Proton Beam Therapy in Prostate Cancer: Clinical Evidence, Controversies and Future Directions

Proton beam therapy (PBT) offers a unique dosimetric advantage over photon-based external beam radiotherapy by concentrating dose at a certain depth (the Bragg peak) and markedly reducing the exit dose to surrounding normal tissues. This narrative review summarises and evaluates the clinical, dosimetric and radiobiological evidence for PBT in localised and locally advanced prostate cancer (PCa), focusing on treatment-related toxicity, oncological outcomes and emerging research directions. Comparative dosimetric studies consistently demonstrate reductions in low-intermediate dose exposure to the bladder and rectum with protons, whereas prospective and large retrospective cohorts report low rates of severe (≥ G3) genitourinary (GU) and gastrointestinal (GI) toxicity, alongside preserved long-term patient-reported quality of life. Meta-analyses reported modest reductions in acute GI events, whilst reporting similar 5-year biochemical control in pooled, heterogeneous series; however, observational and claims-based analyses often fail to demonstrate clear clinical advantages compared with modern intensity-modulated radiation therapy/volumetric modulated arc therapy (IMRT/VMAT). Key radiobiological uncertainties, notably the variable relative biological effectiveness and linear energy transfer (LET) heterogeneity near distal dose fall-off regions, complicate the analysis of toxicity patterns and highlight the need for comprehensive reporting. Limitations of the existing literature include the prevalence of non-randomised designs, heterogeneity in fractionation schedules, inconsistent endpoint definitions and limited use of standardised patient-reported outcomes. The preliminary results of the PARTIQoL randomised clinical trial did not demonstrate significant differences in quality-of-life outcomes between PBT and IMRT/VMAT. Ongoing randomised phase III trials (e.g., Prostate Advanced Radiation Technologies Investigating Quality of Life, Proton Therapy for Postoperative Prostate Cancer Trial and PROton PROstate Trial 1) and advances in adaptive planning, AI-assisted workflows and FLASH (ultra-high dose-rate radiotherapy) dose-rate research are expected to further refine patient selection and treatment delivery. Currently, the routine use of PBT for all patients with localised PCa remains under evaluation; careful patient selection and robust randomised evidence are essential to justify broad clinical implementation.