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WO-2026093014-A1 - A METHOD OF RISK STRATIFICATION FOR LOW RISK PROSTATE CANCER PATIENTS

WO2026093014A1WO 2026093014 A1WO2026093014 A1WO 2026093014A1WO-2026093014-A1

Abstract

The invention relates to methods and products for risk stratification of low risk prostate cancer patients. In particular the methods provide for predicting an outcome for prostate cancer patients with an ISUP score of 1 or 2. In addition the invention describes treatment suggestions based on the methods of the invention.

Inventors

  • HOFFMANN, Ralf Dieter

Assignees

  • KONINKLIJKE PHILIPS N.V.

Dates

Publication Date
20260507
Application Date
20251015
Priority Date
20241028

Claims (15)

  1. 1. A method for predicting an outcome for a prostate cancer subject with International Society for Urological Pathology (ISUP) score of 1 or 2, the method comprising: determining expression levels or receiving determined expression levels of PDE4D isoforms PDE4D5, PDE4D7 and PDE4D9 in a sample obtained from the subject; receiving the Cancer of the Prostate Risk Assessment (CAPRA) score determined for the subject; determining a risk score based on the PDE4D5, PDE4D7 and PDE4D9 expression levels and the CAPRA score; wherein the method further comprises receiving or determining the Body Mass Index (BMI) of the subject; and determining an outcome for the subject based on the risk score and the BMI; wherein the outcome is a favorable outcome or a non-favorable outcome.
  2. 2. The method according to claim 1 wherein the favorable outcome is low chance of post- surgical disease progression and wherein the non-favorable outcome is high chance of post-surgical disease progression.
  3. 3. The method according to claim 1 or 2, wherein the sample is a sample obtained from the subject wherein the sample comprises at least one tumor cell, preferably wherein the sample is a tumor sample, a blood sample, a urine sample, or a biopsy such as a needle biopsy.
  4. 4. The method according to any one of the preceding claims, wherein the PDE4D5, PDE4D7 and PDE4D9 expression levels and the CAPRA score are combined to obtain a risk score using a regression function derived from a population of prostate cancer subjects.
  5. 5. The method according to any one of the preceding claims, wherein the risk score is a modified CAPRA score for the subject, wherein the PDE4D5, PDE4D7 and PDE4D9 expression levels used to calculate the modified CAPRA score are combined to a value representing the expression score in a predefined range, wherein depending on the value a number of points in the range from 0 to 3 are added to the CAPRA score to obtain the modified CAPRA score.
  6. 6. The method according to claim 5, wherein the value representing the expression score is determined with a scoring function, based on the PDE4D5, PDE4D7 and PDE4D9 expression level, the scoring function having been derived from gene expression profdes for biological samples of prostate cancer subjects.
  7. 7. The method according to any one of the preceding claims, wherein the PDE4D5, PDE4D7 and PDE4D9 expression levels are normalized using one or more of the reference genes hypoxanthine phosphoribosyl transferase 1 (HPRT1), Tubulin- Alpha- lb (TUBA IB) pumilio RNA- Binding Family Member (PUM1), and TATA box binding protein (TBP).
  8. 8. The method according to any one of the preceding claims, wherein the method further comprises proposing a primary treatment for the subject based on the determined outcome.
  9. 9. The method according to claim 8, wherein - the recommended treatment is active surveillance with de-escalation of monitoring when the risk score is low and the BMI is low or high; or - the recommended treatment is a treatment with one or more therapies selected from a GLP-1 receptor agonist, a weight lowering medication, surgery, radiation therapy, focal ablation, androgen hormone reducing therapy using either androgen deprivation therapy or androgen receptor signaling inhibition therapy as a monotherapy when the risk score is high and the BMI is high; or - the recommended treatment comprises treatment with one or more therapies selected from androgen hormone reducing therapy using either androgen deprivation therapy or androgen receptor signaling inhibition therapy or a combination thereof, an PDE4D7 expression increasing therapy, surgery, radiation therapy, chemotherapy, targeted radionuclide therapy, and immunotherapy, when the risk score is high and BMI is low.
  10. 10. A computer program product comprising instructions which, when the program is executed by a computer, cause the computer to carry out a method comprising: determining a risk score based on received PDE4D5, PDE4D7 and PDE4D9 expression levels and a received CAPRA score, the expression levels being determined in a sample of a prostate cancer subject with ISUP score of 1 or 2, and the CAPRA score obtained from the subject; determining an outcome for the subject based on the risk score and a received BMI from the subject; wherein the outcome is a favorable outcome or a non-favorable outcome.
  11. 11. Use of a kit to determine an outcome for a prostate cancer subject with ISUP score of 1 or 2, the use comprising using the kit to determine the expression levels of PDE4D isoforms PDE4D5, PDE4D7 and PDE4D9 in sample obtained from the subject; determining a risk score based on the PDE4D5, PDE4D7 and PDE4D9 expression levels and a CAPRA score obtained from the subject; determining an outcome for the subject based on the risk score and a BMI obtained form the subject; wherein the kit comprises at least one primer and/or probe for determining the gene expression profile for each of PDE4D5, PDE4D7 and PDE4D9, and optionally, at least one primer and/or probe for determining the gene expression profile for one or more reference genes selected from the group consisting of: hypoxanthine phosphoribosyl transferase 1 (HPRT1), Tubulin- Alpha- lb (TUBA1B) pumilio RNA-Binding Family Member (PUM1), and TATA box binding protein (TBP); and optionally, at least one agent for determining a prostate-specific antigen (PSA) level in a biological sample obtained from the subject.
  12. 12. GLP-1 receptor agonist for use in the treatment of prostate cancer in a subject with ISUP score 1 or 2, the use comprising receiving or determining the ISUP score of the subject and administering the GLP-1 receptor agonist when the ISUP score of the subject is 1 or 2.
  13. 13. GLP-1 receptor agonist for use according to claim 12, wherein the use further comprises receiving or determining the Body Mass Index (BMI) of the subject and administering the GLP-1 receptor agonist when the ISUP score of the subject is 1 or 2 and the BMI of the subject is high.
  14. 14. GLP-1 receptor agonist for use according to claim 12 or 13, wherein the use comprises: determining or receiving the determined expression levels of PDE4D isoforms PDE4D5, PDE4D7 and PDE4D9 in a sample obtained from the subject; receiving the CAPRA score determined for the subject; determining a risk score based on the PDE4D5, PDE4D7 and PDE4D9 expression levels and the CAPRA score; receiving or determining the BMI of the subject; wherein the GLP-1 receptor agonist is administered to the subject when the ISUP score of the subject is 1 or 2, the risk score of the subject is high, and the BMI of the subject is high.
  15. 15. GLP-1 receptor agonist for use according to any one of claims 12 to 14, wherein the GLP-1 receptor agonist is selected from dulaglutide, exenatide, exenatide extended-release, liraglutide, lixisenatide, semaglutide injection, emaglutide tablets, albiglutide, and tirzepatide.

Description

A METHOD OF RISK STRATIFICATION FOR LOW RISK PROSTATE CANCER PATIENTS FIELD OF THE INVENTION The invention relates to methods and products for risk stratification of low risk prostate cancer patients. In particular the methods provide for predicting an outcome for prostate cancer patients with an ISUP score of 1 or 2. In addition the invention describes treatment suggestions based on the methods of the invention. BACKGROUND OF THE INVENTION Cancer is a class of diseases in which a group of cells displays uncontrolled growth, invasion and sometimes metastasis. These three malignant properties of cancers differentiate them from benign tumors, which are self-limited and do not invade or metastasize. Prostate Cancer (PCa) is the most commonly-occurring non-skin malignancy in men. It displays as a heterogeneous disease with varying potential to develop progressively to deadly forms of the disease. Of the estimated 417,000 annual new cases in Europe, around 92,000 will die from their disease (see Ferlay I. et al., GLOBOCAN 2012 vl.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet], Lyon, France, International Agency for Research on Cancer, 2013). Clinically, various schemes for pre-surgical risk classification have been developed based upon longitudinal biological patient outcomes (see Rodrigues G. et al., “Pre-treatment risk stratification of prostate cancer patients: A critical review”, Canadian Urological Association loumal, Vol. 6, No. 2, pages 121-127, 2012). While active surveillance (AS) is recommended by the various national and international guidelines for men with very low and low risk prostate cancer (see Mohler I. et al., “NCCN clinical practice guidelines in oncology: Prostate cancer, Version 1.2016”, loumal of the National Comprehensive Cancer Network, Vol. 14, No. 1, pages 19-30, 2016), there is a significant sub-group in this patient population with a risk of 10 to 25% cancer recurrence after primary treatment (see, for example, Hernandez D.I. et al., “Contemporary evaluation of the D’Amico risk classification of prostate cancer”, loumal of Urology, Vol. 70, No. 5, pages 931-935, 2007). These patients suffer from the burden of follow-up treatments that are typically triggered by biochemical relapse. Likewise, in the intermediate risk group there is a sub-population with low risk of biochemical progression (see, for example, lung I.W. et al., “Stratification of patients with intermediate-risk prostate cancer”, BIU International, Vol. 115, No. 6, pages 907-912, 2015). Nevertheless, this group is heterogeneous, comprising patients with varied outcomes, including those with aggressive pathological characteristics (see Abem M.R. et al., “Delayed radical prostatectomy for intermediate-risk prostate cancer is associated with biochemical recurrence: Possible implications for active surveillance from the SEARCH database”, The Prostate, Vol. 73, No. 4, pages 409-417, 2013). WO2019122037A1 describes a method of pre-surgical risk stratification of a prostate cancer subject, comprising determining a gene expression profile for phosphodiesterase 4D variant 7 (PDE4D7) in a biological sample obtained from the subject, determining an expression based risk score for the subject based on the gene expression profile, and determining a pre-surgical prognostic risk score for the subject based on the expression based risk score and pre-surgical clinical variables of the subject. The typical treatment for low risk prostate cancer patients (ISUP score of 1 or 2) is typically active surveillance, however about 30-50% of this patient population experiences disease progression during active surveillance. Therefor there is a need to provide further risk stratification and treatment options for low risk prostate cancer patients. These unmet needs are addressed by the methods and product as defined by the appended claims. SUMMARY OF THE INVENTION In a first aspect, the invention relates to a method for predicting an outcome for a prostate cancer subject with International Society for Urological Pathology (ISUP) score of 1 or 2, the method comprising determining or receiving the determined expression levels of PDE4D isoforms PDE4D5, PDE4D7 and PDE4D9 in a sample obtained from the subject; receiving the CAPRA score determined for the subject; determining a risk score based on the PDE4D5, PDE4D7 and PDE4D9 expression levels and the Cancer of the Prostate Risk Assessment (CAPRA) score; wherein the method further comprises receiving or determining the Body Mass Index (BMI) of the subject; and determining an outcome for the subject based on the risk score and the BMI; wherein the outcome is a favorable outcome or a non- favorable outcome. In a second aspect the invention relates to a computer program product comprising instructions which, when the program is executed by a computer, cause the computer to carry out a method comprising: determining a risk score based on received PDE4D5, PDE4D7 and PDE4D9 ex