INSPIRE: INnovative SABR for Prostate Cancer All IREland

This is a Phase II, single arm, multi-centre, prospective clinical trial evaluating next generation Stereotactic Ablative Radiotherapy (SABR) for low, intermediate, and eligible high-risk prostate cancer. Eligible patients will receive next generation prostate SABR incorporating toxicity reduction strategies: urethral/trigone sparing, rectal hydrogel spacer, and neurovascular bundle preservation [as per Desai POTEN-C trial, Desai et al., 2025].

Treatment will prioritise the dominant intraprostatic lesion (DIL) while sparing surrounding organs at risk (OARs). Planned doses are: DIL 40-50 Gy in 5 fractions delivered on alternate days, prostate CTV 35 Gy, PTV 33.25 Gy, and urethral PRV 32.5 Gy. Eligible high-risk and some intermediate-risk patients may receive 6-12 months of androgen deprivation therapy (ADT)/hormonal therapy at the physician's discretion, provided they have not received >14 weeks prior to registration.

Radiotherapy planning will include advanced image-guided verification with fiducial markers, pre-treatment dosimetry to minimise dose to OARs, and adherence to protocol-defined constraints for urethra, rectum, and neurovascular bundles. Peri-rectal spacers will be inserted 7-10 days prior to CT-simulation to reduce rectal dose. Dose prioritisation allows full coverage of the DIL while sparing urethra, bladder trigone, and neurovascular bundles to minimise genitourinary, rectal, and sexual toxicity.

Follow-up assessments will include clinical evaluation, toxicity reporting using v5 NCI CTCAE, and patient-reported outcome measures (PRO/QoL) at 2-, 4-, 8-, and 12-weeks post-treatment, 6 and 9 months, and annually up to 5 years. Data on biochemical/clinical failure, progression-free survival, and initiation or re-initiation of ADT will also be collected.

A total of 136 patients will be enrolled to achieve 122 evaluable participants, allowing detection of a statistically significant reduction in Grade ≥2 late genitourinary toxicity compared to historical SABR controls.

Inclusion criteria

• Written informed consent obtained prior to any study-related procedures
• Males ≥ 18 years of age
• ECOG performance status (PS) 0-2
• Biopsy-proven prostate adenocarcinoma without neuro-endocrine differentiation (within 18 months prior to registration, unless on active surveillance and re-biopsy not clinically indicated)
• Gleason score ≤ 4+3
• Clinical and/or MRI stage T1c-T3a, N0-X, M0-X
• PSA ≤ 30 ng/ml (within 60 days prior to registration / prior to starting androgen-deprivation therapy (ADT/hormone therapy) [PSA ≤ 15 ng/ml for patients on 5-alpha reductase inhibitors]
• Patients belonging to one of the following risk groups:

• Low risk - patients meeting all of the following criteria:

• Gleason ≤ 6
• Clinical stage T1c-T2a
• PSA < 10 ng/ml (within 60 days prior to registration)
• Intermediate risk - patients meeting any of the following criteria, assuming no high-risk features apply:

• Gleason 7 (3+4 or 4+3)
• MRI stage T2b-T2c (N0, M0-X)
• PSA 10-20 ng/ml (within 60 days prior to registration)
• High risk - patients with tumours that meet a maximum of one of the following criteria:

• MRI stage T3a (N0, M0)
• PSA >20 - ≤30 ng/ml (within 60 days prior to registration)

Exclusion criteria

• Previous malignancy within the last 2 years (except basal cell carcinoma (BCC) or squamous carcinoma of the skin), or if previous malignancy is expected to significantly compromise 5 year survival
• Prior pelvic radiotherapy
• Any prior active treatment for prostate cancer (with the exception of ADT). Patients previously on active surveillance are eligible if they continue to meet all other eligibility criteria.
• Life expectancy <5 years.
• Bilateral hip prostheses or any other implants/hardware that would introduce substantial CT artefacts
• Medical conditions likely to make radiotherapy inadvisable e.g. inflammatory bowel disease, significant urinary symptoms.
• Anticoagulation with warfarin/bleeding tendency making fiducial placement or surgery unsafe in the opinion of the clinician. Note: Anti-platelet agents e.g. aspirin, clopidogrel and DOACs such as apixaban, rivaroxaban are not contraindications to trial entry.
• Participation in another concurrent treatment protocol for prostate cancer (not including QoL, survivorship, exercise or registry studies).