PRO-BOOST-LC is a prospective, multicenter, randomized phase II/III clinical trial for men with localized or locally advanced prostate cancer without lymph node or distant metastases, confirmed using prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT).
Radiotherapy is an established curative treatment option for prostate cancer. Several modern radiotherapy strategies can safely deliver high radiation doses to the prostate while limiting dose to surrounding organs. These include stereotactic body radiotherapy (SBRT), high-dose-rate (HDR) brachytherapy, low-dose-rate (LDR) brachytherapy, and combinations of external beam radiotherapy with a prostate boost. However, the optimal dose-escalation strategy for balancing cancer control, treatment-related toxicity, and long-term quality of life remains uncertain in patients staged with modern PSMA PET imaging.
The aim of PRO-BOOST-LC is to compare definitive SBRT monotherapy with whole-gland prostate boost strategies delivered after a short course of external beam radiotherapy. Participants will be randomly assigned, according to center capability and patient-level technical suitability, to one of the protocol-defined treatment options. The control group receives SBRT monotherapy. The experimental groups receive external beam radiotherapy followed by one of three whole-gland boost techniques: HDR brachytherapy, LDR brachytherapy, or single-fraction SBRT boost.
The primary objective is to determine whether assignment to a prostate boost strategy improves failure-free survival compared with SBRT monotherapy. Failure-free survival includes biochemical recurrence, local or regional progression, distant metastases, progression-driven salvage treatment, or death from any cause. Key secondary outcomes include metastasis-free survival, overall survival, physician-reported treatment-related toxicity, and patient-reported quality of life, including urinary, bowel, and sexual function.
Participants will undergo baseline clinical evaluation, PSA testing, prostate MRI, PSMA PET/CT, and quality-of-life assessments. After treatment, participants will be followed regularly with clinical assessments, PSA testing, toxicity evaluation, patient questionnaires, and imaging when clinically indicated. The study is designed to provide long-term evidence on how best to use modern radiotherapy dose escalation for patients with PSMA-staged localized or locally advanced prostate cancer.
Male patients aged ≥18 years.
Histologically confirmed adenocarcinoma of the prostate.
Localized or locally advanced prostate cancer classified as cT1-4, cN0, cM0.
Negative pelvic nodal and distant metastatic disease on baseline PSMA PET.
Evidence of pelvic nodal (cN1) or distant metastatic disease (cM1) on baseline imaging.
Prior definitive local treatment for prostate cancer, including prostatectomy, brachytherapy, or definitive external beam radiotherapy.
Prior pelvic radiotherapy for any malignancy.
Prior systemic therapy for prostate cancer other than protocol-allowed neoadjuvant ADT.
Parallel
Stereotactic Body Radiotherapy (SBRT) Monotherapy
RadiationStereotactic body radiotherapy (SBRT) delivered to the prostate as definitive monotherapy using an ultrahypofractionated schedule. Treatment is planned with highly conformal techniques and daily image guidance according to protocol-defined target coverage objectives and organ-at-risk constraints. This intervention represents a non-invasive definitive radiotherapy strategy without additional intraprostatic boost.
External Beam Radiotherapy (EBRT) Backbone
RadiationUltrahypofractionated external beam radiotherapy delivered to the prostate using volumetric modulated arc therapy (VMAT) or equivalent intensity-modulated techniques. This intervention serves as a standardized treatment backbone prior to intraprostatic dose escalation and is delivered according to protocol-defined target volumes, margins, and dose constraints.
High-Dose-Rate Brachytherapy Boost
RadiationIntraprostatic high-dose-rate brachytherapy delivered as a single-fraction boost following completion of external beam radiotherapy. The procedure involves transperineal catheter placement with afterloading and is performed according to protocol-defined technical, dosimetric, and safety criteria to achieve focal dose escalation while respecting organ-at-risk constraints.
Low-Dose-Rate Brachytherapy Boost
RadiationIntraprostatic low-dose-rate permanent seed brachytherapy delivered as a boost following completion of external beam radiotherapy. Radioactive seeds are implanted transperineally according to protocol-defined planning and implantation guidelines to provide continuous low-dose-rate irradiation while maintaining predefined target coverage and organ-at-risk constraints.
Stereotactic Body Radiotherapy (SBRT) Boost
RadiationIntraprostatic stereotactic body radiotherapy delivered as a single-fraction boost following completion of external beam radiotherapy. This intervention provides non-invasive dose escalation using highly conformal planning and image guidance according to protocol-defined coverage objectives and organ-at-risk constraints.
Androgen Deprivation Therapy (ADT)
DrugAndrogen deprivation therapy (ADT) administered according to protocol-defined risk group and standard clinical practice. ADT may include luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, with or without short-course antiandrogens, delivered as neoadjuvant, concurrent, and/or adjuvant therapy in accordance with contemporary clinical guidelines. ADT is not randomized and is applied uniformly within each risk group across all treatment arms.
Failure-Free Survival (FFS)
Failure-Free Survival (FFS) is defined as the time from randomization to the earliest occurrence of any of the following events: biochemical recurrence according to the Phoenix definition (PSA nadir + 2 ng/mL), confirmed local recurrence within the prostate, regional pelvic nodal progression, distant metastatic disease, initiation of salvage therapy, or death from any cause. Local recurrence is defined by radiologic progression on multiparametric MRI or PSMA PET/CT confirmed on repeat imaging ≥6 months later, or biopsy-proven viable adenocarcinoma in the presence of radiologic progression. Regional nodal progression includes pelvic nodal relapse (obturator, internal iliac, external iliac, presacral nodes). Patients without an event will be censored at the date of last disease assessment.
Metastasis-Free Survival (MFS) hierarchical
Metastasis-Free Survival (MFS) is defined as the time from randomization to the occurrence of distant metastatic disease or death from any cause, whichever occurs first. Distant metastases are defined as non-pelvic nodal disease (including common iliac nodes) or visceral or bone metastases detected preferentially by PSMA PET/CT and confirmed according to protocol-defined imaging criteria. MFS is analyzed as a key confirmatory endpoint within a hierarchical testing strategy and will be formally tested only if the primary comparison for Failure-Free Survival is statistically significant. MFS is assessed in accordance with EAU/ASTRO/STRATOS consensus definitions and is recognized as a validated surrogate for overall survival in localized and locally advanced prostate cancer.
Intraprostatic Local Control (iLC)
Intraprostatic local control is defined as the time from randomization to confirmed local recurrence within the prostate gland. Local recurrence is determined by radiologic progression on multiparametric MRI or PSMA PET/CT confirmed on repeat imaging performed at least 6 months later, or by biopsy-proven viable adenocarcinoma in the presence of radiologic progression. This endpoint evaluates the effectiveness of intraprostatic dose escalation strategies.
Regional Pelvic Nodal Control (rNC)
Regional pelvic nodal control is defined as the time from randomization to pelvic nodal progression detected on imaging. Pelvic nodal progression includes involvement of obturator, internal iliac, external iliac, or presacral lymph nodes. Progression in common iliac lymph nodes is classified as distant metastatic disease and is not considered a regional nodal event. Nodal progression must be confirmed on imaging according to protocol-defined criteria.
Acute Genitourinary and Gastrointestinal Toxicity
Acute genitourinary (GU) and gastrointestinal (GI) toxicity is defined as treatment-related adverse events occurring within 90 days from completion of radiotherapy. Toxicity will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 6.0. The incidence and severity of acute adverse events will be systematically recorded at scheduled follow-up visits.
Late Genitourinary and Gastrointestinal Toxicity
Late genitourinary (GU) and gastrointestinal (GI) toxicity is defined as treatment-related adverse events occurring more than 90 days after completion of radiotherapy. Toxicity will be graded using CTCAE version 6.0. This endpoint assesses long-term safety and tolerability of dose-escalated and boost-based radiotherapy strategies.
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