PROPOSe: A Real-Life Prospective Study of Proclarix®, a Novel Blood-Based Test to Support Challenging Biopsy Decision-Making in Prostate Cancer - Beyond the Abstract

Prostate Cancer (PCa) is the second most frequently diagnosed cancer in men, with an estimated 1.3 million new cases and 359,000 deaths worldwide in 2018.1 Incidence of PCa varies widely across the world: PCa is least common in Asia, more common in Europe, and most common in the US.2 Moreover, according to the American Cancer Society, the incidence of PCa in the US is lower among Asian men and higher among Afro-American men, with intermediate values for Caucasian and Hispanic men.3 In Europe, PCa is the most commonly diagnosed cancer in men with an incidence of more than 470,000 new cases in 2020 and notably, approximately 110,000 men died of PCa in 2020.4

PCa occurs mainly in older men, nearly two-thirds are diagnosed in men aged 65 or older. The mean age at the time of diagnosis is about 67 years.5 However, in a substantial subset of patients, the disease will be slow-growing and harmless,6 given the fact that autopsy data show histological prostate cancer in 80% of men at 80 years of age.7 This highlights one of the major issues with PCa screening and diagnosis: The risks of overdetection and overtreatment, i.e. to diagnose and invasively treat indolent cancers that may lead to reduced quality of life without increasing overall survival.

The systematic screening for PCa with prostate-specific antigen (PSA) testing over men’s lifetime leads to an estimated gain of 56 QUALY’s per 1,000 men screened (confidence interval [CI] from -21 to +121).8 However, as screening addresses a healthy population and screened men may suffer from disadvantages (overdiagnosis and overtreatment, unnecessary biopsies), screening in PCa remains controversial.

PSA is not a PCa specific marker, has a low predictive value, and blood concentration can raise due to many benign conditions such as benign prostate enlargement or inflammation.9,10 The consequences are unnecessary biopsies in 65–70% of men presenting with increased PSA in the range of 4-10 ng/ml,11 a potentially harmful procedure.12

Current guidelines recommend besides biomarker-based tests or risk calculators the use of multiparametric magnetic resonance imaging (mpMRI) to support biopsy decisions in subjects with inconclusive PSA results in the 2-10 ng/ml range.13 However, the use of mpMRI for the diagnosis of PCa is frequently reported as indeterminate, often leading to further examinations or unneeded biopsies with associated patient anxiety and risks. In addition, mpMRI is considered to be costly or the access to prostate MRI and radiologists is limited.

Proclarix®, a blood-based biomarker test has been developed to improve the biopsy decision algorithm. Proclarix® combines thrombospondin-1 (THBS1), cathepsin D (CTSD), total PSA (tPSA), free PSA (fPSA), and patient age to compute a risk score. Proclarix®, as an easy to use simple protein-based blood test, can be done with the same sample as the PSA test. No additional intervention is required with results becoming quickly available. Any local diagnostic laboratory can easily add this affordable multiparametric test to the existing infrastructure.

The novel biomarkers THBS1 and CTSD were originally discovered using a genetics-guided biomarker discovery approach focusing on the PI3K/PTEN cancer pathway which plays a dominant role in PCa development and progression (Figure 1).14,15

Translational approach for biomarker discovery and validation workflow

Figure 1. Translational approach for biomarker discovery and validation workflow. Cancer genetics-guided discovery of protein biomarker signatures in serum that correlate with diagnosis, prognosis, and therapy response of prostate cancer, tested in human serum from patients harboring localized prostate cancer and control patients.

Using a PTEN knock-out mouse model and mass-spectrometry based proteomics in murine tissue and human serum including a glycoprotein enrichment technology,16 several proteins directly linked to the molecular cause of cancer and therefore correlating to the disease status in the prostate were identified (Figure 2).17

biomaker mouse models

Figure 2. Translational approach for biomarker discovery and validation workflow. (a) Candidate biomarkers are discovered using a genetic mouse model and (b) tested in human serum from patients harboring localized prostate cancer and control patients.

Following discovery and identification, the diagnostic potential was evaluated in several studies (Figure 3).18,19

ROC curves depicting the accuracy in predicting prostate cancer

Figure 3. Receiver operating characteristic (ROC) curves depicting the accuracy in predicting prostate cancer. In predicting prostate cancer the combination of free PSA (%fPSA), age, CTSD, THBS1 was significantly better than %fPSA (p<0.001).

The analytical and clinical performances of Proclarix® have been established with retrospective data20,21 and the test is CE-marked, with sensitivity and negative predictive value (NPV) for clinically significant prostate cancer (csPCa) defined as Gleason grade (GG) ≥2 of 90% and 95%, respectively. Furthermore, recent results of Proclarix® showed a strong correlation with the mpMRI-based Likert score, a scoring system used to evaluate prostate mpMRI, indicating that Proclarix® could accurately discriminate among patients within the indeterminate (Likert score 3) mpMRI category.22 In this study, Proclarix® had an NPV of 100%, at 100% sensitivity and a specificity of 34%, indicating that in men with an indeterminate mpMRI-result, Proclarix® could allow one-third to safely avoid biopsies without missing any csPCa. Using the Proclarix® density could even further increase the specificity and thus save unneeded interventions.

The multicentre PROspective Prostate biOmarker Study (PROPOSe) (NCT03565289, AUO Study AP 98/18) was initiated to confirm the previously established diagnostic accuracy of Proclarix® in everyday practice. Ten clinical sites prospectively enrolled 457 men presenting for prostate biopsy with PSA between 2-10 ng/ml, normal DRE and prostate volume ≥35 cm³ (Figure 4).

Participating clinical centers in the PROPOSe study

Figure 4. Participating clinical centers in the PROPOSe study. Ten clinical centers from three countries including Austria (1), Denmark (1), and Germany (8) prospectively collected serum samples.

This prospective study confirmed Proclarix® performance as established during CE validation in clinical routine use. Proclarix® detected clinically significant cancer with high sensitivity above 90% and reliably ruled out patients with no or indolent cancer with a negative predictive value greater than 90%. When the biopsy performed was guided by mpMRI both sensitivity (97%) and NPV (96%) were even higher. Importantly, Proclarix® was significantly superior to the current clinical standard percent free PSA in ruling out unneeded biopsies (22% vs. 14%) and the primary study endpoint was met (p-value < 0.005).

Prof. Dr. med. Thomas Steuber from the renowned Martini-Klinik Hamburg and principal investigator of the study stated: “In a routine use setting, Proclarix® accurately discriminated clinically significant PCa from no or indolent PCa. This study provides strong support for the use of Proclarix® in routine practice to improve the biopsy decision algorithm.”

Co-investigator Prof. Dr. med. Carsten Ohlmann from the Johanniter Krankenhaus Bonn added: “Proclarix® is a novel blood-based test with the potential to accurately rule out no or insignificant cancer, and therefore to reduce the number of unneeded biopsies.”

Written by: Oliver Straub, PhD, Medical Advisor, Proteomedix AG, Zürich, Switzerland, and Thomas Steuber, MD, Martini-Klinik, University Hospital Hamburg-Eppendorf, Hamburg, Germany


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