Acute adverse events in the DESTINATION 1 trial: A prospective prostate SBRT dose de-escalation feasibility study

BACKGROUND: Stereotactic body radiotherapy (SBRT) is effective for localised prostate cancer but increases genitourinary adverse events (AE). Focal boost to the dominant lesion may improve disease control. The DESTINATION study investigates whole gland dose de-escalation, with focal boost, using MR-guided adaptive radiotherapy (MRgART), to maintain cancer control whilst demonstrating acceptable AE. METHODS: DESTINATION is a prospective, phase II federated study that enrolled men with localised prostate cancer across three institutions (The Royal Marsden Hospital, Sunnybrook Health Sciences Centre, and The Netherlands Cancer Institute). Patients received MRgART with daily online replanning to deliver 30 Gy in 5 fractions to the whole prostate with no margin. The gross tumour volume (GTV) + 4 mm intra-prostatic margin received an isotoxic boost of 45 Gy. Acute AE were assessed using CTCAEv5 at baseline, end of treatment, 4 weeks, and 12 weeks post-treatment. Patient-reported outcomes were collected using IPSS, EPIC-26 and IIEF5. RESULTS: All 60 patients completed 12-weeks follow-up. Grade 2 genitourinary AE occurred in 55 % of patients by 12 weeks. Grade 2 gastrointestinal AE occurred in 11.7 %. Patient-reported outcomes demonstrated expected symptom flare at final fraction of treatment followed by gradual recovery. EPIC scores were consistently higher at NKI compared to RMH/SB, with sexual function decline during follow-up across all centres. CONCLUSION: The DESTINATION study demonstrates that dose de-escalation 5-fraction SBRT with isotoxic focal boost produces acute AE rates similar to or above the levels seen in the PACE-B trial. The focal boost may have offset any potential decrease in AE from whole gland de-escalation.