Per$nent ques$ons. Is ADT promo+ng CVD? Why ADT may promote CVD? What can we do about it?

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Eunice Osborne
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2 Per$nent ques$ons Is ADT promo+ng CVD? Why ADT may promote CVD? What can we do about it?

3 PC pa$ents are at high risk of CVD Ø Risk of MI, stroke, or CV death in PC pa+ents >2% per year 1, 2 Ø Risk of MI, stroke, or CV death in PC pa+ents on ADT >4% per year 1, 2 Ø CVD risk considered high if global risk es+mate for hard CVD events of 2% per year 3 1. Kea+ng, et al. JNCI 2010; 102: O Farrell, et al. JCO 2015; 102: Greenland et al American Heart Associa+on Guideline for Assessment of Cardiovascular Risk in Asymptoma+c Adults. Circula0on 2010; 122: e584

4 Risk of Diabetes, CAD, MI, Sudden Death and Stroke with ADT Treatment US Veterans with Locoregional PCa (% per year) % Risk per year Diabetes CAD MI Sudden Cardiac Death Stroke No ADT LHRH agonist Orchiectomy Combined androgen blockade Oral an+androgen Keating NL, et al. J Natl Cancer Inst 2009;102:39-46

5 ADT is associated with an increased risk of CVD in observa$onal studies Zhao, et al. PLoS One 2014; 9: e107516

6 Randomized Trials of ADT vs. Control: CV Mortality No./ Total No. of Events Source ADT Control Relative Risk (95% CI) Favors ADT Favors Control P Value D Amico et al, (DFCI ) 13/102 13/ ( ).96 Messing et al, (ECOG/EST 3886) 3/47 1/ ( ).30 Bolla et al, (EORTC 22863) 22/207 17/ ( ).39 Schröder et al, (EORTC 30846) 10/119 10/ ( ).94 Studer et al, (EORTC 30891) 88/492 97/ ( ).47 Efstathiou et al, (RTOG 85-31) 52/477 65/ ( ).17 Roach et al, (RTOG 86-10) 31/224 26/ ( ).40 Denham et al, (TROG 96.01) 36/532 23/ ( ).37 Overall Test for heterogeneity: Q = 5.12; P =.64; I 2 = 0% 255/ / ( ) Relative Risk (95% CI) 10 Nguyen, et al. JAMA 306: 2359.

7 The Role of Androgen Depriva+on Therapy in CArdiovascular Disease A Longitudinal Prostate Cancer Study (RADICAL PC1) A RAndomizeD Interven+on for Cardiovascular And Lifestyle Risk Factors in Prostate Cancer Pa+ents (RADICAL PC2)

8 Baseline Cancer Characteris+cs Characteris$c New PC; no ADT N=497 ADT N=140 P- value Metasta+c PC, % 5% 15% < Radical prostatectomy, % 26% 16% Radiotherapy, % 13% 20% 0.039

9 Characteris$c Tobacco use, % Never Former Current Baseline CV Characteris$cs New PC; no ADT N=497 47% 43% 10% ADT N=140 34% 57% 9% P- value Diabetes, % 15% 24% Coronary disease, % 12% 25% Cerebrovascular disease, % 6% 5% 1.0 Sta+n, % 42% 55% Total cholesterol, mmol/l 4.5± ± LDL cholesterol, mmol/l 2.5± ± An+platelet/an+coagulant, % 33% 45% Systolic BP, mmhg 138±18 138± Diastolic BP, mmhg 82±12 81± Unrecognized HT, % 22% 21% 0.91 Age, years 67±8.0 72±8.8 <0.0001

10 Is ADT promo+ng CVD? Higher baseline CVD More prevalent CVS preven+on PC pa+ent with no ADT PC pa+ent commencing on ADT

11 Primary preven$on Hypertension Pre- exis$ng CAD Hyper- chol Obesity cardio- friendly ADT modality Age Prostate cancer pa$ent

12 How might ADT accelerate CVD? CVS (atherosclerosis) risk factors Dysglycemia Central adiposity Dyslipidemia Changes in life style Testosterone FSH Plaque vulnerability Cardiovascular event Testosterone FSH

13 Control (sham surgery + vehicle) Bilateral orchiectomy (+ vehicle) GnRH-agonist, leuprolide (+ sham surgery) GnRH-antagonist, degarelix (+ sham surgery)

14 ADT induced obesity N = 6 per group Hopmans SN, et al. Urol Oncol 2014;32:

15 ADT induced glucose intolerance Hopmans SN, et al. Urol Oncol 2014;32:

16 ADT induced (de- novo) atherosclerosis Hopmans SN, et al. Urol Oncol 2014;32:

18 Suppression of serum FSH and its physiological ac$vity is significantly be]er with GnRH antagonists than agonists

FSHR expression in different tissue Affymetrix ID# 21111-_s_at 1.

19 FSHR expression Follicle-stimulating hormone receptor Gene/RefSeq 2 : FSHR (NP_000136) Normalized expression FSHR expression in different tissue Affymetrix ID# _s_at 1. Data source: 2. Tivesten A, Pinthus J et al. Submitted 2014

20 24h 100 ng/ml FSH cona- induced control Foam cells play a signiﬁcant role in plaque progression and instability 93 kda LHR 75 kda FSHR 42 kda ac+n Jan Steffel et al. Circulation. 2006;113: Mac3- ICC Control (charcoal- stripped FBS) 24h 100 ng/ml FSH

21 Clinical data Retrospec$ve post- hoc analysis

25 Clinical data Pilot prospec$ve randomized trial AUA 2017 annual mee+ng Abstract #

26 Abstract # (PI- Prof. David Margel) Sixty- six pa+ents with pre- exis+ng CVD were randomized (33 antagonist vs.33 agonist). A Cardiovascular event was considered one of the following: myocardial infarc+on, ischaemic or haemorrhagic cerebrovascular event, arterial embolic and thrombo+c events, emergency room visit or hospitaliza$on due to ischaemic heart disease, coronary artery or iliofemoral artery revasculariza+on, peripheral vascular disease (vascular surgery/ interven+on). median follow up of 8.5 months

28 Those were real events.

29 Adjusted Odds Ra$os for Pre- Opera$ve BNP/NT- probnp to Predict Cardiovascular Outcomes at 30 Days Ager Surgery Karthikeyan et al Journal of the American College of Cardiology 2009

30 No event Event 47% of pa+ents who had a decreased of <60% in serum FSH levels within 3m had an event compared to 7% event rate in pa+ents experiencing >60% decreased in d FSH in 3m (p=0.0014) Within the agonist arm, pa+ents with a lower than 40% FSH decrease were twice as much likely to experience a cardiovascular event (28% vs. 57%).

31 Prostate cancer pa+ents needing ADT have higher baseline cardiovascular disease characteris+cs and risk factors. The ques+on therefore may be not as much as whether ADT promotes CVD, but rather how to prevent it in this pa+ent popula+on? 1. GnRH antagonists? Other FSH inhibitors? and/or 2. Rou+ne Primary/secondary CVD preven+on?

32 Treatment Strategies for CVD Primary Preven$on Non- Drug 1. Diet 2. Exercise 3. Non- smoking Drug 1. Aspirin 2. Cholesterol Sta+n 3. Blood pressure ACE- I or ARB

34 RADICAL PC2 - Objec$ves PRIMARY: To determine whether systema+c CV and lifestyle risk factor modifica+on strategy reduces the risk of CVD in men with a new diagnosis of PC or who are commencing ADT

New prostate cancer (diagnosed within 1 year) or commencing ADT for the 1 st +me N=6000 RADICAL PC1 Observa+onal registry N=1884 RADICAL PC2 Randomized,

35 New prostate cancer (diagnosed within 1 year) or commencing ADT for the 1 st +me N=6000 RADICAL PC1 Observa+onal registry N=1884 RADICAL PC2 Randomized, controlled trial N=4116 Interven$on: Systema+c CV risk factor management N=2058 Control: Usual care N=2058 Clinical outcomes (N=6000) at average 3 years follow- up

36 Pa+ents are eligible for RADICAL PC1, but not eligible for RADICAL PC2 if: they see a cardiologist every year; or they are undertaking ALL of the following: aspirin use sta+n use ACE- I or ARB use exercise 4 +mes per week

37 Interven$on in RADICAL PC2 Randomized in an open manner to STANDARD CARE, or INTERVENTION, which consists of a systema+c risk factor management approach: Aspirin Sta+n ACE- I for BP >130/80 Dietary counseling Exercise advice Support to quit smoking

38 Study procedure Baseline visit *3- month phone *6- month phone 12- month visit *18- month phone 24- month visit *36- month phone Close- out visit Past medical history X Medica$ons X X X X X X X X Vital signs X X X X Anthropometrics Handgrip strength Timed get- up- and- go test Six- minute walk test Results of rou$ne blood tests X X X X FFQ X X X X X X X X PAQ X X X X X X X X ECOG X X DSS test PHQ- 9 SAGE IIEF5 Clinical outcome X X X X X X X events Drug adverse effects X X X X X X X *Telephone visits for RADICAL PC2 only

39 Outcomes Composite primary efficacy outcome: Cardiovascular death Myocardial infarc+on Stroke Heart failure Arterial revasculariza+on Does systema+c CV and lifestyle risk factor modifica+on strategy reduces the risk of CVD in men with a new diagnosis of PC? Does systema+c CV and lifestyle risk factor modifica+on strategy reduces the risk of CVD in PC pa+ents commencing ADT? With systema+c CV and lifestyle risk factor modifica+on strategy is there a CVS safety benefit for a specific ADT modality?

40 Special thanks to: Darryl Leong MD, PhD Helga Duivenvoorden, PhD David Margel MD, PhD

Cardiovascular Complica/ons of ADT: Reviewing Pre- clincal and Clinical Data and Introducing the RADICAL- PC Trial

Cardiovascular Complica/ons of ADT: Reviewing Pre- clincal and Clinical Data and Introducing the RADICAL- PC Trial Jehonathan H. Pinthus MD, Ph.D. Associate professor Department of Surgery- Urology McMaster