ADT AND CARDIOVASCULAR RISK: should Antagonists be the primary choice for ADT? Igor Tsaur University Medicine Mainz
COI Urologische Klinik und Poliklinik 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 relationships to disclose: Sanofi Janssen Ferring Bayer Disclosure code L C, L L C 2
DAVID Rubens, 1616 GOLIATH 3
AGONISTS Rubens, 1616 ANTAGONISTS 4
Different forms of ADT different CVE risks? Urologische Klinik und Poliklinik Diabetes CHD MI Sudden death No treatment REF REF REF REF GnRH-Agonists 1,44 1,16 1,11 1,16 <0,001 <0,001 0,03 0,004 OT 1,34 0,99 0,94 1,01 <0,001 0,74 73.196 patients, 34,6% GnRH-Agonists, 6,9 % OT Follow-up 2-9 a. 0,44 0,85 Keating NL et al, J Clin Oncol, 2006 5
Agonists vs. antagonists Urologische Klinik und Poliklinik Everyday Urology Oncology Insights, Vol. 2 (1) 6
Different forms of ADT different CVE risks? Urologische Klinik und Poliklinik 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 3. Hedlund PO et al, Scand J Urol Nephrol, 2011 7
Different forms of ADT different CVE risks? Urologische Klinik und Poliklinik Crawford ED et al, Urol Oncol, 2017 8
Different forms of ADT different CVE risks? Urologische Klinik und Poliklinik 9
Pooled data analysis of 6 RCTs Urologische Klinik und Poliklinik Study Duration (mo.) Comparator Publication CS21 T 0.5 ng/ml CS35 IPSS/QoL/PSA/T CS37 PSA/QoL CS28 LUTS improvement CS30 prostate size reduction CS31 prostate size reduction 12 Leuprolide Klotz et al. BJU Int 2008 12 Goserelin Shore et al. SUO 2012 7-12 Leuprolide unpublished in complete design 3 Goserelin b Anderson et al. Urol Int 2012 3 Goserelin b Mason et al. Clin Oncol 2013 3 Goserelin b Axcrona et al. BJU Int 2012 Data on pre-existing comorbid diseases reported by pts. and classified by study investigators according to MedDRA before analysis 10
Design Urologische Klinik und Poliklinik 2328 pts. 1491 Degarelix 837 GnRH Agonist 458 Goserelin 379 Leuprolide 463 (31%) Preexisting CV conditions 245 (29 %) CVE defined as arterial embolic and thrombotic events, hemorrhagic and ischemic CV conditions, MI or other ischemic heart disease Primary end point: CVE or death 11
Results: pts. with preexisting CVE Urologische Klinik und Poliklinik HR=0,44 (95 % CI 0,26 0,74) p=0,002 No differences in men without preexisting CV conditions! 12
Results: all pts. Urologische Klinik und Poliklinik HR=0,60 (95 % CI 0,41 0,87) p=0,008 Total significance achieved by pts. with preexisting CV conditions! 13
Results: all pts. Urologische Klinik und Poliklinik Powered by CS37 unpublished at the time of the analysis 14
Significance overall vs. subgroups Urologische Klinik und Poliklinik significant nonsignificant CV conditions No preexisting CV conditions Practice changing for all? 15
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
Hypothesis generating Practice changing Not only HTN, but also AV-malformation, aneurysms https://maismaismedicina.wordpress.com 17
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
Population-based data 19
Population-based data Primary end point: HR for MI or ischemic stroke requiring hospitalization more focussed on the issue of arterial plaques stability!!!!!! 20
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
Comparison of covariates Statin Alcohol Hypertension Smoker Cholesterol Type 2 diabetes treated Hypertension treated Age Testosterone BMI Age CAD Diabetes Heart failure Arterial thrombosis Hypertension Obesity Alcohol Dyslipidamia Anticoagulant drugs CKD Smoker Statin Hemorrhagic stroke Ischemic stroke COPD Atrial fibrillation Anti-platelet agents 22
Arch of Titus, Rome 23
Meta-analysis CS 37 not included because not published!!! Study quality cannot be assessed!!! 24
Meta-analysis Severe CVE defined as QT-interval increase, angina pectoris, atrial fibrillation, cardiac failure and myocardial ischemia No significant difference Agonists Antagonists!!! 25
Recommendations EAU Guideline Prostate Cancer 2018 26
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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