Active surveillance is a common approach for men with low-risk or favorable intermediate-risk prostate cancer, aimed at avoiding or delaying treatment while closely monitoring the disease. Multiparametric MRI (mpMRI) is widely used to guide diagnosis and follow-up, but it can miss clinically significant prostate cancer and may be limited by access, cost, and variability in interpretation.

Micro-ultrasound is a high-resolution ultrasound technique that may improve real-time detection of suspicious prostate lesions using a standardized scoring system (PRI-MUS). The purpose of this study is to evaluate the diagnostic performance of micro-ultrasound for detecting clinically significant prostate cancer in men with negative or stable mpMRI findings, either at initial diagnosis or during active surveillance follow-up.

Participants will undergo micro-ultrasound assessment of the prostate. Areas considered suspicious on micro-ultrasound may be targeted for biopsy, followed by systematic prostate sampling. Biopsy results will be used as the reference standard to determine whether clinically significant prostate cancer is present.

The study will assess measures such as sensitivity, specificity, and predictive values of micro-ultrasound, as well as procedure-related complications.

Study Rationale This is a prospective, single-arm, two-stage phase II diagnostic study designed to evaluate micro-ultrasound (mUS) as a supplemental imaging modality for the detection of clinically significant prostate cancer (csPCa) in men undergoing active surveillance (AS), or newly diagnosed men eligible for AS, with negative (PI-RADS ≤2) or stable multiparametric MRI (mpMRI) findings.

Active surveillance is widely adopted for men with low-risk and selected favorable intermediate-risk prostate cancer (PCa), aiming to defer or avoid definitive treatment while maintaining oncologic safety through structured monitoring.

mpMRI has become central to risk stratification, patient selection, and follow-up. However, clinically significant disease can be missed despite negative or stable mpMRI findings due to false-negative scans, inter-reader variability, limited access, and cost constraints. These limitations may lead to underdetection of csPCa and potential delays in appropriate treatment. In contrast to mpMRI, mUS can be performed at the point of care during the urology visit, enabling real-time lesion assessment and immediate targeted biopsy without the need to wait for radiology reporting, which may help mitigate MRI-related access delays and workflow bottlenecks.

mUS is a high-frequency ultrasound technology (29 MHz) providing real-time, high-resolution imaging of the prostate, enabling lesion characterization using the Prostate Risk Identification using Micro-Ultrasound (PRI-MUS) scoring system. mUS may detect suspicious features not identified on mpMRI and may therefore improve detection of csPCa, particularly in men with negative or stable mpMRI who are still undergoing biopsy due to clinical triggers or surveillance protocols.

Study Objectives The primary objective of this study is to determine the diagnostic performance of mUS for detecting csPCa in this population, using histopathology as the reference standard.

Secondary objectives include:

• Evaluating positive and negative predictive values of mUS.
• Estimating the incremental detection of csPCa provided by mUS compared with mpMRI alone.
• Evaluating concordance between mpMRI and mUS lesion identification and risk classification.
• Describing biopsy-related adverse events and complications using standardized reporting and grading.

Study Design This is a prospective, single-arm, diagnostic accuracy study incorporating a two-stage phase II design (Simon two-stage design). The study will evaluate whether the detection rate and sensitivity of mUS for csPCa meets a pre-specified threshold that would justify broader implementation or future comparative studies.

The two-stage design allows for early termination for futility if interim results indicate that the diagnostic performance of mUS is insufficient. If the performance targets are met in Stage 1, the study proceeds to Stage 2 to complete the planned sample size and provide more precise estimates of diagnostic accuracy.

Study Population Participants are men aged 45 to 75 years with localized PCa enrolled in AS or newly diagnosed and eligible for AS, who have either negative mpMRI (PI-RADS ≤2) or stable mpMRI findings over time.

Eligibility criteria include features consistent with low-risk or favorable intermediate-risk disease, as determined by prior biopsy results, PSA values, and clinical staging.

Study Procedures All participants will undergo mUS assessment of the prostate according to a standardized imaging protocol. The prostate will be systematically examined, and lesions will be scored using the PRI-MUS risk stratification system. Lesions scored PRI-MUS ≥3 will be considered suspicious and will be targeted for biopsy under micro-ultrasound guidance. Following targeted sampling (when applicable), all participants will undergo systematic prostate biopsy (12-core sampling) during the same procedure session. Targeted and systematic biopsy cores will be analyzed by experienced genitourinary pathologists using standardized reporting. Histopathology will serve as the reference standard for determining the presence or absence of csPCa.

Definition of (csPCa) Clinically significant PCa is defined as Grade Group ≥2 (Gleason score ≥3+4) detected in any biopsy core (targeted or systematic). This definition is aligned with contemporary AS risk thresholds and is intended to capture disease that may warrant treatment escalation or intensified monitoring.

Outcomes

• Primary outcome measures include sensitivity and specificity of mUS for detecting csPCa (Grade Group ≥2). mUS "test positivity" will be defined based on PRI-MUS score thresholds (PRI-MUS ≥3) and/or the presence of a targetable lesion on mUS.
• Secondary outcome measures include positive predictive value (PPV), negative predictive value (NPV), and overall diagnostic accuracy. Incremental csPCa detection attributable to mUS will be assessed by describing csPCa detected in mUS-targeted cores and comparing detection patterns relative to mpMRI findings (negative vs stable findings) and other clinical parameters.

Agreement between mpMRI and mUS lesion identification will be assessed using appropriate concordance metrics (e.g., Cohen's kappa) when applicable.

-Safety outcomes will include biopsy-related adverse events, including infectious complications, urinary retention, bleeding events, pain, and other procedure-related outcomes. Adverse events will be collected prospectively and categorized according to standardized definitions, and clinically relevant complications will be graded using established severity classifications (e.g., Clavien-Dindo).

Statistical Considerations Diagnostic accuracy metrics (sensitivity, specificity, PPV, NPV) will be reported with confidence intervals. The study's two-stage phase II design provides an efficient approach to determining whether mUS demonstrates adequate diagnostic performance for csPCa detection in this clinically important subgroup of men with negative or stable mpMRI findings. Interim analysis will be performed after completion of Stage 1 enrollment and histopathology outcomes, with progression to Stage 2 contingent on meeting the predefined performance threshold.

Clinical Significance This study addresses an unmet need within the AS pathway: improving detection of csPCa in men with negative or stable mpMRI who remain at risk of harboring higher-grade disease. If mUS demonstrates high sensitivity and useful NPV, it may support improved risk stratification, reduce missed csPCa, and optimize biopsy decision-making. The findings may inform future diagnostic strategies and pathway refinement, including how mUS can be integrated with mpMRI in AS and early detection settings.

Inclusion Criteria:

• Male participants aged 45 to 75 years
• Localized prostate cancer on active surveillance or newly diagnosed and eligible for active surveillance
• Negative multiparametric MRI (PI-RADS ≤2) or stable mpMRI findings on surveillance
• Prior prostate biopsy showing Grade Group 1, or Grade Group 2 (Gleason 3+4) with ≤10% pattern 4
• PSA ≤15 ng/mL
• PSA density <0.15 ng/mL/cc
• Clinical stage ≤T2a
• Life expectancy >10 years
• Ability to provide written informed consent and comply with study procedures

Exclusion Criteria:

• Prior definitive treatment for prostate cancer (e.g., radical prostatectomy, radiotherapy)
• Prior prostate surgery that may affect biopsy or imaging interpretation
• Contraindication to prostate biopsy
• Active urinary tract infection or prostatitis
• Inability to tolerate the biopsy procedure or follow study procedures

Eligible participants are individuals with a prostate who meet all study inclusion and exclusion criteria.

Individual participant data will not be shared publicly to protect participant privacy and confidentiality. De-identified data may be made available upon reasonable request and subject to institutional approvals and applicable ethics requirements.