The goal of this clinical trial is to find out whether lowering the radiation dose to parts of the prostate without visible tumor on MRI can reduce side effects while still effectively treating prostate cancer in men with low or intermediate-risk prostate cancer.

The main questions it aims to answer are:

• Does reducing the radiation dose to healthy prostate tissue lower the risk of bowel and urinary side effects?
• Can we maintain good cancer control by keeping a high dose for MRI-visible tumor areas?

Researchers will compare two treatment approaches:

• One group receives a uniform high dose to the entire prostate.
• The other group receives a lower dose to healthy prostate tissue and a high dose only to visible tumor areas.

Participants will:

• Receive two sessions of MRI-guided radiotherapy using an MR-Linac.
• Complete questionnaires about urinary, bowel, and sexual health before and after treatment.
• Have follow-up visits to monitor side effects and PSA levels for up to 2 years.

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 (ISUP Grade groups (GG) 1, 2 or 3)
4. 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. MRI must be performed within 3 months of trial entry
5. The MRI-defined lesion must be confirmed as malignant on biopsies (any Gleason grade is sufficient as long as Gleason score is reported).
6. MRI stages mT1 and T2 or mT3a with ≤ 1mm tumour outside gland AND otherwise favourable intermediate risk characteristics (Gleason 3+3, 3+4)(as staged by AJCC TNM 2018)
7. PSA <20 ng/ml prior to starting androgen deprivation therapy (ADT).
8. WHO Performance status 0-2
9. Ability of the participant to understand and the willingness to sign a written informed consent (IC) form.
10. 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. IPSS Score > 19
3. High grade disease (GG3) occult to MRI-defined lesion. As a guide, any pathology for which you would consider surveillance is allowed outside of the MRI-defined area.
4. Prostate volume >90cc
5. Comorbidities which predispose to significant toxicity (e.g. inflammatory bowel disease) or preclude long term follow up
6. Hip replacement, or other pelvic metalwork which causes artefact on diffusion-weighted imaging
7. Previous pelvic radiotherapy
8. Patients needing >6 months of ADT due to disease parameters.
9. Previous invasive malignancy within the last 2 years excluding basal or squamous cell carcinomas of the skin, low risk non-muscle invasive bladder cancer (assuming cystoscopic follow up now negative) or small renal masses on surveillance.

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.

5 years