Management of ADT Metabolic

Complications: Assessment,

Monitoring, Interventions

Neal Shore , MD, FACS

Carolina Urologic Research Center

Myrtle Beach, SC, USA

APCCC 2019

carolinaurologicresearchcenter.com

Disclosures

• Research funding/consulting:– Amgen, Astellas, AstraZeneca, Bayer, BMS, Dendreon, Ferring,

Janssen, Merck, Myovant, Modra, Nymox, Pfizer, Sanofi-Genzyme, Tolmar

• Stock/salary: none

• Slide Content Contribution: Tanya Dorff, MD; Julie Graff, MD; and Alicia Morgans, MD

Complications of ADT

•Medical complications• Skeletal events• Cardiovascular disease• Diabetes• Neurocognitive disease• Other

•QOL complications• Hot flashes• Loss of libido• Erectile dysfunction• Fatigue• Other

ADT and Prostate Cancer

• ADT is the “Mainstay aka centerpiece, foundation, lynchpin, etc”

• Huggins and Hodges Nobel Prize 1966: ADT sine qua non of PCa management

• Delays progression/prolongs survival but with significant attendant risks

• Is our current management adequately addressing these risks?

Bluethmann SM, et al. Cancer Epidemiol Biomarkers Prev. 2016;25(7):1029-36

Heron M. National Vital Statistics Reports. 2016.

Leading cause of death in the US: CVD

• Coronary vasodilation• Intracoronary T causes coronary vasodilation• In men with CAD, T prolongs the time to ischemia on stress testing

• Plaque stability• Anti-arrhythmic effect and QT shortening• Favorable effect on body composition • In men with CAD low T is a marker of increased all-cause and

CV mortality

Protective Role of Androgens on the Cardiovascular System

Webb et al, Circulation 1999

• Low T Obesity• Weight gain after a year on ADT is about

1.5 - 4 kg and greater in younger and non-obese patients

• Increase in total body fat of up to 9-11% and decrease in lean body mass of 3-4%

• Sarcopenic obesity - abdominal obesity + reduced muscle mass associated with an increase in all-cause mortality

Tzortzis et al, Hormones 2017

Metabolic Changes with ADT - Obesity

ADT increases• Triglycerides levels (~26%)• Total cholesterol (~10%)• LDL levels (~7%)• HDL (8%-10 %)

ADT increases HDL but T is needed for reverse cholesterol transport from the arterial wall to the liver

Net effect is proatherogenic

ADT and Dyslipidemia

Braga-Basaria et al JCO 2006

• ADT metabolic aberrations are similar to but not identical to classic MEtS

• Prevalence 20-25% in adult population

• Male hypogonadism is an independent risk factor for metabolic syndrome, while low T and SHBG levels can predict MEtS in men

• 36-55% of men receiving ADT > 1 year develop MEtS, independent of age, race, and stage of PCa

ADT and Metabolic Syndrome

Tzortzis et al, Hormones 2017

Comorbid Conditions Are Highly Prevalent in Prostate Cancer

GI, gastrointestinal; NCI, National Cancer Institute; PCOS, Prostate Cancer Outcomes Study; SEER, Surveillance, Epidemiology and End Results.Republished with permission of American College of Physicians, from Effect of age, tumor risk, and comorbidity on competing risks for survival in a U.S. population-based cohort of men With prostate cancer, Daskivich TJ et al, Ann Intern Med. 2013;158(10):709-717, © 2013; permission conveyed through Copyright Clearance Center, Inc.

PCOS: A population-based cohort of men diagnosed with nonmetastatic prostate cancer ascertained from the NCI (SEER) program [N=3,183]

ComorbidityWith 1 Comorbidity

(n, %)With 2 Comorbidities

(n, %)With >3 Comorbidities

(n, %)Cardiovascular Diseases* 526 (51) 511 (49) 874 (56)Arthritis / Rheumatism 207 (20) 176 (17) 207 (13)Diabetes Mellitus 93 (9) 176 (17) 179 (11)Depression 50 (5) 63 (6) 105 (7)Bleeding GI Ulcer 48 (5) 38 (4) 61 (4)Chronic Lung Disease 45 (4) 35 (3) 61 (4)Inflammatory Bowel Disease 35 (3) 32 (3) 59 (4)Cirrhosis / Hepatic Disease 16 (2) 15 (1) 26 (2)

*Cardiovascular diseases include angina, congestive heart failure, hypertension, myocardial infarction, and stroke.

Comorbidities Impact Survival Among Men With Prostate Cancer

10-Year Non-prostate Cancer–related Survival Rates in Men Undergoing

Treatment for Prostate CancerComorbidity Survival Rate (%)No Comorbidity* 84

DM Without End-Organ Damage 65

History of Alcoholism 64

Peripheral Vascular Disease 51

DM With End-Organ Damage 50

Chronic Obstructive Pulmonary Disease 35

Chamie K et al. J Gen Intern Med. 2011;27(5):492-499.

*For men aged >75 years, 58% lived beyond 10 years.

DM, diabetes mellitus; VA, Veterans Administration.

41,362 men with PCa on ADT vs age-matched, PCa-free comparison

21% increased CVD risk in men on GnRH agonists c/w controls

CVD risk highest in the first 6 months of ADT in men who experienced two or more CV events within the year prior to therapy

O’Farrell et al. JCO 2015

Does ADT cause CVD?

Keating, et al. J Natl Cancer Inst. 2012. Tsai HK, et al. J Natl Cancer Inst. 2007.Alibhai SMH, et al. J Clin Oncol. 2009. Nguyen PL, et al. JAMA. 2011.

Current literature on ADT and increased CV risk is inconsistent. RCTs did not include higher cardiac risk elderly patients and hence

underpowered to assess CV outcomes. Cardiovascular outcomes were not studied as a primary end point. Not surprisingly, secondary analysis from these trials has failed to show an association between ADT and adverse cardiovascular sequelae, a finding that has been consistently shown in

large-scale observational studies.

ADT and Cardiovascular Risk

O’Farrell et al. JCO 2015

CVD Guidelines for Men on ADT

•NCCN Guidelines 2018:• Assess traditional risk factors for cardiovascular disease

• ABCDE approach• Team approach

• Primary care• Geriatrician• Cardio-oncologist or cardiologist

NCCN Prostate Cancer V2.2018 Bhatia N, et al. Circulation.

2016

Bhatia et. al. Circulation 2016

10,422 men with nonmetastatic Pca in the CPS-II Nutrition Cohort

In men with high-risk PCa post diagnosis daily aspirin use was associated with lower PCSM (HR = 0.60; 95% CI, 0.37 to 0.97)

Platelet inhibition has anti-tumor activity. Activated platelets promote cancer metastasis through multiple mechanisms

Jacobs et al. JCO. 2014

Cardiovascular Disease

• GnRH agonistØ Coronary Heart Disease

adjusted HR, 1.16; P< 0.001Ø Myocardial Infarction

adjusted HR, 1.11; P = 0.03Ø Sudden Cardiac Death

adjusted HR 1.16; P = 0.004

FDA Warning in 2010

Are GnRH antagonists safer?

Retrospective pooled Analysis of 6 trials. N = 2328708 had baseline CV disease

Predictors of cardiac event or death

Eur Urol 2014; 65: 565-573JCO 2006: 24: 4448-4456

Future Directions

• PRONOUNCE Study (NCT02663908): degarelix v. leuprolide• 900 participants with predefined cardiac disease• Primary endpoint: Time from randomization to first confirmed (adjudicated)

occurrence of composite Major Adverse Event (MACE) timepoint (up to 336 days)

• MACE = death from any cause, non-fatal myocardial infarction, non-fatal stroke

Algorithms Developed to Address Treatment for Prostate Cancer Patients

Bhatia N et al. Circulation. 2016;133(5):537-541.

Screen for Pre-Existing CV Disease and Untreated or Under-Treated Metabolic CV Risk Factors

Pre-Existing CV Disease

History and Physical Examination Lipid Panel Hemoglobin A1c

• Evaluate and Treat per ACC/AHA Guidelines

• Consider ACE Inhibitors for Hypertension

• Angina• Congestive Heart

Failure• Valvular Disease• Arrhythmias• Hypertension

• Treat per ACC/AHA Guidelines

• Consider High Potency Statin

• Manage as High Risk per ADA Guidelines

• Consider Metformin

Screen and Counsel for Psychological Stress

• Health Promotion per Prostate Cancer Survivorship Guidelines

• Consider Aspirin 81 mg

• No Evidence of CV Disease

• Electrocardiogram• Echocardiogram, if

Indicated

• Abnormal

Diagnosis of Prostate Cancer and Consideration for Starting ADT

Refer to Cardio-Oncology Clinic If Concern for Presence or Risk of CV Disease

The Emergence of Cardio-Oncologists

• Cardiologists not trained to treat cancer patients• Centers with cardio-oncology services have doubled since

2014• Cardio-oncologists involved in:

• Assessing pre-treatment risk• Regimen decisions• CV adverse effects of cancer treatment• Diminishing risks of CVD in survivorship

• Almost 1/2 cardiovascular training programs now incorporate cardio-oncology topics in their core curriculum

Hayak SS, et al. J Am Coll Cardiol. 2019;73(17):2226-2235

Questions:•What is the clinician’s role in assessing cardiovascular risk factors in PCa patients who undergo ADT?

•Should patients be referred for co-management of cardiovascular risk factors with a PCP or a cardiologist?

•Are other medications indicated for primary prevention of cardiovascular or prostate cancer risk (aspirin, statin, metformin,etc.)?

•Role of nutrition and exercise?

• Abdominal obesity + pro-inflammatory adipokines such as TNF-α, IL-6, and resistin are increased

• ADT decreases insulin sensitivity in non-diabetic men within 12 weeks

• Increased fasting plasma insulin by 26% and decreased insulin sensitivity by 13%

• Data from SEER, n = 73,196 PCa treated with GnRH agonists had a higher DM incidence (HR 1.42)

• ADT might worsen glycemic control and increase HbA1c in diabetics

Metabolic Changes with ADT - Insulin Resistance

Keating et al, JCO 2006

• MET addition to ADT had no impact on risk of metabolic syndrome and no additional anti-tumor effects

• MET-controlled hyperinsulinemia related to diabetes does not imply MET has similar action on ADT-related hyperinsulinemia

AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3269

DM Guidelines for Men on ADT

• NCCN Guidelines 2018:• Rely on traditional assessments of risk factors for

diabetes• Team approach

• Primary care• Geriatrician• Endocrinology

NCCN Prostate Cancer V2.2017

Bhatia N, et al. Circulation. 2016

Nutrition: General Comments

• Heart disease remains a greater threat to many prostate cancer patients than the cancer itself

• Heart healthy diet: less meat, more veggies

• Some evidence that diet can influence prostate cancer• Low fat/vegan1 diet in active surveillance decreased PSA 4%

compared to average 6% increase in control

• MEAL study: plant-based diet failed to note improvement in PSA (7 veg servings per day, 1 serving legumes)2

• U Mass study showed improvement in PSA DT – pt + spouse taught to increase whole grain, legume, green/yellow veg and decrease animal origin, and processed foods3

1. Ornish D et al, J Urol 2005; 174:10652. Parsons JK et al. Urol 20083. Saxe GA et al. J Urol 2001; 166:2202

15 studies, 1135 patients

Exercise can significantly improve the upper and lower muscle strength, increase exercise tolerance, help PCapatients receiving ADT control their body fat mass, BMI, lower cholesterol and keep sex function

No systematic difference was observed between resistance and aerobic exercise training

Yunfeng et al, Medicine 2017

Optimization of Androgen Deprivation Therapy in Prostate Cancer: A Practical Guide for Clinicians

ØEither the urologist or the PCP should monitor blood pressure (at each visit), HbA1c (annually in non-diabetic patients), and lipid profile (annually) in patients receiving ADT.

93% Yes; 7% Indeterminate

ØPrior to initiating ADT, patients with CVD comorbidities should be referred to a cardiologist for co-management.

100% Yes

Publication in progress.

N. Shore, MD; E. Antonarakis , MD; M. Cookson , MD; E. Crawford, MD; A. Morgans, MD; D. Albala, MD; J. Hafron, MD; R. Harris, MD; D. Saltzstein, MD; G. Brown, DO; J. Henderson, MD; B. Lowentritt, MD; J. Spier, MD; R. Concepcion, MD

Optimization of Androgen Deprivation Therapy in Prostate Cancer: A Practical Guide for Clinicians

Publication in progress.

N. Shore, MD; E. Antonarakis , MD; M. Cookson , MD; E. Crawford, MD; A. Morgans, MD; D. Albala, MD; J. Hafron, MD; R. Harris, MD; D. Saltzstein, MD; G. Brown, DO; J. Henderson, MD; B. Lowentritt, MD; J. Spier, MD; R. Concepcion, MD

Ø There is no evidence to support taking metformin to improve PCa-specific outcomes.

86% Yes, 14% Indeterminate

Ø The urologist should communicate with the PCP or endocrinologist when patients with diabetes initiate ADT as they may need closer monitoring of diabetes.

86% Yes; 14% Indeterminate

Ø HbA1c should be monitored up to annually by a cancer care provider or PCP in patients without a history of diabetes.

86% Yes; 7% No; 7% Indeterminate

Ø Cancer-treating physicians should encourage physical activity/exercise, healthy diet, weight control, and smoking cessation in all patients on ADT throughout the course of their treatment.

100% Yes

Have a Drink!

• Men without cancer who drink alcohol have a lower risk of lethal prostate cancer

• Men with Prostate Cancer who drink red wine have a lower risk of lethal disease progression

• 15 – 30 grams of total alcohol after Prostate Cancer diagnosis associated with lower risk of death

Downer MK, et al. J Clin Oncol. 2019;37(17):1499-1511

Conclusions

•Treatment with ADT is a ‘mainstay’ in one of the most common cancers among men, globally.

•Silver Tsunami-expanding geriatric aPC pop.

•Understanding the complications of ADT is critical to optimizing health outcomes for our patients.

Patients need primary care and cancer care providers to work together to prevent ADT

complications

Illness is the night-side of life, a more onerouscitizenship. Everyone who is born holds dualcitizenship, in the kingdom of the well and in thekingdom of the sick. Although we all prefer to useonly the good passport, sooner or later each of us isobliged, at least for a spell, to identify ourselves ascitizens of that other place.

…..Susan Sontag