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

Urologische Klinik und Poliklinik

University Medicine Mainz

ADT AND CARDIOVASCULAR RISK: should Antagonists be the primary choice for ADT?

Igor Tsaur

Urologische Klinik und Poliklinik

 Off-label use of drugs, devices, or other agents: none  Data from IRB-approved human research is presented: is not

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I have the following financial interests or relationships to disclose: Disclosure code Sanofi L Janssen C, L Ferring L Bayer C

COI

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Rubens, 1616 GOLIATH DAVID

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Rubens, 1616 ANTAGONISTS AGONISTS

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Keating NL et al, J Clin Oncol, 2006

Diabetes tes CHD MI MI Sudden en death No t treatm tment ent REF REF REF REF REF REF REF REF GnRH-Ag Agon

• nist

sts 1,44 44 <0,001 001 1,16 16 <0,001 001 1,11 11 0,03 03 1,16 16 0,004 004 OT OT 1,34 34 <0,001 001 0,99 99 0,74 74 0,94 94 0,44 44 1,01 01 0,85 85

73.196 .196 pati tient ents, 34 34,6% % GnRH RH-Agon gonist sts, 6,9 9 % OT Foll llow

• w-up

up 2-9 9 a. a.

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Different forms of ADT – different CVE risks?

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Everyday Urology – Oncology Insights, Vol. 2 (1)

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Agonists vs. antagonists

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 ADT associated with CVE

• Higher risk for GnRH-Agonists than OT1
• Highest risk for pts. with CVE in the past2,3

 Different function of GnRH-Antagonists compared to GnRH-Agonists

• Different CVE risk?
• Less arterial plaque rupture by GnRH-Antagonists blocking GnRH receptors
• n 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

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Different forms of ADT – different CVE risks?

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Different forms of ADT – different CVE risks?

Crawford ED et al, Urol Oncol, 2017

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Different forms of ADT – different CVE risks?

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 Data on pre-existing comorbid diseases reported by pts. and classified by study investigators according to MedDRA before analysis

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Study Duration (mo.) Comparator Publication CS21

T≤0.5 ng/ml

12 Leuprolide Klotz et al. BJU Int 2008 CS35

IPSS/QoL/PSA/T

12 Goserelin Shore et al. SUO 2012 CS37

PSA/QoL

7-12 Leuprolide unpublished in complete design CS28

LUTS improvement

3 Goserelinb Anderson et al. Urol Int 2012 CS30

prostate size reduction

3 Goserelinb Mason et al. Clin Oncol 2013 CS31

prostate size reduction

3 Goserelinb Axcrona et al. BJU Int 2012

Pooled data analysis of 6 RCTs

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2328 pts. 1491

Degarelix

837

GnRH Agonist

463 (31%)

Preexisting CV conditions

458 Goserelin 379 Leuprolide 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

Design

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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!

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Results: all pts.

HR=0,60 (95 % CI 0,41–0,87) p=0,008

 Total significance achieved by pts. with preexisting CV conditions!

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Results: all pts.

 Powered by CS37 – unpublished at the time of the analysis

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significant

Significance overall vs. subgroups nonsignificant

CV conditions No preexisting CV conditions

Practice changing for all?

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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!

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Hypothesis generating ≠ Practice changing

https://maismaismedicina.wordpress.com

Not only HTN, but also AV-malformation, aneurysms

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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?

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Population-based data

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Population-based data

 Primary end point: HR for MI or ischemic stroke requiring hospitalization more focussed on the issue of arterial plaques stability !!!!!!

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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

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Comparison of covariates

Statin Alcohol Hypertension Smoker

Cholesterol

Type 2 diabetes treated Hypertension treated Age

Testosterone

BMI Age

Dyslipidamia CAD Anticoagulant drugs

Diabetes

CKD Heart failure

Smoker

Arterial thrombosis

Statin Hypertension

Hemorrhagic stroke

Obesity

Ischemic stroke

Alcohol

COPD Atrial fibrillation Anti-platelet agents

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Arch of Titus, Rome

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Meta-analysis CS 37 not included because not published!!! Study quality cannot be assessed!!!

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Meta-analysis

 Severe CVE defined as QT-interval increase, angina pectoris, atrial fibrillation, cardiac failure and myocardial ischemia  No significant difference Agonists ↔ Antagonists!!!

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Recommendations

EAU Guideline Prostate Cancer 2018

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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……

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