Salvage Ultrahypofractionated Postoperative External Radiotherapy For Biochemical Recurrence

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