Two-session MR‑Linac radiotherapy with targeted dose reduction for intermediate‑risk prostate cancer

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

This trial tests whether two MR‑guided radiotherapy sessions with a lower dose to non‑tumor prostate tissue can reduce side effects for men with intermediate‑risk prostate cancer while keeping tumor control.

Quick facts

• Phase: Not applicable
• Study type: Interventional
• Enrollment: 54 (estimated)
• Ages: 18 Years and up
• Sex: Male
• Sponsor: Royal Marsden NHS Foundation Trust (Academic / other)
• Locations: 3 sites (Toronto and 2 other locations)
• Trial ID: NCT06638541 on ClinicalTrials.gov

What this trial studies

DESTINATION 2 randomises 54 men with intermediate‑risk localized prostate cancer to receive two fractions of MR‑guided stereotactic body radiotherapy delivered on an MR‑Linac. One arm delivers a uniform 27 Gy in 2 fractions to the whole prostate and seminal vesicles with a 0 mm margin, while the other arm de‑escalates dose to benign prostate to 20 Gy in 2 fractions and boosts MRI‑visible intraprostatic tumor nodules to 27 Gy with a 4 mm GTV‑PTV margin. All treatments use daily MRI adaptation and allow concurrent androgen‑deprivation therapy where standard of care. Primary outcome is acute genitourinary CTCAE v5 grade 2+ toxicity within three months, with secondary endpoints including acute gastrointestinal toxicity, late toxicity, patient‑reported outcomes (EPIC‑26, IPSS, IIEF‑5) up to two years, and PSA control.

Who should consider this trial

Good fit: Men aged 18 or older with histologically confirmed Gleason 3+3, 3+4, or 4+3 prostate adenocarcinoma, MRI‑visible tumor(s) ≤2.5 cm, MRI stage T3a or less, and PSA <20 ng/mL are ideal candidates.

Not a fit: Men with higher‑risk disease (beyond Gleason 4+3 or MRI stage >T3a), MRI‑invisible tumors, lesions larger than 2.5 cm, or those unable to undergo MRI/MR‑Linac treatment are unlikely to benefit.

Why it matters

Potential benefit: If successful, this approach could lower urinary and bowel side effects while preserving cancer control and shorten treatment to two sessions.

How similar studies have performed: Previous MR‑guided SBRT and focal‑boost trials have shown promising early toxicity and control data, but this specific two‑fraction de‑escalation approach is relatively novel and less tested.

Eligibility criteria

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

Where this trial is running

Toronto and 2 other locations

• Sunnybrook Health Sciences Centre — Toronto, Canada (Not_yet_recruiting)
• The Christie NHS Foundation Trust — Manchester, United Kingdom (Recruiting)
• The Royal Marsden NHS Foundation Trust — Sutton, United Kingdom (Recruiting)

Study contacts

• Study coordinator: Francesca Mason

Conditions Prostate Cancer; De-escalation; Radiotherapy; MR-Linac