Castrate resistance prostate cancer: Integrating novel agents 
into a therapeutic algorithm Charles J Ryan, MD Associate Professor of Medicine and Urology Helen Diller Family Comprehensive Cancer Center University of California, San Francisco U C S F

Since 2010… Four new drugs approved for advanced prostate cancer by the US FDA Three based on improvements in survival (Cabazi, Abiraterone, Sipuleucel T) (Initial phase I studies of abiraterone and Sip T done at UCSF in GU Medical Oncology Program) Two Others- Alpharadin (Radium 223) and MDV-3100 have shown OS Benefit in trials, FDA approval not yet granted.

+ = 1. How do we define Castration Resistant Prostate Cancer? Progression of Disease despite a suppressed (castrate) testosterone level (<50ng/dL) 2. What makes prostate cancer lethal and how do we assess prognosis in patients? + = Lethal Prostate cancer

Prostate Cancer Standards and Novel Therapies: Clinically Localized Rising PSA post RP/RT ADT Resistant Pre-Chemotherapy Chemotherapy CRPC Docetaxel Resistant AR Targeted Therapy Chemotherapy Immunotherapy Targeted Therapy U C S F

Prostate Cancer Standards and Novel Therapies: 2009 Clinically Localized Rising PSA post RP/RT ADT Resistant Pre-Chemotherapy Chemotherapy CRPC Docetaxel Resistant AR Targeted Therapy Chemotherapy Docetaxel (Standard) Immunotherapy Targeted Therapy U C S F Therapies showing a survival benefit

New Treatments for Advanced Prostate Cancer Targeting the T Cell Androgen Synthesis Inhibitors Second line chemotherapy Alpha-emitting Radio-isotopes U C S F

New Treatments for Advanced Prostate Cancer Targeting the T Cell U C S F

Theoretical Kinetics of Treatment Response: Cytotoxic Therapy vs Immunotherapy Cytotoxic chemotherapy quickly debulks tumors Resistance and tumor regrowth may occur Immunotherapy activates the immune system Clinical effect may take time to develop Responses may be sustained due to immunologic memory Time on treatment Chemotherapy Tumor size Progression Immunotherapy Time Webster et al. J Clin Oncol. 2005;23:8262.

Sipuleucel-T: Background Small EJ et al., J Clin Oncol 18: 3894, 2000

Sipuleucel-T : (second) Pivotal Trial Results Phase 3 design allowed for crossover from placebo to vaccine Adverse Events The pivotal trial was a randomized, multicenter, double-blind, controlled Phase 3 trial that enrolled 512 men with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer1,2,3 Men were randomized 2:1 to the treatment groups with 341 men randomized to receive PROVENGE and 171 men randomized to receive control1,2,3 Control was nonactivated, autologous, peripheral blood mononuclear cells 1,3 The primary endpoint was overall survival1,2,3 Following independent confirmation of objective disease progression (as determined by bone scan and CT imaging2,3), subjects were treated at the physician’s discretion1,2,3 Patients randomized to the control group had the option to enter a Phase 2, open-label protocol to receive an autologous immunotherapy made from cells that were cryopreserved at the time of control generation2 63.7% of patients in the control group entered the Phase 2, open-label protocol3 References PROVENGE [package insert]. Dendreon Corporation; April 2010. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration–resistant prostate cancer. N Engl J Med. 2010;363:411-422. D9902B Clinical Study Report; Biologics License Application: PROVENGE® (sipuleucel-T). October 2009. Seattle, WA: Dendreon Corporation. †Control was nonactivated, autologous, peripheral blood mononuclear cells. U C S F Kantoff PW et al. N Engl J Med. 2010;363:411-422.

Sipuleucel-T in CRPC: How do we use it? Sipuleucel-T prolongs life in patients with asymptomatic met CRPC Sipuleucel-T is extremely well tolerated For use only in asymptomatic CRPC with no visceral mets Not remission inducing My bias – use it early before advancing to prednisone-containing regimens (abiraterone, docetaxel, cabazitaxel, mitoxantrone all require steroids) U C S F

FDA Approves Sipuleucel-T on April 29, 2010 You +1‘d U C S F

New Treatments for Advanced Prostate Cancer CYP-17 Inhibitors U C S F

Keeping our eyes on the AR target…… “Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.” Charles Huggins MD Nobel Lecture Dec 13, 1966 Journal of Clinical Oncology 1997 Small and Vogelzang define “secondary hormonal therapy”

Matching Biology to Therapy along the Path to AR signaling Signaling Event Aberration Intervention Drugs Intracrine Production Ketoconazole - Abiraterone Tak-700 Tok-001 Androgen Production SCC Inhibitors CYP 17 Inihibitors Androgen Transport/Circulation/Uptake Pre -Receptor None Block Transport Polymorphisms 5-Alpha Reductase inhibitors Conversion to DHT Amplified 5 Alpha Reductase Dutasteride MDV-3100 ARN-509 Tok-001 AR Binding Amplified AR Splice Variant AR Novel AR Inhibitors Receptor

From Ryan and Tindall JCO 2011

Higher AR levels in CRPC tumors CRPC samples have robust AR expression Mohler et al Holzberlein et al Am J Pathology AR expression in Bone Marrow Mets Stanbrough et al Cancer Research 2006 At autopsy – 73% of 15 samples exhibit AR amplification. Friedlander/Paris et al U C S F Friedlander et al

Prostate Cancer can make its own androgens Montgomery RB et alCancer Res. 2008 Jun 1;68(11):4447-54

Abiraterone: Provides durable androgen suppression Abiraterone - no rise in Androgens at PD. Ketoconazole – Androgens Rise at PD DHEAS TEST Small et al JCO 2004 Ryan et al JCO 2010 U C S F

COU-AA-301: Abiraterone Acetate Improves Overall Survival in post chemotherapy mCRPC Abiraterone acetate: 14.8 months 100 80 HR = 0.646 (0.54-0.77) P < 0.0001 60 Survival (%) 40 Placebo: 10.9 months 20 AA Placebo 100 200 300 400 500 600 700 Days From Randomization AA 797 728 631 475 204 25 Placebo 398 352 296 180 69 8 1 U C S F 20

Survival Benefit Consistently Observed Across Patient Subgroups Curatio PowerPoint Template Survival Benefit Consistently Observed Across Patient Subgroups 4/19/2017 6:18 PM Variable Subgroup N HR 95% CI All subjects All 1195 0.66 0.56–0.79 Baseline ECOG 0–1 1068 0.64 0.53–0.78 2 127 0.81 0.53–1.24 Baseline BPI <4 659 0.50–0.82  4 536 0.68 0.53–0.85 No. of prior chemo regimens 1 833 0.63 0.51–0.78 362 0.74 0.55–0.99 Type of progression PSA only 363 0.59 0.42–0.82 Radiographic 832 0.69 0.56–0.84 Baseline PSA above median YES 591 0.65 0.52–0.81 Visceral disease at entry 709 0.60 0.48–0.74 Baseline LDH above median 581 0.71 0.58–0.88 Baseline ALK-P above median 587 Region North America 652 0.51–0.80 Other 543 0.54–0.90 Fact check: Similar to but not identical with fig 2 p2001 0.5 0.75 1 1.5 Favors AA Favors placebo ALK-P, alkaline phosphatase de Bono et al. N Engl J Med. 2011;364:21.

UCSF Study: Abiraterone Provides Durable and Complete Responses in the chemotherapy naïve setting Baseline Post Cycle 6 Response n (%) PSA Decline ≥30% 27/31 (87.1) PSA Decline ≥50% 26/31 (83.9) PSA Decline ≥90% 13/31 (41.9) Undetectable PSA (≤0.1) 2/31 (6.0%) U C S F Ryan et al CCR 2011

COU-AA-302: Does Abiraterone Improve Survival in its physiologic space (pre-chemotherapy mCRPC)? Arm A RANDOMIZE Abiraterone plus Prednisone Progressive Prostate Cancer WITHOUT prior Docetaxel based chemotherapy Arm B Placebo plus Prednisone Endpoints – PFS, Overall Survival U C S F

Abiraterone in CRPC: How do we use it? Abiraterone prolongs life in patients with met CRPC post chemotherapy Does benefit translate into the pre-chemotherapy setting? Can it be combined with other therapies? Should it be continued after disease progression? What are the mechanisms of resistance? Pharmaco-kinetic? Pharmaco-genomic? Alternate signaling paths? AR mediated progression? U C S F

MDV3100 Second-generation AR antagonist Binds AR more potently than does bicalutamide Not a partial agonist of AR Inhibits translocation of AR into nucleus and decreases AR binding to DNA Oral agent; 160 mg daily (seizures at higher doses) Compared with placebo in ongoing randomized phase 3 trial (post-chemotherapy, ketoconazole-naïve) Tran et al. Science. 2009;324(5928):787-790. Clinicaltrials.gov. NCT00974311. Accessed December 28, 2010. Scher et al. Lancet. 2010;375(9724):1437-1446. 27

MDV3100: Phase 1/2 Study Radiographic Responses Total No prior chemotherapy Prior chemotherapy Soft tissue Partial response Stable disease 59 13 (22%; 13%-35%) 29 (49%; 36%-62%) 25 9 (36%; 19%-57%) 11 (44%; 25%-65%) 34 4 (12%; 4%-28%) 18 (53%; 30%-70%) Bone scan (week 12) 109 61 (56%; 46%-65%) 41 26 (63%; 47%-77%) 68 35 (51%; 39%-64%) FDG-PET (week 12) ≥25% ↓ from baseline <25% ↓ from baseline 22 10 (45%; 25%-67%) 12 (55%; 33%-75%) 12 4 (33%; 11%-65%) 8 (67%; 35%-89%) 10 6 (60%; 27%-86%) 4 (40%;14%-73%) MDV3100 induced >50% PSA declines in 56% of mCRPC patients, including those were prechemotherapy (n = 65) and postchemotherapy (n = 75). . FDG-PET, 2-¹⁸F-fl uoro-2-deoxy-D-glucose positron emission tomography. Scher et al. Lancet. 2010;375(9724):1437-1446. 28

MDV-3100 Time to PSA Progression Curatio created slide Scher HI et al. Lancet. 2010;375:1437.

MDV3100: Phase 3 Trial (AFFIRM) POSITIVE MDV3100 160 mg once daily + prednisone 5 mg twice daily Placebo once daily + R A N D O M I Z E N = 1170 Men with docetaxel-pretreated mCRPC (keto-naïve) 2 1 Primary objective: OS Clinicaltrials.gov. NCT00974311. Accessed December 28, 2010.

MDV-3100 And Abiraterone both extend survival post-docetaxel Placebo MDV-3100 P value Overall Survival 13.6 mo 18.4 mo <0.001 Rx Duration 3.0 mo 8.3 mo Soft Tissue resp 8.3% 2.9% Subsequent therapy -Abiraterone -Cabazitaxel 24.3% 12% 21% 14% *Seizures 0.6% (5cases) Scher-Proc ASCO GU 2012 San Francisco 2/2/2012

New Treatments for Advanced Prostate Cancer Second Line Chemotherapy U C S F

SeSecond Line Chemotherapy CRPC patients inevitably progress following Docetaxel treatment1-5 Despite Many studies (6,7,8): There has been no data showing that we can improve survival with second line chemotherapy UCSF led early studies of second line chemotherapy (Rosenberg, Harzstark) and helped establish this the estimates for survival and response in this setting. 1. Petrylak DP, et al. N Engl J Med. 2004;351(15):1513-1520. 2. Tannock IF, et al. N Engl J Med. 2004;351(15):1502-1512. 3. Oudard S, et al. J Clin Oncol. 2005;23(15):3343-3351. 4. Nelius T, et al. BJU Int. 2006;98(3):580-585. 5. Nelius T, et al. Onkologie. 2005;28(11):573-578. 6. Garmey EG, et al. Clin Adv Hematol Oncol. 2008;6(2):118-132. 7. Rosenberg JE, et al. Cancer. 2007;110(3):556-563. 8. Sternberg CN, et al. J Clin Oncol. 2009;27(32):5431-5438.

Two Different Chemical Entities Docetaxel Cabazitaxel (XRP6258) Cabazitaxel chemical structure differs from docetaxel chemical structure: R2 and R7 positions: cabazitaxel OCH3; docetaxel OH. According to Raub, replacing electronegative atoms such as O with CH2 is one structural change/step to likely decrease the affinity of binding to Pgp. Ojima et al described a series of taxoids with 19 C-10 modifications where acetyl analogues are more active in resistant cell lines; and, adding aliphatic or aromatic H-bonding groups and more hydrophobicity decreases the effect, or presumably increases Pgp recognition. Additional studies showed that a C-10 substitution results in a 7-10 fold increase in BBB permeability in rat brain and improved efficacy in vivo versus paclitaxel. (C43H53NO14) Docetaxel is an esterified product of 10-deacetyl baccatin III (C45H57NO14) Cabazitaxel is a 7,10 dimethoxy analogue of docetaxel Mita AC, et al. Clin Cancer Res 2009;15:723-730; Ojima I, et al. J Med Chem 1996;39:3889-3896; Greenberger LM, Sampath D. Resistance to taxanes. In: Teicher BA, ed. Cancer Drug Discovery and Development: Cancer Drug Resistance. Totowa, New Jersey: Humana Press; 2006:329-358; Raub TJ. Mol Pharm 2005;3:3-25; www.Taxotere.com. 34

The TROPIC study: cabazitaxel or mitoxantrone with prednisone in patients with metastatic CRPC previously treated with docetaxel (De Bono et al) Mitoxantrone 12 mg/m² q 3 wk + prednisone for 10 courses (MP, n=377) Cabazitaxel 25 mg/m² q 3 wk + prednisone for 10 courses (CBZP, n=378) Men with metastatic CRPC progressing during and after docetaxel (N=755) R A N D O M I Z E Primary objective: Overall survival Secondary objectives: PFS (tumor progression, pain progression, PSA progression, or death from any cause), response rate, safety U C S F

Primary Endpoint (Overall Survival) Met TROPIC slide deck. Slide5 100 80 60 40 20 MP CBZP Median OS (months) 12.7 15.1 Hazard ratio 0.72 95% CI 0.61–0.84 P-value <.0001 Proportion of OS (%) Censored MP CBZP Combined median follow-up: 13.7 months 6 12 18 24 30 Time (months) U C S F

Summary of Hematologic AEs Hematologic AEsa JEVTANA® 25 mg/m² q 3 wk + prednisone 10 mg qd (n=371) mitoxantrone 12 mg/m² q 3 wk + prednisone 10 mg qd (n=371) Grade 1–4, n (%) Grade 3–4, n (%) Neutropeniab 347 (94%) 303 (82%) 325 (87%) 215 (58%) Febrile neutropenia 27 (7%) 5 (1%) Anemiab 361 (98%) 39 (11%) 302 (82%) 18 (5%) Leukopeniab 355 (96%) 253 (69%) 343 (93%) 157 (42%) Thrombocytopeniab 176 (48%) 15 (4%) 160 (43%) 6 (2%) JEVTANA.USPI.Jun. 2010. p10-11/T2 DOF.CSR.TROPIC p9/L12-13 a In ≥5% of patients. b Based on laboratory values: JEVTANA® (n=369), mitoxantrone (n=370). Protocol did not permit primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) at cycle 1 JEVTANA® Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010. Data on file. Clinical study report/EFC6193 (TROPIC).

Cabazetaxel: How do we use it? Cabazitaxel significantly improved survival when compared to mitoxantrone, in patients with metastatic CRPC who had received prior docetaxel. It may prolong sensitivity to taxane chemotherapy in patients with acquired docetaxel resistance Its use in the overtly taxane refractory patient may be limited U C S F

Cabazitaxel: Where do we go? As an incremental step forward, it merits testing as front line chemotherapy Combination studies are also warranted. As before, a study of the mechanisms of resistance to this therapy are warranted. (Friedlander/Paris project) FDA mandated 25mg/m2 vs 20 mg/m2 study. U C S F

XL184: Cabozantanib XL- Oral Multi-targeted TKI RET 3.8 nM MET 1.8 nM VEGFR2 0.035 nM KIT 4.6 nM How do we use it? Where do we go? Stay tuned….

New Treatments for Advanced Prostate Cancer Radium 223 U C S F

Radium-223 Targets Bone Metastases Radium-223 acts as a calcium mimic Naturally targets new bone growth in and around bone metastases Radium-223 is excreted by the small intestine Ca Ra

Radium-223 Targets Bone Metastases Range of alpha-particle Radium-223 Bone surface Alpha-particles induce double-strand DNA breaks in adjacent tumour cells1 Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissue 1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT 6 injections at 4-week intervals PATIENTS R A N D OM I S E D 2:1 STRATIFICATION Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel Radium-223 (50 kBq/kg) + Best standard of care Total ALP: < 220 U/L vs ≥ 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No Placebo (saline) + Best standard of care N = 922 Planned follow-up is 3 years Clinicaltrials.gov identifier: NCT00699751.

ALSYMPCA Patient Demographics and Baseline Characteristics (ITT; N = 809) Parameter Radium-223 (n = 541) Placebo (n = 268) Age, y Mean 70.2 70.7 Race, n (%) Caucasian 507 (94) 252 (94) Baseline ECOG score, n (%) ≤ 1 2 467 (86) 71 (13) 229 (85) 37 (14) Extent of disease, n (%) < 6 metastases 6-20 metastases > 20 metastases/superscan 88 (16) 235 (44) 217 (40) 33 (12) 129 (48) 106 (40) WHO ladder, cancer pain index ≥ 2, n (%) 294 (54) 142 (53)

ALSYMPCA Patient Baseline Characteristics, cont (ITT; N = 809) Parameter Median (min, max) Radium-223 (n = 541) Placebo (n = 268) Haemoglobin, g/dL 12.2 (8.5-15.7) 12.1 (8.4-16.4) Albumin, g/L 40 (24-53) 40 (23-50) Total ALP, µg/L 213 (32-4661) 224 (29-3225) LDH, U/L 317 (76-2171) 328 (132-3856) PSA, µg/L 159 (3.78-6026) 195 (1.5-14500)

ALSYMPCA Overall Survival 100 HR 0.695; 95% CI, 0.552-0.875 P = 0.00185 90 80 70 60 Radium-223, n = 541 Median OS: 14.0 months % 50 40 30 Placebo, n = 268 Median OS: 11.2 months 20 10 Month 3 6 9 12 15 18 21 24 27 Radium- 223 541 450 330 213 120 72 30 Placebo 268 218 147 89 49 28 7

The Future – My predictions Oral, Well tolerated therapies will extend the option of treatment for m CRPC to more patients than previous….(only about 50% of CRPC pts get docetaxel) Prostate cancer will become a model for ( or a victim of ?) cost effectiveness research. Management of CRPC will be done by those most capable of understanding biology and the integration of therapies – no matter what their prior training. Combined oral therapies will push therapy and survival further – e.g with better survival more patients will be available for therapy (“If you build it, they will come”)_ New targeted therapies will need to be developed in conjunction with biomarkers that predict response (e.g. Her 2  trastuzumab in breast cancer) U C S F

Thank You U C S F