PRO-BOOST-N: Prostate-First Versus Combined Prostate and Nodal Dose Escalation in PSMA PET-Staged Node-Positive Prostate Cancer

Summary

Patients with prostate cancer and pelvic lymph node involvement (cN1M0) identified on PSMA PET imaging represent a biologically aggressive yet potentially curable disease population. Contemporary management relies on multimodality treatment combining definitive radiotherapy to the prostate and pelvic lymph nodes with long-term androgen deprivation therapy (ADT), often intensified with androgen receptor pathway inhibitors. Despite these advances, a substantial proportion of patients still develop distant metastatic disease, highlighting the need to optimize local-regional treatment strategies in the era of molecular imaging. The introduction of PSMA PET has fundamentally altered staging accuracy in prostate cancer, enabling earlier and more precise detection of pelvic nodal disease. However, most existing evidence guiding radiotherapy dose prescription in node-positive prostate cancer originates from the pre-PSMA era. As a result, it remains unclear how best to integrate prostate-directed and nodal-directed dose escalation strategies when disease extent is defined by modern molecular imaging. In particular, it is unknown whether long-term disease control is primarily driven by durable intraprostatic tumor eradication, by aggressive treatment of involved lymph nodes, or by a combination of both. PRO-BOOST-N is a prospective, multicenter, randomized phase II/III clinical trial designed to address this critical evidence gap. The trial evaluates prostate-first versus combined prostate and nodal dose escalation strategies in patients with PSMA PET-staged node-positive (cN1M0) prostate cancer treated within a standardized ultrahypofractionated whole-pelvis radiotherapy framework. All enrolled patients indicated for definitive treatment undergo mandatory baseline PSMA PET/CT to confirm pelvic lymph node involvement and exclude distant metastatic disease. All patients receive a uniform radiotherapy backbone consisting of ultrahypofractionated whole-pelvis radiotherapy delivered in five fractions, combined with long-term ADT. Use of androgen receptor pathway inhibitors is permitted and encouraged according to contemporary clinical practice and local availability, ensuring the relevance of the trial to real-world treatment settings. Using a 2×2 factorial randomized design, PRO-BOOST-N evaluates two independent treatment factors. The primary randomized comparison assesses whether ablative prostate dose escalation improves oncologic outcomes compared with contemporary SBRT-based definitive prostate radiotherapy without additional boost. Prostate dose escalation may be delivered using one of three protocol-defined modalities-high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT-according to institutional expertise. This comparison directly tests the hypothesis that durable intraprostatic disease control is the dominant determinant of long-term systemic disease suppression in node-positive prostate cancer. The key secondary, hierarchically tested comparison evaluates the role of nodal dose escalation by comparing two predefined dose levels delivered to PSMA PET-positive pelvic lymph nodes. These dose levels reflect intermediate versus higher nodal boost strategies based on biologically effective dose concepts specific to prostate cancer radiobiology. To ensure patient safety and protocol feasibility, organ-at-risk-driven nodal dose de-escalation is permitted within the higher-dose arm, without altering randomization assignment. The primary endpoint of the trial is metastasis-free survival. Secondary endpoints include overall survival, radiographic progression-free survival assessed primarily using PSMA PET imaging, intraprostatic and regional nodal control, time to castration-resistant prostate cancer, time to next systemic therapy, treatment-related toxicity graded according to CTCAE version 5.0, and patient-reported outcomes assessing urinary, bowel, sexual, and global quality of life. By prospectively and hierarchically evaluating prostate and nodal dose escalation strategies within a modern PSMA PET-guided and ultrahypofractionated radiotherapy platform, PRO-BOOST-N aims to define the optimal radiotherapy intensification approach for patients with node-positive prostate cancer. The results of this study are expected to directly inform clinical practice, guideline development, and future treatment individualization in the PSMA PET era.

Eligibility

Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the prostate.
* Prostate cancer with clinically positive pelvic lymph nodes (cN1) without evidence of distant metastatic disease.
* Pelvic lymph node involvement limited to regional pelvic lymph nodes (obturator, internal iliac, external iliac, presacral), as assessed by conventional imaging and/or PSMA PET/CT.
* No evidence of distant metastatic disease (M0), including absence of non-regional nodal, bone, or visceral metastases.
* Candidate for definitive radiotherapy to the prostate and elective pelvic lymph nodes.
* Planned treatment with androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
* Adequate organ function allowing delivery of protocol-defined radiotherapy and systemic therapy.
* Age ≥18 years.
* Ability to understand and willingness to sign a written informed consent.

Exclusion Criteria:

* Evidence of distant metastatic disease (M1), including non-regional lymph node, bone, or visceral metastases.
* Prior definitive local therapy for prostate cancer, including radical prostatectomy, whole-gland radiotherapy, or brachytherapy.
* Prior pelvic radiotherapy for any indication that would overlap planned treatment fields.
* Prior systemic therapy for prostate cancer other than protocol-allowed neoadjuvant androgen deprivation therapy.
* History of castration-resistant prostate cancer.
* Concurrent malignancy requiring active treatment, except non-melanoma skin cancer or other malignancies with negligible risk of interference with study outcomes.
* Severe uncontrolled comorbidities that would preclude safe delivery of radiotherapy or systemic therapy.
* Any condition that, in the opinion of the investigator, would interfere with patient safety or compliance with the study protocol.

Conditions6

Interventions2

Browse More Trials