## 1 Introduction  
Prostate cancer (PCa) represents the second most common malignancy in men worldwide, with the highest prevalence in developed countries [1]. Patients affected by clinically localized PCa with an intermediate- and high-risk disease, according to National Comprehensive Cancer Network (NCCN) guidelines, can be considered eligible for several local treatment modalities, including external-beam radiotherapy (EBRT) or brachytherapy \(\pm\) androgen deprivation therapy (ADT) and surgery [2]. Exploiting the radiobiological rationale of the low PCa a/b ratio, resulting in enhanced sensitivity of PCa to higher doses per fraction [3], several trials and metanalysis reported comparable rates of biochemical control, progression-free survival (PPS), overall survival (OS), and toxicity of moderate hypoffractionated radiation therapy (RT) respect to conventional fractionation [4; 5; 6; 7; 8; 9; 10; 11; 12; 13]. Given these premises, two non-inferiority Randomized Controlled trials (RCTs) explored the role of ultra-hypoffractionated RT (UH-RT) (defined as more or equal to 6.25 Gy/fraction) compared to conventional RT. The HYPO-RT-PC trial confirmed, with 5 years of follow-up, the same profiles of failure-free survival and genitourinary (GU)/gastrointestinal (GI) toxicity for both UH-RT and standard fractionation [14]. Recently published 12 months of GU and GI toxicity profile results from the PACE-B trial corroborate the non-inferiority of UH-RT with respect to conventional and moderate hypoffractionated RT [15]. Considering these findings, UH-RT represents a well-established treatment option for localized PCa in high-expertise centers, as suggested by the NCCN guidelines in 2023 [2]. Because PCa local recurrences after RT often originates from the primary tumor site [16; 17], a focal boost to the dominant intraprostatic lesion (DIL), identified through multi-parametric magnetic resonance imaging (mpMRI), has been proposed in order to increase biochemical disease-free survival (bDFS) in intermediate-to-high risk PCa patients. This hypothesis has been confirmed by the results of the FLAME trial [18], which showed that, in conventional fractionation schemes, a focal boost on the DIL improves oncological outcomes without any relevant additional toxicity. Furthermore, as seen from the initial results of the SPARC Trial [19], dose-escalation to the DIL could increase the probability of an undetectable level of prostate-specific antigen (PSA) (<0.1 ng/mL) at least in the first 18 months after treatment in patients receiving ADT. In our center at the European Institute of Oncology (IEO) IRCCS, Milan, Italy, a high level of expertise has been achieved in the setting of PCa UH-RT, counting more than one thousand patients treated with very low treatment-related toxicities reported [20]. In addition, data for patients receiving UH-RT and simultaneous integrated boost (SIB) on the DIL at IEO has already been published, demonstrating the safety and effectiveness of this treatment [20; 21; 22]. Several SBRT techniques for UH-RT administration have been explored in order to increase patients' compliance and safety. Interestingly, the recently published update at 2 years of the PACE-B trial [23] showed that CyberKnife (CK)-SBRT has significantly reduced Common Terminology Criteria for Adverse Events (CTCAE) GU toxicity than SBRT with conventional linacs. CK-SBRT radiosurgery has been successfully used to treat the whole prostate up to 40 Gy, with excellent rates of bDFS while maintaining low rectal and genitourinary toxicities [24; 25; 26; 27; 28; 29]. Given the above, CK-SBRT could represent the \"winning horse\" in the race for the best ablative treatment for localized PCa, considering both patient compliance and treatment effectiveness. Dose escalation to the DIL with CK LINAC starting from these promising toxicity results is expected to further improve oncological outcomes even in UH schedules.