the primary choice for ADT? Igor Tsaur University Medicine Mainz - PowerPoint PPT Presentation

Urologische Klinik und Poliklinik ADT AND CARDIOVASCULAR RISK: should Antagonists be the primary choice for ADT? Igor Tsaur University Medicine Mainz

Urologische Klinik und Poliklinik COI  Off-label use of drugs, devices, or other agents: none  Data from IRB-approved human research is presented: is not I have the following financial interests or Disclosure code relationships to disclose: Sanofi L Janssen C, L Ferring L Bayer C 2

Urologische Klinik und Poliklinik DAVID Rubens, 1616 GOLIATH 3

Urologische Klinik und Poliklinik AGONISTS Rubens, 1616 ANTAGONISTS 4

Urologische Klinik und Poliklinik Different forms of ADT – different CVE risks? Diabetes tes CHD MI MI Sudden en death No t treatm tment ent REF REF REF REF REF REF REF REF GnRH-Ag Agon onist sts 1,44 44 1,16 16 1,11 11 1,16 16 <0,001 001 <0,001 001 0,03 03 0,004 004 OT OT 1,34 34 0,99 99 0,94 94 1,01 01 <0,001 001 0,74 74 0,44 44 0,85 85 73.196 .196 pati tient ents, 34 34,6% % GnRH RH-Agon gonist sts, 6,9 9 % OT Foll llow ow-up up 2-9 9 a. a. 5 Keating NL et al, J Clin Oncol, 2006

Urologische Klinik und Poliklinik Agonists vs. antagonists 6 Everyday Urology – Oncology Insights, Vol. 2 (1)

Urologische Klinik und Poliklinik Different forms of ADT – different CVE risks?  ADT associated with CVE • Higher risk for GnRH-Agonists than OT 1 • Highest risk for pts. with CVE in the past 2,3  Different function of GnRH-Antagonists compared to GnRH-Agonists • Different CVE risk? • Less arterial plaque rupture by GnRH-Antagonists blocking GnRH receptors on lymphocytes? • FSH-drop related protective effects on CVE? 1. Taylor LG et al, Cancer, 2009 2. Nanda AN et al, JAMA, 2009 7 3. Hedlund PO et al, Scand J Urol Nephrol, 2011

Urologische Klinik und Poliklinik Different forms of ADT – different CVE risks? 8 Crawford ED et al, Urol Oncol, 2017

Urologische Klinik und Poliklinik Different forms of ADT – different CVE risks? 9

Urologische Klinik und Poliklinik Pooled data analysis of 6 RCTs Study Duration (mo.) Comparator Publication CS21 12 Leuprolide Klotz et al. BJU Int 2008 T≤ 0.5 ng/ml CS35 12 Goserelin Shore et al. SUO 2012 IPSS/QoL/PSA/T unpublished in complete CS37 7-12 Leuprolide design PSA/QoL CS28 3 Goserelin b Anderson et al. Urol Int 2012 LUTS improvement CS30 Goserelin b 3 Mason et al. Clin Oncol 2013 prostate size reduction CS31 Goserelin b 3 Axcrona et al. BJU Int 2012 prostate size reduction  Data on pre-existing comorbid diseases reported by pts. and classified by study investigators according to MedDRA before analysis 10

Urologische Klinik und Poliklinik Design 2328 pts. 1491 837 Degarelix GnRH Agonist 458 379 Goserelin Leuprolide Preexisting CV 463 (31%) 245 (29 %) conditions  CVE defined as arterial embolic and thrombotic events, hemorrhagic and ischemic CV conditions, MI or other ischemic heart disease 11  Primary end point: CVE or death

Urologische Klinik und Poliklinik Results: pts. with preexisting CVE HR=0,44 (95 % CI 0,26 – 0,74) p=0,002  No differences in men without preexisting CV conditions! 12

Urologische Klinik und Poliklinik Results: all pts. HR=0,60 (95 % CI 0,41 – 0,87) p=0,008  Total significance achieved by pts. with preexisting CV conditions! 13

Urologische Klinik und Poliklinik Results: all pts.  Powered by CS37 – unpublished at the time of the analysis 14

Urologische Klinik und Poliklinik Significance overall vs. subgroups nonsignificant significant CV conditions No preexisting CV conditions  Practice changing for all? 15

Urologische Klinik und Poliklinik Hypothesis generating ≠ Practice changing  Retrospective post hoc analysis  CVE reportes as AE, not as independent end point  Uncontrolled bias in not monitored risk factors for CVE (e.g. lipide profiles)  Open-label studies – prone for bias due to underreporting of AEs  Hemorrhagic vs. ischemic – different pathophysiology  Short-term data, small number of events  Benefit only for pts. with preexisting CV conditions (1/3 of the cohort, n=463 vs. 245), not for the majority of the cohort! 16

Urologische Klinik und Poliklinik Hypothesis generating ≠ Practice changing Not only HTN, but also AV-malformation, aneurysms 17 https://maismaismedicina.wordpress.com

Urologische Klinik und Poliklinik Hypothesis generating ≠ Practice changing  Retrospective post hoc analysis  CVE reportes as AE, not as independent end point  Uncontrolled bias in not monitored risk factors for CVE (e.g. lipide profiles)  Open-label studies – prone for bias due to underreporting of AEs  Hemorrhagic vs. ischemic – different pathophysiology  Short-term data, small number of events  Benefit only for pts. with preexisting CV conditions (1/3 of the cohort, n=463 vs. 245), not for the majority of the cohort! Convincing? 18

Urologische Klinik und Poliklinik Population-based data 19

Urologische Klinik und Poliklinik Population-based data  Primary end point: HR for MI or ischemic stroke requiring hospitalization more focussed on the issue of arterial plaques stability !!!!!! 20

Urologische Klinik und Poliklinik Population-based data  Median time to ischemic event: 478 d.!!! Pooled data (3-12 mo. trials) representative enough?  CVE profile of GnRH-Antagonists not better than that of – Agonists 21

Urologische Klinik und Poliklinik Comparison of covariates Dyslipidamia Age Statin Anticoagulant Alcohol CAD drugs Hypertension Diabetes CKD Smoker Cholesterol Heart failure Smoker Arterial Type 2 diabetes Statin thrombosis treated Hypertension Hemorrhagic Hypertension treated stroke Age Ischemic Obesity stroke Testosterone Alcohol COPD BMI Atrial Anti-platelet 22 fibrillation agents

Urologische Klinik und Poliklinik Arch of Titus, Rome 23

Urologische Klinik und Poliklinik Meta-analysis CS 37 not included because not published!!! Study quality cannot be assessed!!! 24

Urologische Klinik und Poliklinik Meta-analysis  Severe CVE defined as QT-interval increase, angina pectoris, atrial fibrillation, cardiac failure and myocardial ischemia  No significant difference Agonists ↔ Antagonists!!! 25

Urologische Klinik und Poliklinik Recommendations 26 EAU Guideline Prostate Cancer 2018

Urologische Klinik und Poliklinik Conclusions  Antagonists are not the primary choice for ADT in all patients!  Poor evidence to favour Antagonists over Agonists for CV safety  Antagonists MIGHT be considered in pts. with preexisting CV  Antagonists SHOULD be considered in pts. requiring rapid remission  PRONOUNCE trial ongoing, lets wait …… 27

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