Update on the Treatment of Prostate Cancer David M. Nanus, MD Chief, Division of Hematology and Medical Oncology Weill Medical College of Cornell University New York Presbyterian Hospital

Demographics 238,590 estimated new cases in 2013 - 27.9% of all cancers in males most common cancer in men Lifetime risk: 16% (1 in 6) 29,720 estimated deaths - 9.7% of cancer deaths in males - second to lung cancer in men

Death from other causes Death from Prostate cancer Clinical Metastases Non-Castrate Clinically Localized Disease Rising PSA Castrate Metastatic Disease Castrate Rising PSA Adapted from Scher et al.

PSA – Like a Clint Eastwood Movie The Good PSA-based early detection decreases mortality The Bad Not perfectly sensitive or specific  Over-detection compounded by Over-treatment The Ugly Treatment arbitrary, variable, often unnecessary and increasingly costly

Screening Recommendations Shared decision making Annual PSA and DRE from age of 40 (AUA); age 50 (ACS) High risk: 40-45 (African American; 1rst degree relative) Frequency AUA: annually (based on initial PSA) ACS: annually (every 2 year if PSA < 2.5 ng/ml) Discontinue: life expectancy <10 years

The Changing Face of Prostate Cancer in the United States Cooperberg et al. J Urol 2007; 178:S14

Significance of cancer: Determining need for treatment Patient (age, comorbidities) Gleason score - sum of two predominant areas Tumor characteristics - Number of positive cores - Percent positive within each core Molecular profile

Active Surveillance Rationale Hypotheses Surveillance in low risk patients is feasible and associated with a limited risk of progression Progression can be quantitated Predictors of progression and treatment can be identified Screening results in the detection of very early stage/grade lesions - many indolent Current staging/grading techniques accurate Natural history prolonged and can be measured

Intervention Overall Survival Ca-Specific Survival N=452 97% at 10 years N=452 5/452 patients All PSADT ≤ 1.6 years 62% free of intervention at 10 y Klotz L, et al. J Clin Oncol 2010;26:126–31

Defining the Triggers for Intervention Change in PSA kinetics: PSADT <3 y Progression on follow-up biopsy Increase in Gleason grade Increase in tumor volume Increase in absolute cores involved with cancer Increase in percent of positive cores >33% Increase in absolute tumor length (mm) Increase in percent of tumor tissue >50% within single core Patient preference Clinical/radiographic evidence of local/distant progression

What’s new in prostate cancer therapy? Targeting the androgen axis Immunotherapy Chemotherapy Bone targeted therapies Molecular genetics Circulating prostate cancer tumor cells

3040 hormone naïve metastatic patients Intermittent versus continuous androgen deprivation in hormone sensitive metastatic prostate cancer patients: Results of S9346 (INT-0162), An international phase III trial 3040 hormone naïve metastatic patients PS 0-2 PSA ≥ 5 ng/ml treated with 7 months of goserelin + bicalutamide 1535 pts PSA ≤4 ng/ml - randomized to CAD or IAD Primary objective: non-inferior Median Follow up: 10 years

Management of Castrate Resistant Metastatic Prostate Cancer Androgen Signaling Axis Therapy Abiraterone Enzalutamide (MDV3100) Chemotherapy Docetaxel Cabazitaxel Mitoxantrone Bone Targeted Radium-223

Intra-cellular androgen Alternatively-spliced AR Adapted from Harris et al. Nature Reviews Clin Onc 2009

CYP17 CYP17 Simplified view of cholesterol  testosterone synthesis Occurs in: Testes, Adrenal Gland, Prostate cancer cells cholesterol pregnenolone 17α-hydroxy- DHEA androstenedione Testosterone DHT CYP17 Mineralocorticoids CYP17 Cortisol Montgomery et al. Cancer Res 2008 Locke et al. Cancer Res

Abiraterone Acetate CYP17 CYP17 Oral irreversible inhibitor of CYP17 - 17α –hydroxylase - C17,20-lyase Inhibits testosterone production in testis, adrenal, and prostate Abiraterone Acetate cholesterol pregnenolone 17α-hydroxy- DHEA androstenedione Testosterone DHT CYP17 Mineralocorticoids CYP17 Cortisol Montgomery et al. Cancer Res 2008 Locke et al. Cancer Res

COU-AA-301Abiraterone Acetate + prednisone vs Placebo + prednisone in men with progressive metastatic CPRC after docetaxel Overall survival HR=hazard ratio. AA=abiraterone acetate. P=prednisone. de Bono JS et al. N Engl J Med 2011;364:1995-2005. Fizazi et al. Lancet Oncol 2013;13:983.

de Bono JS et al. N Engl J Med 2011;364:1995-2005. Secondary End Points de Bono JS et al. N Engl J Med 2011;364:1995-2005.

Hazard Ratios for the Risk of Death, According to Subgroup de Bono JS et al. N Engl J Med 2011;364:1995-2005.

Asymptomatic or mildly symptomatic COU-AA-302 Abiraterone 1000 mg/d Prednisone mg bid Chemo-naïve CRPC (n=1088) Asymptomatic or mildly symptomatic Placebo daily Prednisone mg bid Primary endpoint: Radiographic PFS, OS Secondary endpoints: Time to – opiate use; chemotherapy; EOCS-PS deterioration; progression

COU-AA-302: Updated interim results Prednisone Abiraterone + Prednisone Radiographic PFS 8.3 mos 16.5 mos HR 0.53; p < 0.0001 Overall Survival 30.1 mos 35.3 mos HR 0.79; p = 0.0151* > 50% PSA decline 69% 29% Median Time to Chemotherapy 16.8 mos 26.5 mos HR: 0.61 Median Time to Opiate Use 23.7 mos NR HR 0.71 p = 0.0002 * did not cross the prespecified boundary for significance (p = 0.0035) Ryan CJ et al. N M2013;368:138-148 + GU ASCO 2013

Adverse Events of Special Interest. Ryan CJ et al. N Engl J Med 2013;368:138-148.

AFFIRM: Enzalutamide (MDV3100) Scher HI et al. N Engl J Med 2012;367:1187-1197.

Figure 1. Kaplan–Meier Estimates of Primary and Secondary End Points in the Intention-to-Treat Population. Shown are data for overall survival, the primary end point (Panel A), and for two secondary end points, the time to prostate-specific antigen (PSA) progression (Panel B) and radiographic progression-free survival (Panel C), in the enzalutamide group, as compared with the placebo group. CI denotes confidence interval.

Subgroup Analyses of Hazard Ratios for Death in the Two Study Groups Figure 2. Subgroup Analyses of Hazard Ratios for Death in the Two Study Groups. Hazard ratios are based on a nonstratified proportional-hazards model. Dashes indicate that the median time to death had not been reached for the indicated subgroup. The size of the circles is proportional to the size of the subgroup. The horizontal bars represent 95% confidence intervals. The Eastern Cooperative Oncology Group (ECOG) grades the performance status of patients with respect to activities of daily living, with 0 indicating that the patient is fully active and able to carry out all predisease activities without restriction; 1 indicating that the patient is restricted in physically strenuous activity but is ambulatory and able to carry out work of a light or sedentary nature; and 2 indicating that the patient is ambulatory and up and about for more than 50% of waking hours and is capable of self-care but unable to carry out work activities. Scores on the Brief Pain Inventory–Short Form (BPI-SF) range from 0 to 10, with scores of 0 to 3 indicating that clinically significant pain is absent and scores of 4 to 10 indicating that clinically significant pain is present, and with higher scores indicating greater pain. LDH denotes lactate dehydrogenase, and PSA prostate-specific antigen. Scher HI et al. N Engl J Med 2012;367:1187-1197.

Enzalutamide PREVAIL trial: Phase 3 CRPC before chemotherapy TERRAIN trial: Phase 2 comparing Enzalutamide with bicalutamide in men who have progressed on LHRH analogue therapy or following surgical castration Other studies: Enzalutamide + docetaxel Enzalutamide + abiraterone

Cabazitaxel/Prednisone vs Mitoxantrone/Prednisone de Bono et al, Lancet 2010: 1147-54

Immunotherapy Cancer vaccines Modulation of immune regulatory mechanisms Blocking CTLA-4 Blocking PD-1 or PDL-1 Monoclonal antibody targeting of tumour growth

IMPACT Trial HR=0.759 (95% CI: 0.606, 0.951) P=.017 (Cox model) Median Survival Benefit: 4.1 months Sipuleucel-T (n=341) Median Survival: 25.8 months 36-months survival: 32.1% Control (n=171) Median Survival: 21.7 months 36-months survival: 23.0% Kantoff et al, ASCO GU 2010

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 Parker et al; ECCO-ESMO 2011

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 Clinicaltrials.gov identifier: NCT00699751. Parker et al; ECCO-ESMO 2011

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 Parker et al; ECCO-ESMO 2011

CRPC Therapeutic Options Increase in median survival Relative reduction in risk of death Hazard ratio (95% CI; P-value) Abiraterone/P vs. placebo/P 3. 9 mos 35% 0.65 (0.54-0.77; P<0.001) Enzalutamide vs. placebo 4.8 mos 37% 0.63 (P<0.0001) Docetaxel(q3w)/P vs. Mitoxantrone/P 2.4 mos 24% 0.76 (0.62-0.94; P=0.009) Cabazitaxel/P vs. mitoxantrone/P 2.8 mos 30% 0.70 (0.59-0.83; P<0.0001) Sipuleucel T vs. placebo 4.1 mos 22% 0.78 (0.61- 0.98; P:0.03) Alpharadin vs. placebo 31% (0.55-0.88; P:0.00185)

Phase III Randomized Trials vs. Docetaxel + Prednisone Primary Endpoint: Overall Survival Trial Name Arm B: DocPred plus Mechanism ASCENT-2 DN101 Calcitriol CALGB 90401 Bevacizumab VEGF SWOG 0421 Atrasentan Endothelin receptor antagonist MAINSAIL Lenalinomide Anti-angiogenic; immune VENICE Aflibercept Soluble VEGF fusion protein ENTHUSE 33 Zibotentan READY Dasatinib SRC kinase inhibitor SYNERGY OGX-11 Antisense to clusterin (cell survival protein) FIRSTANA vs. Cabazitaxel (unTxed) Taxane Chemotherapy

Molecular Markers Beyond the microscope May be diagnostic, prognostic, and/or predictive Gene fusions TMRPSS2-ERG Expression of abnormal proteins Many may be targetable Circulating Tumor Cells (CTCs)

Molecular Classification of Prostate Cancer * Discoveries led by NYP-Weill Cornell Medical College

Frequency Therapy Ets gene fusion 50-60% PARP inhibitor PTEN/MAGI2 25-40% PI3K inhibitor BRAC2/ATM 20% Spink1 10-15% EGFr inhibitor Aurora kinase A 5-40% AURK inhibitor SPOP 10% ? BRaf fusion 1% Raf inhibitor

Neuroendocrine or anaplastic prostate cancer Frequency Therapy Ets gene fusion 50-60% PARP inhibitor PTEN/MAGI2 25-40% PI3K inhibitor BRAC2/ATM 20% Spink1 10-15% EGFr inhibitor Aurora kinase A 5-40% AURK inhibitor SPOP 10% ? BRaf fusion 1% Raf inhibitor Neuroendocrine or anaplastic prostate cancer

MLN8237 50 mg bid orally x 7 d on 21 day cycle Molecular biomarkers Multi-institutional Phase II Trial of The Aurora kinase A inhibitor MLN8237 for Patients with Neuroendocrine Prostate Cancer Inclusion Criteria: Pathologic diagnosis Clinical diagnosis: visceral metastases in absence of PSA progression, elevated serum neuroendocrine marker MLN8237 50 mg bid orally x 7 d on 21 day cycle Molecular biomarkers Tumor biopsies CTC analyses Exome/transcriptome sequencing

Bone Targeted Therapy

Smith MR et al. 2013 GU Cancers Symposium CALGB 90202: A Randomized, Double-Blind, Placebo-Controlled Phase III Study of Early versus Standard Zoledronic Acid (ZA) to Prevent Skeletal Related Events in Men with Prostate Cancer Metastatic to Bone Eligibility: > 1 bone metastasis, ADT therapy within 6 mos of enrollment Therapy: Zoledronic acid or placebo q 4 weeks Median time to first SRE (skeletal-related event) 32.5 vs 29.8 mos (HR = 0.96 [0.76-1.22]; P=0.74) > Grade 3 toxicity same (15% vs. 12% in ZA and P) Overall survival (HR= 0.89 [0.70-1.14]; P=0.34) Smith MR et al. 2013 GU Cancers Symposium

Y denosumab Y Y Y Y Y Y Y Y Y Y Y Y Y

Targeted Therapy: Denosumab vs zoledronic acid for Skeletal Related Events risk-reduction in CRPC Fizazi et al, Lancet 2011; 377: 813

Denosumab vs placebo to improve bone-metastases free survival Smith et al, Lancet 2011

Management of Metastatic CRPC Sequencing??? Chemotherapy Docetaxel, Cabazitaxel, Mitoxantrone Androgen Signaling Axis Therapy Abiraterone Enzalutamide Bone Targeted Denosumab Alpharadin

Prostate cancer clinical states model enzalutamide Prostate cancer clinical states model; framework for patient management and drug development. PSA, prostate-specific antigen. Data adapted.6,8 Scher H I et al. JCO 2011;29:3695-3704

Prostate cancer clinical states model enzalutamide Prostate cancer clinical states model; framework for patient management and drug development. PSA, prostate-specific antigen. Data adapted.6,8 Scher H I et al. JCO 2011;29:3695-3704

Cabozantinib (XL184): orally bioavailable tyrosine kinase inhibitor against MET and VEGFr2 in men with CRPC Smith D C et al. JCO 2013;31:412-419

PFS in (A) randomly assigned patients with CRPC; and (B) patients with CRPC by docetaxel pretreatment status Kaplan-Meier estimates of progression-free survival (PFS) in (A) randomly assigned patients with castration-resistant prostate cancer (CRPC) and (B) patients with CRPC by docetaxel pretreatment status. Panel A shows the probability of PFS from week 12 random assignment for patients with CRPC randomly assigned to continued treatment with cabozantinib (n = 14) or placebo (n = 17). Panel B shows the probability of PFS for all patients with CRPC (n = 171) by docetaxel pretreatment status from first dose of cabozantinib. HR, hazard ratio. Smith D C et al. JCO 2013;31:412-419

Bone scan effects of cabozantinib treatment on study patients Bone scan effects of cabozantinib treatment on study patients. Sequential whole-body technetium methylene diphosphonate bone scintigraphy is shown of four patients with advanced metastatic prostate cancer. Baseline scans show multiple areas of increased radiotracer uptake indicative of extensive bone metastases. Treatment with cabozantinib resulted in complete or partial resolution of bone scans at week 12. Bone scan resolution correlated with partial response of tumor lesions in soft tissue and pain relief in each patient. Smith D C et al. JCO 2013;31:412-419

Where We Are Now: Positive Phase 3 Trials in Met CRPC Design HR Endpoint Comment Canadian N = 161 Mitoxantrone/prednisone vs prednisone NR Palliation in 29% vs 12% (duration 42 vs 18 wks) Approval of mitoxantrone (also CALGB 9182) TAX 327 N = 1006 Docetaxel/prednisone vs mitoxantrone/prednisone 0.76 OS 18.9 vs 16.5 mo Docetacel/pred approved as new standard SWOG 9916 N = 770 Docetaxel/estramustine vs mitoxantrone/prednisone 0.80 OS 17.5 vs 15.6 mo Support docetaxel as new standard ZAPCSG N = 643 Zoledronic acid vs placebo SRE 33.2% vs 44.2% Zoledronic acid reduces SRE’s IMPACT N = 512 Sipuleucel-T vs Control 0.78 OS 25.8 vs 21.7 mo Sip-T approved min symptomatic metCRPC Dmab 103 N = 1904 Denosumab vs zoledronic acid 0.82 SRE-free 20.7 vs 17.1 mo Denosumab approved TROPIC N = 755 Cabazitaxel/prednisone vs mitoxantrone/prednisone 0.70 OS 15.1 vs 12.7 mo Cabazitaxel approved post-docetaxel COU-AA-301 N = 1195 Abiraterone/prednisone vs Placebo/prednisone 0.65 OS 14.8 vs 10.9 mo Abi/pred approved post-docetaxel ALSYMPCA N = 922 Radium-223/BSC vs placebo/BSC OS 14.0 vs 11.2 mo Pending approval AFFIRM N=1199 Enzalutamide vs Placebo 0.63 OS 18.4 vs 13.6 mo Enzalutamide approved post-docetaxel COU-AA-302 N = 1088 0.43 16.5 mos vs 8.3 mo Strong trend for OS