PRO-BOOST-LC: Whole-Gland Boost Strategies Versus SBRT Monotherapy in PSMA-Staged Localized and Locally Advanced Prostate Cancer

Официальное название

PRO-BOOST-LC: A Prospective, Multi-arm Phase II/III Clinical Trial Evaluating the Efficacy and Safety of Whole-Gland Boost Using HDR Brachytherapy, LDR Brachytherapy, or Single-Fraction SBRT Following an Ultrahypofractionated EBRT (VMAT) Backbone (5 Gy x 5 Fractions) Compared to Standard SBRT Monotherapy in Patients With Localized and Locally Advanced Prostate Cancer Staged With PSMA PET/CT

Обзор

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.

Подробное описание

The PRO-BOOST-LC study is a prospective, multicenter, randomized phase II/III clinical trial designed to evaluate whether biologically intensified whole-gland prostate dose escalation improves clinically meaningful oncologic outcomes compared with contemporary stereotactic body radiotherapy (SBRT) monotherapy in patients with localized or locally advanced prostate cancer staged as cN0/cM0 on mandatory baseline prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT).

Scientific Background and Rationale Radiobiological and clinical evidence supports the concept that prostate cancer is sensitive to hypofractionation and dose escalation. Multiple randomized and prospective studies have shown that higher biologically effective radiation doses delivered to the prostate can improve biochemical control and delay disease progression. Modern dose-escalation techniques, including high-dose-rate (HDR) brachytherapy boost, low-dose-rate (LDR) brachytherapy boost, and stereotactic boost strategies, allow intraprostatic dose intensification while limiting dose to surrounding organs at risk.

Brachytherapy boost strategies enable delivery of very high biologically effective doses to the prostate. HDR boost offers optimized dose distribution and rapid dose fall-off, whereas LDR brachytherapy provides continuous low-dose radiation exposure over time through permanent seed implantation. SBRT boost is a non-invasive alternative capable of delivering a highly conformal ablative dose in a single fraction.

Although these approaches are used in clinical practice and have individually demonstrated favorable oncologic outcomes, direct prospective randomized comparison within a uniform treatment framework remains limited. In addition, many prior dose-escalation studies were conducted before the widespread use of PSMA PET/CT, which may have resulted in inclusion of patients with occult nodal or distant metastatic disease. PRO-BOOST-LC is designed to evaluate prostate dose-escalation strategies in a contemporary population staged with mandatory PSMA PET/CT.

Study Hypothesis The central hypothesis is that assignment to a whole-gland ablative boost strategy following a standardized ultrahypofractionated external beam radiotherapy backbone will improve failure-free survival compared with SBRT monotherapy, without an unacceptable increase in clinically significant toxicity or deterioration in patient-reported quality of life.

Overall Study Design PRO-BOOST-LC is a prospective, multicenter, randomized, controlled, multi-arm, multi-stage phase II/III trial with a seamless internal safety and feasibility stage.

Eligible patients are randomized using a centralized capability-based allocation procedure. The patient-level randomization set is determined before allocation according to center credentialing and technical suitability for the individual patient. The protocol-defined treatment strategies are:

SBRT monotherapy as the control strategy. Ultrahypofractionated external beam radiotherapy followed by HDR brachytherapy boost.

Ultrahypofractionated external beam radiotherapy followed by LDR brachytherapy boost.

Ultrahypofractionated external beam radiotherapy followed by single-fraction SBRT boost.

The primary comparison is pooled whole-gland boost strategy versus SBRT monotherapy. Comparisons among individual boost modalities are exploratory.

Seamless Phase II/III Structure The trial includes an internal phase II safety and feasibility component. During this stage, treatment delivery compliance, acute toxicity, technical feasibility, and major radiotherapy protocol deviations are prospectively monitored. Predefined safety and feasibility thresholds are reviewed by the Data Safety Monitoring Board. An experimental treatment arm may be continued, modified, temporarily suspended, or discontinued based on safety, feasibility, or protocol-compliance findings. Arms meeting predefined criteria proceed into the confirmatory phase III stage without interruption of accrual.

Treatment Principles All treatments are delivered with curative intent using contemporary image-guided radiotherapy techniques. Multiparametric MRI-based planning is mandatory for all patients. Baseline PSMA PET/CT is mandatory for staging confirmation of node-negative and non-metastatic disease.

The ultrahypofractionated external beam radiotherapy backbone consists of five high-dose fractions delivered using intensity-modulated radiotherapy or volumetric modulated arc therapy with daily image guidance. This backbone serves as a standardized platform across experimental boost arms.

Whole-gland boost delivery differs by modality. HDR brachytherapy boost consists of a single high-dose fraction delivered through temporary transperineal catheter implantation under image guidance. LDR brachytherapy boost consists of permanent seed implantation. SBRT boost consists of a single ablative stereotactic fraction delivered with dedicated immobilization and high-precision image guidance. The control arm consists of SBRT monotherapy delivered in five fractions.

Androgen deprivation therapy is administered according to contemporary guideline-based risk stratification. Protocol-planned androgen receptor pathway inhibitors may be used in selected very high-risk or locally advanced patients when declared before randomization and handled according to the protocol and statistical analysis plan.

Imaging Integration Baseline staging requires PSMA PET/CT and multiparametric MRI within protocol-defined timeframes before randomization. Imaging is used to confirm cN0/cM0 status and to support radiotherapy planning.

Follow-up imaging is performed when clinically indicated. PSMA PET/CT is prioritized for evaluation of suspected recurrence or distant metastatic progression. Local recurrence requires radiologic progression confirmation and is not defined solely by PSA kinetics or isolated biopsy findings.

Endpoint Strategy

The primary endpoint is failure-free survival (FFS). Failure-free survival includes biochemical recurrence, radiologically documented local, regional, or distant progression, progression-driven salvage treatment, or death from any cause.

Metastasis-free survival (MFS) is a key hierarchical confirmatory endpoint and is tested only if the primary failure-free survival comparison is statistically significant. Secondary and exploratory analyses evaluate local and regional control, treatment-related toxicity, patient-reported quality of life, PSA kinetics, time to salvage therapy, cancer-specific survival, and overall survival.

Patient-Reported Outcomes Patient-reported outcomes are a core component of the study. Validated questionnaires are used to assess urinary, bowel, sexual, hormonal, and general health-related quality of life domains at baseline and during follow-up. These assessments are intended to determine whether improved oncologic control can be achieved while preserving long-term function and quality of life.

Toxicity Monitoring Adverse events are graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0. Acute toxicity is defined as adverse events occurring within 90 days after completion of protocol radiotherapy. Late toxicity includes adverse events occurring beyond 90 days.

Genitourinary, gastrointestinal, sexual, systemic therapy-related, and procedure-related adverse events are recorded prospectively. For clinically significant events, the maximum grade, attribution, onset date, resolution or improvement date, ongoing status, and relationship to treatment components are documented. Safety data are reviewed periodically by the Data Safety Monitoring Board.

Statistical Considerations The study is powered for the primary comparison of pooled whole-gland boost strategies versus SBRT monotherapy for failure-free survival. Time-to-event analyses will use prespecified statistical methods including Kaplan-Meier estimation and Cox proportional hazards modeling. The hierarchical endpoint strategy is designed to preserve the overall type I error rate.

Clinical Significance By integrating PSMA PET/CT staging, contemporary ultrahypofractionated radiotherapy, brachytherapy boost, SBRT boost, standardized radiotherapy quality assurance, toxicity monitoring, and patient-reported outcomes, PRO-BOOST-LC aims to generate high-quality evidence on how best to use prostate dose escalation in localized and locally advanced prostate cancer.

The study is intended to clarify which modern radiotherapy dose-escalation strategy provides the most favorable balance between durable cancer control, treatment-related toxicity, and long-term preservation of urinary, bowel, sexual, and overall quality of life.

Вмешательства

• Лучевая терапия Stereotactic Body Radiotherapy (SBRT) Monotherapy
  Stereotactic 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.
• Лучевая терапия External Beam Radiotherapy (EBRT) Backbone
  Ultrahypofractionated 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.
• Лучевая терапия High-Dose-Rate Brachytherapy Boost
  Intraprostatic 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.
• Лучевая терапия Low-Dose-Rate Brachytherapy Boost
  Intraprostatic 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.
• Лучевая терапия Stereotactic Body Radiotherapy (SBRT) Boost
  Intraprostatic 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.
• Препарат Androgen Deprivation Therapy (ADT)
  Androgen 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.

Первичные конечные точки

• Failure-Free Survival (FFS) [Срок оценки: From randomization up to 10 years]
• Metastasis-Free Survival (MFS) hierarchical [Срок оценки: From randomization up to 10 years]

Вторичные конечные точки (12)

• Intraprostatic Local Control (iLC) [Срок оценки: From randomization up to 10 years]
• Regional Pelvic Nodal Control (rNC) [Срок оценки: From randomization up to 10 years]
• Acute Genitourinary and Gastrointestinal Toxicity [Срок оценки: From start of radiotherapy to 90 days after completion]
• Late Genitourinary and Gastrointestinal Toxicity [Срок оценки: More than 90 days after completion of radiotherapy up to 10 years]
• Expanded Prostate Cancer Index Composite-26 (EPIC-26) [Срок оценки: From baseline up to 10 years]
• EORTC QLQ-C30 Global Health Status Score [Срок оценки: From baseline up to 10 years]
• PSA Nadir [Срок оценки: From randomization up to 10 years]
• Time to Initiation of Salvage Therapy [Срок оценки: From randomization up to 10 years]
• Cancer-Specific Survival (CSS) [Срок оценки: From randomization up to 10 years]
• Overall Survival (OS) [Срок оценки: From randomization up to 10 years]
• International Prostate Symptom Score (IPSS) [Срок оценки: Time Frame: From baseline up to 10 years]
• EORTC QLQ-PR25 Prostate Cancer Module [Срок оценки: From baseline up to 10 years]

Критерии участия

Критерии включения

• 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.
• NCCN favourbale or unfavourbale intermediate-, high-, or very high-risk disease.
• Candidate for definitive radiotherapy with curative intent.
• ECOG performance status 0-2.
• Baseline PSA available prior to randomization.
• Ability to undergo external beam radiotherapy and brachytherapy or SBRT according to protocol.
• Planned androgen deprivation therapy (ADT) permitted according to protocol-defined risk group.
• Ability to understand and willingness to sign written informed consent.

Критерии исключения

• 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.
• History of other active malignancy requiring systemic treatment (except adequately treated non-melanoma skin cancer).
• Contraindications to radiotherapy or anesthesia required for brachytherapy procedures.
• Severe uncontrolled comorbidities that would preclude protocol treatment.
• Inability to comply with study procedures or follow-up schedule.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Польша · 1 центр

• Affidea Nu-Med, Center of Oncological Diagnostics and Therapy — Zamość

Публикации

• National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version current at study initiation. Available at: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
• Sidibe I, Beaudry MM, Carignan D, Froment MA, Foster W, Bachand F, Vigneault E, Magnan S, Aubin S, Morrier J, Poulin E, Lacroix F, Lavallee MC, Beaulieu L, Martin AG. Ultra-hypofractionated radiotherapy combined with HDR brachytherapy: An optimized treatment. Radiother Oncol. 2026 Jan;214:111199. doi: 10.1016/j.radonc.2025.111199. Epub 2025 Oct 9. PMID 41067642
• Mendez LC, Crook J, Martell K, Schaly B, Hoover DA, Dhar A, Velker V, Ahmad B, Lock M, Halperin R, Warner A, Bauman GS, D'Souza DP. Is Ultrahypofractionated Whole Pelvis Radiation Therapy (WPRT) as Well Tolerated as Conventionally Fractionated WPRT in Patients With Prostate Cancer? Early Results From the HOPE Trial. Int J Radiat Oncol Biol Phys. 2024 Jul 1;119(3):803-812. doi: 10.1016/j.ijrobp.202 PMID 38072323
• Beaudry MM, Carignan D, Foster W, Lavallee MC, Aubin S, Lacroix F, Poulin E, Lachance B, Despres P, Beaulieu L, Vigneault E, Martin AG. Comparison of four-year toxicities and local control of ultra-hypofractionated vs moderate-hypofractionated image guided prostate radiation with HDR brachytherapy boost: A phase I-II single institution trial. Clin Transl Radiat Oncol. 2023 Feb 8;40:100593. doi: 10 PMID 36875870
• Gorovets D, Hopkins M, Kollmeier M, Moore A, Goel A, Shasha D, Brennan V, McBride S, Cohen G, Damato AL, Zelefsky MJ. Early outcomes of high-dose-rate brachytherapy combined with ultra-hypofractionated radiation in higher-risk prostate cancer. Brachytherapy. 2021 Nov-Dec;20(6):1099-1106. doi: 10.1016/j.brachy.2021.08.006. Epub 2021 Sep 26. PMID 34588146
• Kollmeier MA, Gorovets D, Flynn J, McBride S, Brennan V, Beaudry J, Cohen G, Damato A, Zhang Z, Zelefsky MJ. Combined brachytherapy and ultra-hypofractionated radiotherapy for intermediate-risk prostate cancer: Comparison of toxicity outcomes using a high-dose-rate (HDR) versus low-dose-rate (LDR) brachytherapy boost. Brachytherapy. 2022 Sep-Oct;21(5):599-604. doi: 10.1016/j.brachy.2022.04.006. Ep PMID 35725549
• Martin J, Keall P, Siva S, Greer P, Christie D, Moore K, Dowling J, Pryor D, Chong P, McLeod N, Raman A, Lynam J, Smart J, Oldmeadow C, Tang CI, Murphy DG, Millar J, Tai KH, Holloway L, Reeves P, Hayden A, Lim T, Holt T, Sidhom M. TROG 18.01 phase III randomised clinical trial of the Novel Integration of New prostate radiation schedules with adJuvant Androgen deprivation: NINJA study protocol. BMJ PMID 31434782
• Wang SC, Ting WC, Chang YC, Yang CC, Lin LC, Ho HW, Chu SS, Lin YW. Whole Pelvic Radiotherapy With Stereotactic Body Radiotherapy Boost vs. Conventionally Fractionated Radiotherapy for Patients With High or Very High-Risk Prostate Cancer. Front Oncol. 2020 May 29;10:814. doi: 10.3389/fonc.2020.00814. eCollection 2020. PMID 32547949

Идентификаторы

NCT: NCT07426055 · PRO-BOOST-LC

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗