Trends, Issues & Treatment in Late-Stage Prostate Cancer Oliver Sartor, M.D. LaBorde Professor for Cancer Research Medical Director, Tulane Cancer Center Tulane Medical School New Orleans, LA

Charles B. Huggins “Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.” Nobel Lecture December 13, 1966

“Castrate-Refractory” Prostate Cancer Progressive prostate cancer despite surgical or medical castration Serum Testosterone (<50 ng/dL)

“Castrate-Refractory” Prostate Cancer: The Face of Change Many changes have occurred in our understanding of this disease –Pathophysiology The evolution from “hormone-refractory” and “androgen-independent”, to “castrate-refractory” –Therapeutic options Current Standards Multiple new paradigms on the rise

Pathophysiology: The Continued Importance of the Androgen Receptor

Androgen Receptor Gene Over-Expression in “Castrate-Refractory” Prostate Cancer Linja et al., Can Res 61:

Tissue Androgen Levels in Benign Prostate vs. Castrated Cancer Tissue Mohler et al., Clin Cancer Res 10:440, 2004 Shaded=Benign Clear=Castrate

Over-Expression of Enzymes in the Androgen Synthesis Pathway in Metastatic Castrate- Refractory Prostate Cancer Cells Stanbrough et al. Cancer Res. 66:2815, 2006

Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify CRPC Hu et al. Cancer Research 69:16-22, 2009

Conclusions Androgen receptor signaling remains a key factor in prostate cancer growth despite castrate serum levels of testosterone The prostate cancer switches from a traditional endocrine paradigm to an autocrine/paracrine paradigm BUT some of the apparent mechanisms of AR activation are ligand-independent

Therapeutic Options for CRPC Today Secondary Hormonal Manipulations –Antiandrogen Withdrawal, Antiandrogen Administration, Adrenal Suppressives (ketoconazole), Corticosteroids (prednisone, dexamethasone, etc.), Estrogens (DES, etc.) External Beam Radiation Therapy Intravenous Bone-seeking Radioisotopes –Samarium-153 EDTMP, Strontium-89 (FDA approvals) Bisphosphonates –Zoledronate (FDA approval) Chemotherapy –Mitoxantrone, docetaxel, estramustine, cabazitaxel (FDA approvals) Immune Therapies –Sipuleucel T (FDA approved) Experimental Therapies (Clinical Trials)

Despite Many New Promising Agents, Docetaxel was, For Many Years, the only FDA Approved Chemotherapy shown to have a Survival Benefit in CRPC

Randomize Mitoxantrone 12 mg/m 2 Prednisone 10 mg q day Q 21 days up to 10 cycles Docetaxel 75 mg/m 2 Prednisone 10 mg q day Q 21 days up to 10 cycles Docetaxel 30 mg/m 2 /wk Prednisone 10 mg q day 5 on; 1 off x 6 cycles N=1006 TAX 327 SWOG 9916 Randomize Mitoxantrone 12 mg/m 2 Prednisone 5 mg bid Q 21 days Docetaxel 60 mg/m 2 d 2 Estramustine 280 mg d1-5* Dexamethasone 20 mg, tid d 1 & 2 N=770 *Warfarin and aspirin Phase III Docetaxel Studies in HRPC Demonstrating Survival Benefit Tannock et al. N Engl J Med 2004:351; ; Petrylak et al. N Engl J Med 2004;351:

D+E M+P # at Risk # of Deaths Median in Months HR: 0.80 (95% CI 0.67, 0.97), p = 0.01 Overall Survival Petrylak et al. N Engl J Med 2004;351:

Overall Survival: Tax 327 Tannock et al. N Engl J Med 2004:351; Median survival Hazard (mos) ratio P-value Combined: D 3 wkly: D wkly: Mitoxantrone16.4 –– Months Probability of Surviving Docetaxel 3 wkly Docetaxel wkly Mitoxantrone

New Agents in CRPC Clinical Trials (#1) Vaccines and immune stimulants –PROSTVAC-VF-Tricom Vaccine (phase III in planning) –Anti-CTLA4 (Ipilimumab phase III underway post-docetaxel) –GMCSF Angiogenesis inhibitors –Lenalinomide (Revlimid phase III well underway) –Bevacizumab (Avastin phase III negative 3/12/10) –VEGF TRAP (Aflibercept phase III accrual completed) Novel Anti-Tubular Agents –Cabazitaxel (phase III announced positive 12/09 and FDA approved June 17, 2010!) –Ixabepalone (phase III in combination with mitoxantrone in planning post-docetaxel)

New Agents in CRPC Clinical Trials (#2) Newer Androgen-Signaling Targeted Therapies –Abiraterone, Cougar phase III post-docetaxel accrual complete in 4/09 and pre-docetaxel accrual completed 5/10) –Takeda and Tokai androgen synthesis now in trials –AR blockade (MDV3100, Sawyers new compound) MDV3100 phase III underway Newer Signal Transduction Inhibitors –PI3 Kinase (Exelexis XL147, Novartis BEZ235, Genentech GDC-0941, Semafore SF 1126) –p60 src and other kinases (dasatinib phase III well underway) –Multi-kinase inhibitor (sunitinib phase III well underway)

New Agents in CRPC Clinical Trials (#3) Bone targeted agents –Isotopes: radium-223 (alpharadin phase III well underway) –Isotopes: strontium-89 (phase III underway with taxotere) –RANK ligand: denusomab phase III accrual complete for metastases prevention vs placebo and also vs zoledronic acid for SREs (announced as positive 2/10) Endothelin antagonists -Atrasentan (failed monotherapy phase III but in docetaxel combination phase III completed accrual 5/10) -ZD4054 (Three phase III trials, one with docetaxel and 2 without (M0 and M+): All but M0 completed accrual

New Agents in CRPC Clinical Trials (#4) Stem cell targeted agents –Anti-Prostate stem cell antigen (PSCA), –Sonic hedgehog (IPI-926, others) Prostate specific surface targets –Anti-PSMA (J591, 7E11, MLN2704, others) –New generation of various aptamers and targeted nanoparticles Chemotherapeutic resistance and apoptotic regulators –Anti-Clusterin (OGX-011 or custirsen) phase IIIs in planning for both chemo-naïve and post-docetaxel –AT-101 (gossypol) phase III in planning

Selected Phase III Trials That Have Completed Accrual in Prostate Cancer Docetaxel/bevacizumab vs docetaxel in chemo-naïve mCRPC (CALGB) –Announced negative March 12, 2009 XRP6258 (cabazitaxel) vs mitoxatrone post-docetaxel in mCRPC (Sanofi-Aventis) –Announced positive 12/09, presented 3/10 at ASCO GU, FDA 6/10 Abiraterone vs prednisone post-docetaxel in mCRPC (Cougar) –Anticipated late 2010 Denusomab vs placebo in metastases prevention in non- metastatic CRPC –Fall/Winter 2010 anticipated Denosumab vs zoledronate for SRE prevention in mCRPC –Announced positive 2/9/10 for SRE, presented ASCO 6/10

Selected Novel Therapeutics and Concepts in for CRPC New hormonal therapies –Abiraterone and MDV3100 A new chemotherapy –Cabazitaxel A new immunotherapy –Sipuleucel-T A brief mention, “Stromal Targeted” therapies

Abiraterone: Potent Inhibitor of CYP17: (17-20 Lyase and 17-Alpha Hydroxylase)

Maximal PSA Declines in Abiraterone Post-Docetaxel Reid et al. JCO 28:1489, 2010

MDV3100: A New Anti-Androgen Tran et al: Science 324: , 2009

MDV3100 PSA Changes in Phase I Trial Scher et al. ASCO GU, 2009, #151

PSA Declines with MDV3100 Pre- and Post-Docetaxel Scher et al. Lancet 375:1437, 2010

Reminder AR targeted therapy effects PSA disproportionately to tumor volume –PSA gene has an androgen response element in the promoter Effects on survival with the new AR targeted therapies are yet to be reported

Cabazitaxel: A New Tubulin-Targeting Agent New semi-synthetic taxane –Selected to overcome the emergence of taxane resistance¹, ² Preclinical data¹, ² –As potent as docetaxel against sensitive cell lines and tumor models –Active against tumor cells/models resistant to currently available taxanes Clinical data –Antitumor activity in mCRPC including docetaxel-resistant disease³ 1. Attard G, Greystoke A, Kaye S, De Bono J. Pathol Biol (Paris). 2006;54(2): Pivot X, Koralewski P, Hidalgo JL, et al. Ann Oncol. 2008;19(9): Mita AC, Denis LJ, Rowinsky EK, de bono JS et al. Clin Can Res. 2009; Jan 15;15(2):

Primary endpoint = Overall Survival, Secondary endpoint = PFS, response rate and safety, interim (futility) PFS based analysis after 225 events TROPIC: Phase 3 Study: 146 Sites, 26 Countries Sartor et a. GU ASCO 2010 Randomization (1:1) Stratified for Measurability of Disease and ECOG PS Randomization (1:1) Stratified for Measurability of Disease and ECOG PS cabazitaxel 25 mg/m² q3w + Prednisone* mitoxantrone 12 mg/m² q3w + Prednisone* 755 patients, Maximum treatment duration 10 cycles, planned 511 events to detect 25% reduction in hazard ratio, 90% power, 2 sided 5% alpha level * Or prednisolone – 10 mg given orally daily Hormone Resistant Metastatic Prostate Cancer Patients Previously Treated With A Taxotere Containing Regimen Hormone Resistant Metastatic Prostate Cancer Patients Previously Treated With A Taxotere Containing Regimen

Eligibility Criteria mCRPC patients with documented disease progression –If measureable: RECIST progression –If non-measurable : Documented rising PSA levels (at least 2 consecutive rises in PSA over a reference value taken at least 1 week apart ) or appearance of new lesion Previous treatment with at least 225 mg/m2 docetaxel- containing regimen (protocol amended) No previous treatment with mitoxantrone ECOG-PS: 0–2 Normal organ function (CBC and serum chemistries) No grade 2 or worse neuropathies

MP (n=377)CBZP (n=378) Age (years) Median [range]67 [47–89]68 [46–92] ≥65 (%) ECOG PS (%) 0, PSA* (ng/mL) Median [range]127.5 [2–11220]143.9 [2–7842] Measurability of disease (%) Measurable Non-measurable Disease site (%) Bone Lymph node Visceral24.9 Summary of Patient Characteristics

Pre-Protocol Treatments MP (n=377)CBZP (n=378) Chemotherapy (%) 1 regimen regimens ≥3 regimens Docetaxel-containing regimens administered (% patients) 1 regimen regimens ≥3 regimens Total prior docetaxel dose (mg/m²) Median Months from last docetaxel dose to progression Median

Pre-Protocol Treatments MP (n=377)CBZP (n=378) Total prior docetaxel dose Median (mg/m²) Median cycles77 % of patients per docetaxel dose <225 mg/m² ≥225 to 450 mg/m² ≥450 to 675 mg/m² ≥675 to 900 mg/m² ≥900 mg/m² Unknown1.30.8

Primary Endpoint: Overall Survival (ITT Analysis) MP CBZP Number at risk Proportion of OS (%) months 6 months12 months18 months24 months30 months Median OS 0.59–0.8395% CI <.0001 P-value Hazard Ratio CBZPMP Sartor et al. GU ASCO, 2010

35 Subgroup Overall Survival Analysis FactorHazard Ratio (95% CI) All patients0.69 (0.57 – 0.84) ECOG status: 0,10.68 (0.57 – 0.82) ECOG status: (0.48 – 1.38) Measurable disease: No0.72 (0.55 – 0.93) Measurable disease: Yes0.68 (0.54 – 0.85) No of prior chemo: (0.54 – 0.93) No of prior chemo: >=20.68 (0.54 – 0.86) Age: < (0.61 – 1.08) Age: >= (0.50 – 0.78) Country: Europe0.68 (0.53 – 0.86) Country: North America0.59 (0.43 – 0.82) Country: Other country1.00 (0.65 – 1.54) Pain: no0.57 (0.43 – 0.77) Pain: Yes0.76 (0.59 – 0.98) Rising PSA: No0.87 (0.59 – 1.29) Rising PSA: Yes0.65 (0.53 – 0.82) Hazard Ratio 012 Favors CBZ

Subgroup Overall Survival Analysis CategoryFactorHazard Ratio (95% CI) ITT populationAll Patients0.69 (0.57 – 0.84) Last taxotere to random< 6 months0.78 (0.62 – 0.97) Last taxotere to random>=6 months0.66 (0.46 – 0.96) Total taxotere dose< 225 mg/m20.96 (0.46 – 2.03) Total taxotere dose>= 225 to 450 mg/m20.61 ( ) Total taxotere dose>= 450 to 675 mg/m20.80 (0.56 – 1.16) Total taxotere dose>= 675 to 900 mg/m20.73 – (0.46 – 1.13) Total taxotere dose>= 900 mg/m20.49 (0.31 – 0.79) Progression During last taxotere treatment 0.67 (0.47 – 0.96) Progression Within first 3 months since last taxotere dose 0.69 (0.52 – 0.91) Progression Between 4 th & 6 th month since last taxotere dose 0.82 (0.48 – 1.40) ProgressionMore than 6 months since0.73 (0.35 – 1.53) Hazard Ratio 0123 Favors CBZ

Progression-Free Survival Proportion of PFS (%) Time (months) % reduction in risk of progression MPCBZP Median PFS (months) Hazard ratio % CI0.65–0.87 P-value Number at Risk MP CBZP Censored MP CBZP Combined median follow-up: 13.7 months

Secondary Endpoints: Response Rate and Time to Progression MP (n=377)CBZP (n=378)Hazard ratio (95% CI)P-value Tumor assessment Response rate* (%) –.0005 Median TTP (months) (0.49–0.76)<.0001 PSA assessment Response rate* (%) –.0002 Median TTP (months) (0.63–0.90).001 Pain assessment Response rate* (%)7.89.2–.6286 Median TTP (months) NR (0.69–1.19).5192 *Determined only for subjects with at baseline measurable disease, PSA ≥20 ng/ml, or pain, respectively. NR=Not reached.

Exposure: Median 6 cycles CBZ vs 4 cycles MTZ Mitozantrone + P (N=1736) Cabazitaxel + P (N=2251) Actual dose level (mg/m 2 ) Full dose level (%) Reduced by 20% More than 20% reduction Unknown actual dose MTX 1648 (94.9) 77 (4.4) 9 (0.5) 2 (0.1) CBZ 2030 (90.2) 193 (8.6) 27 (1.2) 1 (<0.1) Number of cycles delayed Delay 4 to 6 days Delay 7 to 9 days Delay > 9 days 28 (1.6) 82 (4.7) 28 (1.6) 42 (1.9) 115 (5.1) 51 (2.3)

40 MP (n=371) CBZP (n=371) All grades (%) Grade ≥3 (%) All grades (%) Grade ≥3 (%) Any adverse event Febrile neutropenia Diarrhea Fatigue Back pain Nausea Vomiting Hematuria Abdominal pain Most Frequent Treatment-Emergent Adverse Events* * Sorted by ≥2% incidence rate for grade ≥3 events in the cabazitaxel arm.

Hematological Results MP (n=371) CBZP (n=371) All grades (%) Grade ≥3 (%) All grades (%) Grade ≥3 (%) Hematology Anemia Leukopenia Neutropenia* Thrombocytopenia *Prophylactic use of G-CSF was permitted except for cycle 1 of treatment at the discretion of the investigator. 58% grade ≥3 neutropenia in MP arm of the TROPIC study compares to 22% reported for the TAX 327 (first-line) study

Fatal Events—Update (cut-off date 3/10/10) MP (n=371) CBZP (n=371) Total deaths during study304 (81.9%) 270 (72.8%) Due to progression264 (71.2%)218 (58.8%) Due to AE 7 (1.9%) 18 (4.9%) Due to AE (N America, n=235) 1 (0.8%) 1 (0.9%) Due to AE (Europe, n=402) 6 (3.0%) 10 (4.9%) Due to other reasons15 (4.0%) 12 (3.2%) Cause unknown (> 3 mo following last dose) 11 (3.0%)20 (5.4%)

FDA Package Insert on Growth Factors Primary prophylaxis with G-CSF should be considered for pts >65 years, poor performance status, prior febrile neutropenia, poor nutritional status, or other serious co-morbidities

Cabazitaxel Conclusion An effective drug fulfilling an unmet need with a safety profile that demands meticulous attention to detail in particular with careful management of neutropenia and diarrhea It should be reserved for patients with metastatic CRPC with progressive disease post-docetaxel and a good performance status and organ function

Immune Based Therapies

GM-CSF Induces the Greatest Anti-Tumor Immunity in Cytokine Transduced Tumor Cells Dranoff et al, PNAS 90:3539, % Tumor Free Animals IL - 7 GM-CSF IL-3IL-6IL-4 SCF G-CSF IL-2 + IL-1 IL-2 TNF-  IFN-  MIF B7-1 M-CSF CD2 IL-10 ICAM-1 IL-5 MIP-1  MIP-1  IL-1RA

Antigen Delivery Fusion Protein Used to Stimulate Antigen Presenting Cells (APCs) in Preparation of Sipuleucel-T Prostatic Acid Phosphatase (PAP) Granulocyte Macrophase Colony Stimulating Factor (GM-CSF)

Vaccination with Antigen (GM-CSF/PAP) Loaded Antigen Presenting Cells (APCs) Leukapheresis Isolation of APC Antigen-loaded APCs PAP-GM-CSF “Antigen” Patient

Randomized Phase III Trial with Sipuleucel-T (IMPACT or D9902B) Primary endpoint:Overall Survival Secondary endpoint: Time to Objective Disease Progression Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512) Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512) Placebo Q 2 weeks x 3 Sipuleucel-T Q 2 weeks x 3 PROGRESSIONPROGRESSION PROGRESSIONPROGRESSION 2:1 SURVIVALSURVIVAL SURVIVALSURVIVAL Treated at Physician discretion and/or Salvage Protocol Treated at Physician discretion

Sipuleucel T: IMPACT Phase III Trial Overall Survival P = (Cox model) HR = [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Provenge (n = 341) Median Survival: 25.8 Mos. Placebo (n = 171) Median Survival: 21.7 Mos.

Stromal Targeted Therapy

Castrate-Refractory Prostate Cancer Is a Heterogeneous Group of Diseases: Lessons from a Rapid Autopsy Program Shah RB, et al. Cancer Res. 2004;64:

Cancer Stem Cell Model

Heterogeneity and Stem Cells: The Dual Challenge of Advanced Prostate Cancer How do we target cancers that are heterogeneous in both genotype and phenotype in the same patient? –Targeting a stable stroma? How do we kill a stem cell in patients with widespread cancer? –The critical question in oncology today! Destruction of “ecologic” niches that support cancer growth?????

Lessons from the Ivory Bill Woodpecker: Habitat Destruction is the Key to Extinction

Stromal Targeted Therapy: New Concept in Cancer Therapeutics Anti-angiogenesis inhibitors –Bevacizumab, sunitinib, thalidomide, lenalidomide Bone + tumor targeting with endothelin antagonism –Atrasentan and ZD4054 Bone + tumor targeting with anti-p60src –Dasatinib Bone stromal targeted radiopharmaceuticals –Strontium-89, Samarium-153 EDTMP, Radium-223 Osteoclast inhibition –Zolendronic acid and denosumab –No effects seen in CRPC to date

Where do we go from here? It takes 4 drugs to cure Hodgkin’s disease, one of our most curable malignancies –Clearly multiple drugs will be necessary to cure mCRPC and that is our greatest challenge today Multi-targeted therapy to multiple micro- environmental sites and the tumor too? If we ever figure out how to kill metastatic stem cells, then the game changes

Trends, Issues & Treatment in Late-Stage Prostate Cancer Oliver Sartor, M.D. LaBorde Professor for Cancer Research Medical Director, Tulane Cancer Center Tulane Medical School New Orleans, LA