Paul F. Schellhammer, MD, FACS Professor Eastern Virginia Medical School Norfolk, Virginia

5-year prostate cancer specific survival rates have improved from 67% to 99% between 1974 and 2000 Excellent survival data do not reflect the real problems for patients at risk for morbidity and mortality due to advanced or advancing disease

PSA/M1/CaP Deaths Baylor Washington University Mayo Clinic Johns Hopkins Number of Men 1,000 3,478 3,170 2,404 Metastases (10 yrs) 16% N/A 18% 10% Dead due to CaP (10 yrs) 2% 3% 10% 6%

Anatomical A, B, C, D T 1,2,3,4 N+, M+ Biological Grade, PSA (kinetics - Pre / Post) Hormonal Status Androgen dependant Androgen independent Castrate Independent Hormone refractory

First-Line Hormone Therapy, Prostate Cancer, United States, 2008 Hormone Therapy % of Patients LHRH analog only, continuous 38.2 CAB, continuous 25.5 LHRH analog, intermittent 17.3 CAB, intermittent 9.2 Orchiectomy only 5.0 Antiandrogen only 2.7 5-alpha-reductase inhibitor only 1.4 Diethylstilbestrol only 0.8 Abbreviation: CAB=complete androgen blockade. Source: Survey of 128 physicians who treat a total of 10,741 prostate cancer patients monthly, conducted in August 2008; Mattson Jack DaVinci, The Mattson Jack Group, Inc.

6500 men in 20 trials of CAB vs monotherapy nilutamide or flutamide CAB better by 2.9% at 5 years 27.6% vs 24.7% (SE 1.3) Log rank 2p=0.05 Lancet 2000,355:1496

Japanese men with untreated advanced CaP: Stage C/D (T 3, N+, M+) Significant OS advantage in favor of CAB with bicalutamide 80mg vs LHRH-A monotherapy 5-year OS estimated by the Kaplan-Meier method was 75.3% for CAB vs 63,4% for LHRH-A monotherapy log-rank test: P=0.0425 CANCER 2009,115:3437

For M+ CaP, ADT is superior to therapy for any other adult epithelial cancer >50% M+ still alive at 24 months (median) BUT IT CAN BE BETTER!

Surgery / Radiation Under the Care of UROLOGIST Under the Care of ONCOLOGIST Traditional Hormonal Therapy Antiandrogen Androgen Deprivation (CAB) Others Transdermal Estradiol Ketoconizole MDV-3100 Abiraterone Chemotherapy Local Therapy Therapies After LHRH Agonists and Antiandrogens Death Postchemotherapy PROVENGE TAXOTERE JEVTANA ZIBOTENTAN 9

Controversy whether there is a relationship between ADT and cardiovascular events and mortality [CA Cancer J Clin.60(3):194-201, 2010] Patients receiving ADT need to also receive appropriate secondary preventive measures: Lipid lowering therapy Antihypertensive therapy Glucose-lowering therapy Anti-platelet therapy

60 yr old 5 years post RP pt3a, Gleason 4+4 1 st PSA Rise - Two yrs PO Salvage EBRT + 6 mos A.D. 2 nd PSA Rise CAB X 2 yrs 3 rd PSA Rise continues after AAW Age 65 - PSA 3.0 What is Disease State?

Rising PSA after A.D. Hormone refractory - No Androgen independent - No Castrate resistant - Maybe If to med / surg cast - Yes and T<50/20 ng/dl If to all serum and -?? / No tissue T

< 50 ng/dl Traditional FDA cut point (assay limitation/lhrha approval) <20 ng/dl - Orchiectomy cut point/ more senstive assay <1 or 0.1 ng/dl Ultrasensitive assay Furthermore, serum T tissue T

Historically Testosterone = Serum T by conventional assay (endocrine) Today and Future Serum T by ultra-sensative assay Tissue T (paracrine)

Androgen levels in CaP tissue are sufficient to drive the androgen receptor even in a castrate state Benign Prostate (n=32;gray) Castration-Recurrent CaP (n=23;white) Mohler J et al, Clin Cancer Res, 2004;10(2):440-8

Not only is androgen present in the tissue, but enzymes needed to generate androgens are there it is self-sustaining Montgomery R et al. Cancer Res 2008;68(11):4447-4454

50 45 43.8 Patients (%) 40 35 30 25 20 31.5 24.7 < 20 ng/dl 20-50 ng/dl > 50 ng/dl 15 10 5 0 Testosterone (ng/dl) Morote et al. J Urol 2007;178:1290-1295

120 106 P =.0207 AIPC Survival (mo) 100 80 60 40 90 72 < 20 ng/dl 20-50 ng/dl > 50 ng/dl 20 0 Testosterone (ng/dl) Morote et al. J Urol 2007;178:1290-1295

Breakthrough increases of serum T are not only frequent but also have clinical implications for PSA progression There is a direct relationship between T increases (even in 20-50 range) and PSA progression

162 M1 pts monitored with q3mos PSA + T at LHRH-A inj T at 6 months correlates with survival; p<0.05 and remains so on MV analysis EXAMPLE: patient with Gleason Score =7, PSA 50, at 6 months If T = 10ng/ml 60% 5-year survival If T = 40 ng/ml 54% 5-year survival BJU Int 2009;105:648 J Urol 2008; 179 (suppl)

Response should be monitored by measuring serum levels of testosterone

Amplification - Quantitative Hypersensitivity - Qualitative Mutation - Alternative Promiscuity - Available LIAR Ligand Independent (Cytokines, protein kinasis)

Even a small amount of androgen can fuel tumor proliferation AR increase captures any small amount of androgen available Increase coactivators and corepressors, which sensitize the ARs to androgen and nonandrogen ligands Androgen to undetectable levels is critical to control of advanced prostate cancer Question Initial or Subsequent Strategy?

Concept authentic Agents suboptimal against Ligand T Receptor Re-evaluation / Re-application (new agents) Serum Tissue T, DHT, DHEA, Epi A

Adrenal and tissue androgen synthesis inhibitors Ketoconazole, abiraterone acetate AR inhibitors: MDV3100 Estrogen: Estradiol transdermal patch 5-ARI: finasteride, dutasteride Alternate current anti-androgens GnRH antagonists: degarelix

Absorbed best in acidic milieu Dose q. 8 hrs Individualize dose Maximally tolerated dose can range from 100 to 800 mg every 8 hours. Start at 100-200 mgs & slowly increase if necessary

Drugs made more active by Ketoconazole Statins Erythromycin & related (Z-pack) Calcium channel blockers (Norvasc, Procardia) Alprazolam (Xanax) SSRIs (Zoloft, Celexa, Lexapro, Prozac) Pain relief - acetaminophen (Tylenol)

Ketoconazole combined with hydrocortisone and dutasteride in asymptomatic castration-resistant CaP Response proportion to combination was at least comparable to prior studies of ketoconazole alone Time-to-progression for combination was substantially longer Combination warrants further investigation Clin Cancer Res 2009;15 (22):7099-7105

Maximal change in PSA from baseline among 57 CRPC pts treated with KHAD >50% PSA decline = 56% >90% PSA decline = 28% 30% objective response Median response 20 months Clin Cancer Res 2009;15 (22):7099-7105

Orally administered C17,20 lyase, 17 α-hydroxylase inhibitor Inhibits 3 sources of androgen production: testis, adrenals and tumor 10x more powerful Irreversible

Androgens produced at 3 critical sites lead to tumor growth Testes Adrenal glands Prostate tumor cells Abiraterone inhibits biosynthesis of androgens that stimulate tumor cell growth 1-5 Sources: 1. Attard et al. J Clin Oncol. 2008 2. Attard et al. J Clin Oncol. 2009; 3. Reid et al. J Clin Oncol. 2010; 4. Ryan et al. J Clin Oncol. 2009; 5. Danila et al. J Clin Oncol. 2010.

OH O O O HO P450 SCC Aldosterone HO Cholesterol HO O O Pregnenolone Progesterone Corticosterone P450 17α 21-hydroxylase (17α-hydroxylase) 11β-hydroxylase OH O O O OH OH HO OH HO O O 17α-Hydroxypregnenolone 17α-Hydroxyprogesterone Cortisol P450 17α (C 17,20 -lyase) O O testosterone 5α-reductase OH OH HO O O O H Dehydroepiandrosterone Androstenedione Testosterone 5α-Dihydrotestosterone

O O O HO OH P450 SCC Aldosterone HO Cholesterol HO O O Pregnenolone Progesterone Corticosterone P450 17α 21-hydroxylase (17α-hydroxylase) 11β-hydroxylase OH O O O OH OH HO OH HO O O 17α-Hydroxypregnenolone 17α-Hydroxyprogesterone Cortisol P450 17α (C 17,20 -lyase) O O testosterone 5α-reductase OH Synthesi s Increase d By ACTH OH HO O O O H Dehydroepiandrosterone Androstenedione Testosterone 5α-Dihydrotestosterone

96 patients with CRPC 88 M+ chemo-naïve Dose 1000 mg PSA decline > 50% decline: 67% pts > 90% decline: 19% pts Objective response: 37% CTC > 5 to < 5 = 59% JCO 27, 2009

Attard et al. J Clin Oncol. 2009. Prechemotherapy Ryan et al. ASCO. 2010. 30% PSA Decline 90.0% 50% PSA Decline 87.9% 90% PSA Decline 48.5% Danila et al. J Clin Oncol. 2010. Postchemotherapy 30% PSA Decline 68.1% 50% PSA Decline 51.1% 90% PSA Decline 14.9% Reid et al. J Clin Oncol. 2010.

CRPC M1 Randomization 2:1 Abiraterone 1000 mg daily Prednisone 10 mg daily Placebo daily Prednisone 10 mg daily Overall Survival 25% Completed 2009 - Results 2010

Abiraterone (n=797) Placebo (n=398) Total (n=1195) Median age, years (range) 69.0 (42-95) 69.0 (39-90) 69.0 (39-95) Race, % White 93.3 92.7 93.1 Black 3.5 3.8 3.6 Asian 1.4 2.3 1.7 ECOG PS 2, % 10.7 11.1 10.8 Significant pain present, % 44.3 44.0 44.2 2 Prior chemotherapies, % 28.2 28.4 28.3

Primary site of disease, % Abiraterone (n=797) Placebo (n=398) Bone 89.2 90.4 Node 45.4 41.5 Liver 11.3 7.6 Lung 13.0 11.4

100 80 HR=0.646 (0.54-0.77) P <0.0001 Abiraterone: 14.8 months (95% CI: 14.1, 15.4) Overall Survival, % 60 40 20 0 Placebo: 10.9 months (95% CI: 10.2, 12.0) 1 Prior Chemo OS: 15.4 months abiraterone vs 11.5 months placebo 0 100 200 300 400 500 600 700 Days from Randomization Abiraterone 797 728 631 475 204 25 0 Placebo 398 352 296 180 69 8 1

Abiraterone (n=791) Placebo (n=394) AE, % All Grades Grades 3/4 All Grades Grades 3/4 Fluid retention 30.5 2.3 22.3 1.0 Hypokalemia 17.1 3.8 8.4 0.8 LFT abnormalities 10.4 3.5 8.1 3.0 Hypertension 9.7 1.3 7.9 0.3 Cardiac disorders 13.3 4.1 10.4 2.3

CRPC Non-Metastatic 1:1 Abiraterone 1000 mg daily Prednisone 10 mg daily Placebo daily Prednisone 10 mg daily Progression Free & Survival 25%

Blocks androgen receptor with greater affinity than bicalutamide Impairs nuclear translocation and DNA binding of the androgen receptor Disables co-activators

114 pts with CRPC M+ >50% fall in PSA 37/65 (57%) CTx naïve 24/49 (50%) CTx CTC 21/43 ( 50%) unfavorable to favorable Well tolerated dose 160 mg for Phase III Phase III trial to open ASCO GU-2009; Abst 151, 5011

MDV 3100 (160 mg) CRPC M1 Randomized 2:1 Survival 25% Pcb or Prednisone

We suggest that the equivalence of the 1.0 and 5.0 mg doses plus the apparent superiority of 5.0 mg DES over orchiectomy alone in retarding cancer growth indicated that DES acts directly on the cancer cells in addition to inhibiting testosterone secretion. Byer NCI Mongr 1998;7:165-170

BJU 1991; 67:84

VAURG Trial: Oral estrogens: (DES) cancer specific survival but lower overall survival, due to CV & TE events LHRH A: avoids CV & TE events of oral estrogens but causes bone, lipid, cognitive changes Estrogen transdermal delivery can reduce/ avoid CV, TE and bone/cognitive side effects Win:Win - Better efficacy, reduced AE and better QOL

T No aromatization E Erectile dysfunction Osteoporosis Sarcopenia Lipid changes Weight gain Hot flashes Diabetes Cognitive dysfunction

Estradiol suppresses tissue androgens and CaP growth in castration resistant disease Estrogen suppresses tumoral androgens despite castrate T levels BMC Cancer 2010; 10: 244

Newly diagnosed or relapsing patients with locally advanced or metastatic prostate cancer Control Arm 2200 Randomization Investigational Arm LHRH analogues given as per local practice indefinitely Transcutaneous estrogen patches indefinitely Primary endpoint: Overall Survival Secondary Endpoint: Castrate T, PSA failure, Toxicity, QOL, Prostate Specific Mortality

Percent Survival 100 75 50 25 Placebo (n = 171) Median Survival: 21.7 Mos. P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Sipuleucel-T (n = 341) Median Survival: 25.8 Mos. 0 0 6 12 18 24 30 36 42 48 54 60 66 Survival (Months) Kantoff P, et al. NEJM 2010; 363:411

Trial / Agent Approved Disease State Comparator Hazard Ratio Difference in OS, months P Value IMPACT 1 (Provenge) 2010 TAX327 2 (Taxotere) 2004 TROPIC 3 (Jevtana) 2010 COU-AA-301 (Abiraterone acetate) 2010 Chemo-naive CRPC Chemo-naive CRPC Postdocetaxel CRPC Postdocetaxel CRPC Placebo 0.775 4.1 0.032 Mitoxantrone Prednisone Mitoxantrone Prednisone Placebo Prednisone Sources: 1. Kantoff et al. N Engl J Med. 2010;363:411-422; 2. Tannock et al. N Engl J Med. 2004;351:1502-1512; 3. debono et al. Lancet. 2010;376:1147-1154. 0.76 2.4 0.009 0.70 2.4 <0.0001 0.646 3.9 <0.0001

Non-met Or met Rising PSA Met-CRPC Rising PSA Met-CRPC clinical / Symptomatic Met-CRPC Post-Chemo Chemotherapy Urology Medical Oncology

Non-met Or met Rising PSA Met-CRPC Rising PSA Met-CRPC clinical / Symptomatic Met-CRPC Post-Chemo Abiraterone MDV 3100 Sipuleucel T Chemo Abiraterone MDV 3100 Sipuleucel T Urology and Medical Oncology

Paul F. Schellhammer, MD, FACS Professor Eastern Virginia Medical School Norfolk, Virginia

A 68-year-old male with T2b Gleason 4+4 cancer has opted for external beam radiation and three years of androgen deprivation. Past history reveals placement of cardiac stents at age 65, well controlled hypertension and diabetes, a vertebral compression fracture two years ago, and a 30 year pack history.

True / False While on AD, the patient is at risk for: Worsening hypertension Uncontrolled diabetes Osteoporosis

In addition to discussing decreased libido, energy, and prevalence of hot flashes, his urologist should: a. Communicate with primary care regarding BP, glucose, lipid, and anti-platelet therapy b. Schedule bone mineral density and plan antireabsorptive therapy c. Obtain 25 OH vitamin D level and begin vitamin D3 and calcium supplement d. Counsel patient regarding regular exercise and smoking cessation e. All the above

Oliver Sartor, M.D. LaBorde Professor of Cancer Research Depts. of Medicine and Urology Tulane Medical School New Orleans, LA