Neoadjuvant ADT With TULSA in the Treatment of Intermediate Risk Prostate Cancer

Study Overview
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Brief Summary
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Clinical studies have shown that magnetic resonance imaging-guided transurethral ultrasound ablation (TULSA) of the prostate is safe and effective. In the TULSA procedure, prostate tissue is killed by heating with ultrasound. This clinical trial explores if adding drug therapy with Degarelix before TULSA has the potential to improve further the effectiveness of TULSA in the treatment of localized prostate cancer, especially for patients with more aggressive diseases.

Detailed Description
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Androgen deprivation therapy (ADT) has been shown to reduce prostate and tumor size. In this study, magnetic resonance imaging (MRI) is used to investigate the effect of Degarelix ADT on the properties of prostate tissue that can affect the heating of the tissues in the TULSA procedure. The main goal is to find out if ADT can change the tissue structure in a way that improves the ability of the TULSA procedure to heat tissues and better kill the diseased tissue, reducing the chance of the disease reoccurring. ADT and the TULSA procedure can help patients with more aggressive diseases avoid the adverse effects associated with surgery or radiation therapy. Specific objectives are: To measure the change in prostate and tumor size, tissue structural changes, and the blood flow within the prostate after ADT. To measure the distribution of heating over the prostate after TULSA treatment. To evaluate complications and genitourinary function and quality of life with patient-reported outcome measures. To evaluate local cancer control and longer-term oncological outcomes after combination therapy of neoadjuvant ADT and TULSA treatment. About 15 subjects will participate. Each will receive Degarelix for three months, followed by whole-prostate gland TULSA treatment, and be followed for five years. Throughout the study, subjects will receive MRI scans and complete questionnaires regarding functional status and quality of life to understand the side effects.

Official Title
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Effect of Neoadjuvant Degarelix on MRI-guided Transurethral Ultrasound Ablation (TULSA) in Patients With Intermediate-risk Prostate Cancer: A Pilot Study

Conditions
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Localized Prostate Carcinoma, Castration-Naive Prostate Cancer, Intermediate Risk Prostate Cancer, Prostate Cancer

Intervention / Treatment
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* Drug: Degarelix
* Device: MRI-guided transurethral ultrasound ablation (TULSA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male age ≥ 40 years and candidate for radical prostate cancer treatment Estimated life expectancy > 8 years At least one MRI-visible and biopsy-concordant tumor defined as Prostate Imaging-Reporting and Data System v2 (PI-RADS v2.1) ≥ 3 Biopsy-confirmed, intermediate-risk localized prostate cancer: Clinical or radiological tumor stage ≤ T2c, N0, M0 ISUP GG 2 or 3 Biopsy obtained ≥ 6 weeks and ≤ 12 months before treatment PSA ≤ 20 ng/ml No prior definitive treatment of prostate cancer Eligible for MRI Eligible for general anesthesia (American Society of Anesthesiologists Class III or less) Patients taking 5-alpha reductase inhibitors (5-ARIs) are eligible if use is discontinued three months before and throughout the study period. Informed consent: The patient must speak Finnish, English, or Swedish and must be able to understand the meaning of the study. The patient must be willing and able to sign the appropriate Ethics Committee (EC) approved informed consent documents in the presence of the designated staff. Exclusion Criteria: Prior prostate cancer treatment with chemotherapy or hormonal therapy, including chemical or surgical castration, antiandrogen therapy, or androgen-receptor signaling inhibitors. Relative or absolute contraindication to Degarelix Severe, active cardiovascular comorbidity including unstable angina pectoris, congestive heart failure, deep vein thrombosis, pulmonary embolism, or myocardial infarction within the last six months. Inability to undergo MRI due to claustrophobia or contraindications (cardiac pacemaker, intracranial clips, etc.) Severe kidney failure as determined by estimated glomerular filtration rate (eGFR) less than 30 ml/min per 1.73 m2 Prostate calcifications obstructing the planned ultrasound beam path in the line of sight of the MRI visible tumor Prostate cysts at the prostate capsule within the planned ultrasound beam path in the line of sight of the MRI visible tumor Evidence of extraprostatic disease based on imaging (MRI, bone scintigraphy, single-photon emission tomography, computed tomography, prostate-specific membrane antigen-positron emission tomography [PSMA-PET]) or histopathology History of chronic inflammatory conditions (e.g., inflammatory bowel disease) affecting the rectum (also includes rectal fistula and anal/rectal stenosis) Hip replacement surgery or other metal in the pelvic area Known allergy or contraindication to gadolinium or gastro-intestinal anti-spasmodic drug glucagon Concomitant treatment with medications contraindicated to Glucagen used as antispasmolytic agent during TULSA treatment (e.g., Feochromocytoma) Any other conditions that might compromise patient safety, based on the clinical judgment of the responsible urologist Another primary malignancy unless disease-free survival is > 8 years

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Procedure: Magnetic resonance imaging-guided transurethral ultrasound ablation of the prostate (TULSA) Drug: Degarelix
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3-month neoadjuvant Degarelix followed by whole-gland MRI-guided transurethral ultrasound ablation<br>After three months of neoadjuvant ADT with Degarelix, the subject will undergo whole-prostate gland MRI-guided transurethral ultrasound ablation (TULSA) (TULSA-PRO, Profound Medical Inc., Toronto, Canada) treatment. | Drug: Degarelix<br>* Degarelix is injected subcutaneously into the fatty tissue of the abdomen. A typical protocol consists of a starting dose of 240 mg with a maintenance dose of 80 mg administered every 28 days. In this study, one starting dose and two maintenance doses of Degarelix will be administered between baseline and TULSA treatment in accordance with the terms of Degarelix marketing authorizations.<br>* Other names: Firmagon;Device: MRI-guided transurethral ultrasound ablation (TULSA)<br>* MRI-guided transurethral ultrasound ablation (TULSA) (TULSA-PRO, Profound Medical Inc., Toronto, Canada) will be used to deliver whole-prostate gland treatment in accordance with the terms of TULSA marketing authorizations. The treating physicians will contour the entire prostate gland for a whole gland ablation.<br>* Other names: TULSA-PRO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in prostate volume after neoadjuvant ADT | The prostate volume change will be determined by comparing the prostate volume measured on T2-weighted MRI at four, eight, and 12 weeks of ADT to that at baseline. | Baseline and four, eight, and 12 weeks of ADT. | 
| Change in prostate tumor volume after neoadjuvant ADT | The prostate tumor volume change will be determined by comparing the prostate tumor volume measured on T2-weighted MRI at four, eight, and 12 weeks of ADT to that at baseline. | Baseline and four, eight, and 12 weeks of ADT. | 
| The frequency and severity of adverse events | The frequency and severity of adverse events after neoadjuvant Degarelix and TULSA treatment will be determined by using the CTCAE v6.0 classification. Adverse events attributed to TULSA will also be graded using the Clavien Dindo classification for surgical complications. | Every follow-up visit until the first year of follow-up. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in prostate tumor-capsule contact length after neoadjuvant ADT | The prostate tumor-capsule contact length change will be determined by comparing the prostate tumor-capsule contact length measured on T2-weighted MRI at four, eight, and 12 weeks of ADT to that at baseline. | Baseline and four, eight, and 12 weeks of ADT. | 
| Change in prostate vascular perfusion after neoadjuvant ADT | The change in prostate vascular perfusion will be determined by comparing average blood flow values in the prostate measured on dynamic contrast-enhanced T1-weighted MRI at four, eight, and 12 weeks of ADT to that at baseline. | Baseline and four, eight, and 12 weeks of ADT. | 
| Change in prostate tumor vascular perfusion after neoadjuvant ADT | The change in prostate tumor vascular perfusion will be determined by comparing average blood flow values in the prostate tumor measured on dynamic contrast-enhanced T1-weighted MRI at four, eight, and 12 weeks of ADT to that at baseline. | Baseline and four, eight, and 12 weeks of ADT. | 
| Change in periprostatic, prostate and tumor tissue structures after neoadjuvant ADT | The change in periprostatic, prostate and tumor tissue structures will be determined by comparing the radiomics features extracted from T2-weighted, T2 relaxation time mapping, and diffusion-weighted images at four, eight, and 12 weeks of ADT to that at baseline. | Baseline and four, eight, and 12 weeks of ADT. | 
| Thermal coverage after whole-prostate gland TULSA | Thermal coverage of the target volume achieved by whole-prostate gland TULSA will be determined by comparing physician-defined target boundaries to MRI measurements of temperature distributions, thermal dose distributions, and acute treatment-induced perfusion defect immediately post-treatment. | Immediately after the TULSA procedure. | 
| Change in quality of life (QoL) and functional status outcomes after neoadjuvant ADT | The change in QoL and functional status outcomes will be determined by comparing the summary scores of urinary incontinence, urinary irritative/obstructive, bowel, sexual and hormonal domains of the Expanded Prostate Index Composite-26 (EPIC-26) questionnaire at 12 weeks of ADT to that at baseline. EPIC-26 contains 26 items with response options for each EPIC item forming a Likert Scale, and multi-item scale scores transformed linearly to a 0-100 scale, with higher scores representing better functional status/QoL. | Baseline and 12 weeks of ADT. | 
| Change in lower urinary tract symptoms after neoadjuvant ADT | The change in lower urinary tract symptoms will be determined by comparing the International Prostate Symptom Score (IPSS) at 12 weeks of ADT to that at baseline. The possible scores for the IPSS questionnaire range from 0 to 35, with higher scores representing worse symptoms. | Baseline and 12 weeks of ADT. | 
| Change in erectile function after neoadjuvant ADT | The change in erectile function will be determined by comparing the International Index of Erectile Function (IIEF-5) score at 12 weeks of ADT to that at baseline. The possible scores for the IIEF-5 range from 5 to 25, with higher scores representing a better erectile function. | Baseline and 12 weeks of ADT. | 
| Change in quality of life (QoL) and functional status outcomes after neoadjuvant ADT and whole-prostate gland TULSA | The change in QoL and functional status outcomes will be determined by comparing the summary scores of urinary incontinence, urinary irritative/obstructive, bowel, sexual and hormonal domains of the Expanded Prostate Index Composite (EPIC-26) questionnaire at three, six, 12, 36 and 60 months post-TULSA to that at baseline and TULSA procedure. EPIC-26 contains 26 items with response options for each EPIC item forming a Likert Scale, and multi-item scale scores transformed linearly to a 0-100 scale, with higher scores representing better functional status/QoL. | Baseline and 12 weeks of ADT, and three, six, 12, 36 and 60 months after the TULSA procedure. | 
| Change in lower urinary tract symptoms after neoadjuvant ADT and whole-prostate gland TULSA | The change in lower urinary tract symptoms will be determined by comparing the International Prostate Symptom Score (IPSS) at three, six, 12, 36 and 60 months post-TULSA to that at baseline and TULSA procedure. The possible scores for the IPSS questionnaire range from 0 to 35, with higher scores representing worse symptoms. | Baseline and 12 weeks of ADT, and three, six, 12, 36 and 60 months after the TULSA procedure. | 
| Change in erectile function after neoadjuvant ADT and whole-prostate gland TULSA | The change in erectile function will be determined by comparing the International Index of Erectile Function (IIEF-5) score at three, six, 12, 36 and 60 months post-TULSA to that at baseline and TULSA procedure. The possible scores for the IIEF-5 range from 5 to 25, with higher scores representing a better erectile function. | Baseline and 12 weeks of ADT, and three, six, 12, 36 and 60 months after the TULSA procedure. | 
| The frequency and severity of adverse events during extended follow-up | The frequency and severity of adverse events after neoadjuvant Degarelix and TULSA treatment will be determined using the CTCAE v6.0 classification. Adverse events attributed to TULSA will also be graded using the Clavien Dindo classification for surgical complications. | Every follow-up visit until the five years of follow-up. | 
| Salvage therapy-free survival | Salvage therapy-free survival will be defined as freedom from radical salvage treatments for prostate cancer including radical prostatectomy, radiotherapy, or ablation, and reported as the proportion of subjects who have not reached those events. | Every post-TULSA follow-up visit until the five years of follow-up. | 
| Systemic therapy-free survival | Systemic therapy-free survival will be defined as freedom from additional systemic therapy including but not limited to additional ADT or chemotherapy for the treatment of prostate cancer, and reported as the proportion of subjects who have not reached those events. | Every post-TULSA follow-up visit until the five years of follow-up. | 
| Failure-free survival | Failure-free survival will be defined as freedom from salvage treatment, systemic treatment, metastases, or death from prostate cancer, and reported as the proportion of subjects who have not reached those events. | Every post-TULSA follow-up visit until the five years of follow-up. | 
| Metastasis-free, prostate cancer-specific, and overall survival | Metastasis-free, prostate cancer-specific and overall survivals will be assessed one, three, and five years after TULSA and reported as the proportion of subjects who have not reached those endpoints. | One, three and five years after the TULSA procedure. | 
| Biochemical failure-free survival | PSA at each timepoint, as well as PSA nadir, will be reported. The proportion of subjects with biochemical failure, defined as a PSA value more than 2.0 ng/ml above nadir, will be reported. | One, three, and five years after the TULSA procedure. | 
| Freedom from biopsy-proven clinically-significant prostate cancer | Histopathologic verification of treatment response to TULSA treatment will be confirmed at 12 months post-TULSA with targeted plus 10-12-core systematic biopsy. The proportion of subjects with a clinically-significant disease, defined as Gleason grade ≥ 3 + 4 and ISUP (International Society of Urological Pathology) grade group ≥ 2 prostate cancer, on biopsy, will be reported. | Twelve months after the TULSA procedure | 
| Freedom from any biopsy-proven prostate cancer | Histopathologic verification of treatment response to TULSA treatment will be confirmed at 12 months post-TULSA with targeted plus 10-12-core systematic biopsy. The number, location, grade, and percent of cancer involvement within each core will be collected. The proportion of subjects with any prostate cancer on biopsy, will be reported. | Twelve months after the TULSA procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRI-guided transurethral ultrasound ablation, Androgen deprivation therapy, Neoadjuvant androgen deprivation therapy, TULSA, Prostate cancer, Thermal ablation, Therapeutic ultrasound, Ablation therapy