The PARIS-BIO study evaluates whether a novel genomic biomarker, the PCAI ImmunoScore, can predict the response to neoadjuvant treatment with Darolutamide in patients with high-risk localized or locally advanced prostate cancer. Patients will receive Darolutamide monotherapy for 90-120 days prior to radical prostatectomy. The study aims to validate if the biomarker can identify patients who achieve Minimal Residual Disease (MRD) at the time of surgery.
High-risk prostate cancer patients are at risk for recurrence after local therapy. The presence of micro-metastatic disease, undetectable by conventional imaging, likely contributes to the poor prognosis. Neoadjuvant hormonal therapy, particularly with the advent of ARPIs like Darolutamide, has shown promise, but patient selection remains crucial for optimizing outcomes. This Phase II, single-arm, open-label trial investigates the predictive value of the PCAI ImmunoScore, a gene expression signature derived from diagnostic biopsies. 100 participants with high-risk prostate cancer scheduled for radical prostatectomy will be enrolled. They will receive Darolutamide (600 mg twice daily) for a period of 90 to 120 days. MRI imaging will be performed between day 90 and 120 prior to surgery. Radical prostatectomy is performed within the same window. The primary analysis compares the pre-treatment biomarker score with the pathological response (Minimal Residual Disease) observed in the surgical specimen. Secondary analyses include MRI response, PSA kinetics, and patient-reported functional outcomes.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
100
Neoadjuvant Darolutamide alone (without ADT) 2x300 mg orally twice daily is given to all study subjects for 90-120 days prior to prostatectomy.
Robot-assisted radical prostatectomy, with or without extirpation of pelvic lymph nodes according to clinician's choice in concordance with local guidelines
Sahlgrenska University Hospital
Gothenburg, Sweden
RECRUITINGKarolinska University Hospital
Stockholm, Sweden
RECRUITINGThe association between the pre-treatment probability of treatment response given by PCAI ImmunoScore and the occurrence of minimal residual disease (MRD)
The primary outcome is the association between the pre-treatment PCAI ImmunoScore and the occurrence of minimal residual disease (MRD) after 90-120 days of neoadjuvant Darolutamide treatment. MRD is defined as \< 0.05 cm3 residual tumour on final pathology after prostatectomy. The study endpoint MRD will be dichotomized into responder (if MRD is met) or non-responder (if MRD is not met) as input for the statistical data analysis. This classification (ground truth) will be tested in AUROC analysis against the calculated PCAI ImmunoScore-based probability p (0\<p\<1) of Darolutamide response. PCAI ImmunScore is calculated from RNA sequencing of tumor material from diagnostic (pre-treatment) biopsies. The collection of RNA and calculation of PCAI ImmunoScore will take place after the recruitment period. Sequencing will be performed in bulk once all samples have been collected. The objective is to assess the predictive value of the pre-treatment genomic biomarker for pathological response.
Time frame: MRD is ascertained shortly after radical prostatectomy (day 90-120). PCAI ImmunoScore will be ascertained after bulk sequencing of all samples, tentatively 1 year after surgery of the 100th study subject. The association will be calculated thereafter.
The association between PCAI ImmunoScore and pathologic complete response (pCR)
The study endpoint pCR is defined as no residual tumour visible at final pathology and will be dichotomized into responder (if pCR is met) or non-responder (if pCR is not met) as input for the statistical data analysis. This classification (ground truth) will be tested in AUROC analysis against the calculated PCAI ImmunoScore-based probability p (0\<p\<1) (baseline model) of Darolutamide response. The extended model including the additional covariates will be tested equivalent to the baseline model.
Time frame: pCR is ascertained shortly after radical prostatectomy (day 90-120). PCAI ImmunoScore will be ascertained after bulk sequencing of all samples, tentatively 1 year after surgery of the 100th study subject. The association will be calculated thereafter.
Pathological T-stage (pT-stage)
Staging of the tumor at final pathology
Time frame: Pathological T-stage will be ascertained shortly after radical prostatectomy (day 90-120)
Residual tumor size
Measurement of the largest cross-sectional dimensions (mm) of residual tumor
Time frame: At the time of radical prostatectomy (day 90-120)
PSA Kinetics
Change in blood PSA concentration (ng/ml) during treatment
Time frame: Baseline, Day 30, Day 60, Day 90, and within 4 weeks after surgery
Hormonal side effects
Incidence and severity of adverse events assessed by CTCAE v5.0 and patient-reported quality-of-life using the 26-question questionnaire Expanded Prostate cancer Index Composite (EPIC-26), where lower scores indicate worse outcome
Time frame: From baseline up to 12 months post-surgery
Patient-reported urinary continence
Assessment of pre-and post-treatment urinary function using the Swedish national questionnaires (electronic patient-reported outcome measurements -ePROM "Symtom- och biverkningsenkät" that all patients undergoing prostate cancer treatment in Sweden routinely are invited to answer), where urinary continence is assessed using the question "How many protective pads do you use daily due to urine leakage?" The reply alternatives are: None Fewer than 1 per day About 1 per day About 2 per day About 3-4 per day About 5 or more per day
Time frame: Pre-surgery (day 80-119), 3 months post-surgery, 12 months post-surgery
Patient-reported erectile function
Assessment of pre-and post-treatment erectile function using the Swedish national questionnaires (electronic patient-reported outcome measurements -ePROM "Symtom- och biverkningsenkät" that all patients undergoing prostate cancer treatment in Sweden routinely are invited to answer), where erectile function is assessed using the question "How would you describe your erection?" The reply alternatives are: No noticeable filling or firmness Some filling, but not sufficient for full function Moderate firmness Full firmness
Time frame: Pre-surgery (day 80-119), 3 months post-surgery, 12 months post-surgery
MRI tumor response
Change in tumor size and Extraprostatic Extension (EPE) score (Likert scale 1-5) on MRI compared to baseline MRI
Time frame: Pre-surgery (day 90-120)
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