escalated radiotherapy to be delivered on the Elekta Unity MR-linac
Experimental: De-escalated dose; Arm 2 (De-escalated dose) will use two dose levels: The benign prostate (on MRI) will receive 20 Gy in 2 fractions with a 0mm PTV margin. The intraprostatic tumour mass(es) as seen on MRI will receive 27 Gy in 2 fractions. A 4mm GTV-PTV margin will be added to the MR visible tumour to form PTV 27Gy.	Radiation: Prostate radical radiotherapy; Radiation: De-escalated radiotherapy to be delivered on the Elekta Unity MR-linac

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute GU toxicity	To describe the absolute risk and relative risk reduction of acute genitourinary (GU) toxicity (CTCAE v5) when delivering de-escalated two fraction prostate SBRT compared to uniform dose two fraction prostate stereotactic body radiotherapy (SBRT) for intermediate risk prostate cancer.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) toxicity	To describe the absolute and relative risk of toxicity	Baseline, last fraction, week 2, 4 and 12
Late Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) toxicity	To describe the absolute and relative risk of toxicity	Month 6, 12, 24
Feasibility of radiation delivery	Feasibility- estimate percentage of fractions interrupted due to patient discomfort	At time of treatment
Dosimetry	Dosimetry- estimate the accumulated dose differences between the de-escalated and uniform dose delivery	At time of treatment
PSA kinetics	To assess biochemical relapse-free survival at 2 years	Baseline (pre ADT), week 12, month 6, and 1 and 2 years post treatment
Patient reported outcome measures	To assess baseline, acute and late International Prostate Symptom Score (IPSS). IPSS ranges from 0 to 35. Lower scores are better: A lower score indicates fewer or less severe urinary symptoms, while a higher score suggests more severe symptoms.	Baseline, last fraction of treatment, week 2, 4 and 12, 6 months, 1 and 2 years post treatment.
Patient reported outcome measures	Expanded Prostate Cancer Index Composite Short Form (EPIC-26). EPIC-26 scores are transformed to a 0-100 scale for each domain.The questionnaire usually covers urinary incontinence, urinary irritative/obstructive symptoms, bowel, sexual, and hormonal functions. Higher scores represent better health-related quality of life.	Baseline, 4 and 12 weeks, 6 months, 1 and 2 years post treatment.
Patient reported outcome measures	International Index of Erectile Function-5 (IIEF-5). The IIEF-5 score ranges from 5 to 25. Higher scores are better: A higher score indicates better erectile function, while a lower score suggests more severe erectile dysfunction.	Baseline, 6 months, 1 and 2 years post treatment.

Collaborators and Investigators

• Sponsor: Royal Marsden NHS Foundation Trust
• Collaborators: Elekta Limited; MRL Consortium
• Investigators: Study Chair: Alison Tree, Royal Marsden Hospital, Institute of Cancer Research

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: September 23, 2024
• First Submitted That Met QC Criteria: October 9, 2024
• First Posted (Actual): October 15, 2024

Study Record Updates

• Last Update Posted (Actual): March 23, 2026
• Last Update Submitted That Met QC Criteria: March 19, 2026
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Radiotherapy; De-escalation; MR-Linac
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms
• Other Study ID Numbers: CCR5984; 338368 (Other Identifier: IRAS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: It is intended that data will be shared within the MOMENTUM collaboration, between centres delivering treatment in the same way as DESTINATION2. Pseudonymised data will be stored within MOMENTUM for at least 5 years. Storage will be cloud based and as the treating centre we will have free access to the data and control over who else can assess it.
• IPD Sharing Time Frame: 5 years

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No