Recently, the Radiation Oncology Department at Fondazione IRCCS San Gerardo dei Tintori has been renovated and has been equipped with cutting edge technologies to treat prostate cancer. Specifically, the now available technology can track organ motion in real time, thus allowing improved precision in radiation delivery, with increased protection of the surrounding organs at risk. These facilities have already enabled the kickoff of two prospective observational trials, the ABRUPT and the POPART, which are currently ongoing in the treatment of intact prostate and the biochemical recurrence, respectively. Taken together, these observations provide the basis for the prospective clinical study herein proposed. Patients enrolled in the study will undergo salvage single stereotactic RT to the prostate bed by means of image guided volumetric intensity-modulated arc technique (IGRT-VMAT) and state-of-the-art treatment-planning and quality assurance procedures, with emphasis on normal tissue sparing and and pinpoint delivery accuracy via the use of devices that ensure stability and beam location reproducibility

Patients enrolled in this observational prospective trial undergo image-guided (IGRT) with volumetric-modulated arc radiotherapy (VMAT) using the same equipment, techniques, and treatment-planning procedures as per clinical practice. Eligible patients are those with persistently detectable PSA post-operatively or those developing biochemical recurrence after prostatectomy with initially undetectable PSA, without evidence of macroscopic local relapse and/or regional and distant metastases at restaging.

This trial aims to assess the toxicity profile of salvage single-fraction stereotactic radiotherapy (RT) to the prostate bed delivered using an IGRT-VMAT technique. The study is conducted using a two-stage design consisting of an initial dose-finding phase followed by a dose-expansion phase.

Stage 1 - Dose escalation and interim safety analysis. In the first stage, a rolling six dose-escalation design is used to evaluate the safety of 15 Gy, 16 Gy, and 17 Gy, each delivered in a single fraction. Patients are enrolled in cohorts of 3 to 6 patients per dose level. In accordance with the rolling six design, no more than six patients may be concurrently enrolled at a given dose level and considered at risk for dose-limiting toxicity (DLT) during the 90-day evaluation period.

The objective of this stage is to identify the maximum tolerated dose (MTD), defined as the highest dose associated with ≤1 DLT among 6 evaluable patients, with DLT defined as any grade ≥3 toxicity occurring within 90 days from treatment.

An interim safety analysis is planned after approximately 18 patients (ideally 6 per dose level) have been treated and evaluated.

Stage 2 - Dose expansion. Following the interim analysis, the study proceeds with a dose-expansion phase, enrolling additional patients to reach a total sample size of 50 patients. If all three dose levels are deemed tolerable, they will all be carried forward into this expansion phase in a balanced manner.

The sample size of 50 patients was calculated to provide a statistical power of 91.1% for the GU endpoint and 92.9% for the GI endpoint, with a two-sided alpha level of 0.05. The overall statistical power to reject the null hypothesis across both endpoints is 84.6%.

The null hypothesis (H₀) is based on acute toxicity rates reported in the NRG-GU003 phase III randomized trial for the hypofractionated post-prostatectomy radiotherapy (HYPORT) arm, which reported ≥G2 toxicity rates of 31.0% for GU and 22.5% for GI toxicity. The alternative hypothesis (H₁) is derived from prior studies of stereotactic body radiotherapy (SBRT) in the salvage setting, including the POPART and SCIMITAR trials, assuming toxicity rates of 12% for GU and 6% for GI toxicity.

Primary and secondary endpoints will be evaluated across the entire expanded cohort.

Inclusion Criteria:

• Subjects of male sex ≥ 18 years of age.

• Subjects have freely signed the pertinent informed consent before the beginning of the study

  • Adenocarcinoma of the prostate treated with radical prostatectomy (any type of radical prostatectomy is permitted including retropubic, perineal, laparoscopic or robotically assisted; there is no time limit for the date of radical prostatectomy)
  • Detectable post-prostatectomy PSA of ≥ 0.1 - < 2.0 ng/mL either (1) persistently detectable post-operatively or (2) developing biochemical recurrence after prostatectomy (initially undetectable)
  • No evidence of N1 and/or M1 disease assessed by PSMA PET-CT within 90 days prior to registration
  • Negative Magnetic Resonance Imaging (MRI) of the pelvis in case of equivocal evidence of local relapse on PSMA PET-CT
  • Androgen deprivation therapy (ADT) allowed as per physician's discretion
  • ECOG performance status of 0-1
  • Ability to complete the questionnaires

Exclusion Criteria:

• N1 and or M1 patients
• Macroscopic local relapse at pelvic MRI.
• Prior radiation of any kind to the prostate gland or pelvis
• Prior brachytherapy
• History of inflammatory colitis or other active severe comorbidities
• Patients who are on immunosuppressant medication

Patients with biochemical relapse following radical prostatectomy