Prostate : An Evolving Clinical Management Paradigm 62ND ANNUAL MEETING OF THE SOUTHWESTERN CHAPTER SOCIETY OF NUCLEAR AND MOLECULAR IMAGING

March 31, 2017

Jeri Kim, MD Department of Genitourinary Medical Oncology The University of Texas MD Anderson Cancer Center Disclosures

I have no financial relationships to disclose.

I will not discuss off-label use and/or investigational use in my presentation. Outline

• Natural history of prostate cancer • Standard treatment options for specific clinical states of prostate cancer • Potential use of the emerging imaging tools for specific clinical states of prostate cancer U.S. Cancer Death Rates, 1975–2014

All Cancer Types Death rates in U.S. down 25% overall, 1991–2014

American Cancer Society Cancer Facts & Figures 2017 Cancer Incidence and Mortality Rates—U.S. Males NN 1975–2013 1930–2014

American Cancer Society, Cancer Facts & Figures 2017 Why Have Prostate Cancer Death Rates Fallen?

Why? Advent of Screening Improved Therapy Making Prostate Cancer a Curable Disease Improved surgery Improved radiation Adjuvant radiation Improving Survival in Advanced Disease Better drugs Better drug assignments (personalization) Advanced combination therapy Prospects for immunotherapy

Prostate Cancer Reality #1: Overdiagnosis and Overtreatment Are Real Prostate Cancer Reality #2: The Landscape of Early Prostate Cancer Has Changed Stage, Gleason score (GS), Prostate-Specific Antigen (PSA), and Positive Biopsy Findings, 1990–2006, in Low-Risk Prostate Cancer (PSA < 10 ng/ml, GS ≤ 6, Clinical Stage ≤ T2a)

Clinical T Stage Gleason Score

Prostate-Specific Antigen Positive Prostate Biopsies (%)

Cooperberg et al., J Urol 2007 Prostate Cancer Reality #3: Prostate Cancer Increases with Age Greater than 50% of all cases are diagnosed in men 65 years and older

http://seer.cancer.gov/statfacts Effect of Comorbidity on Competing Risks for Survival Other-Cause Mortality Prostate Cancer Mortality

Cumulative Risk: Other-Cause Mortality vs. Prostate Cancer Mortality

Population • Prospective cohort study of 3183 men with nonmetastatic prostate cancer at diagnosis

• Baseline self- reported comorbidity score (Charlson comorbidity index) Daskivich et al., Ann Intern Med, 2013;158:709–717. Genomic Heterogeneity of Prostate Cancer Primary Tumor Metastatic Tumor

Cooper et al., Nat Genetics 2015;47:367–372 Gundem et al., Nature 2015;520:353-357 Seminal Events of the Last Decade: MD Anderson Cancer Center and Beyond

Active Surveillance in Prostate Cancer Protocol

Proton Therapy PIVOT Center MDACC Oncotype Prolaris® DX® Fusion biopsy Minimally Invasive MDACC ProtecT and New Technology TCGA in Oncologic Surgery ERSPC USPSTF (MINTOS) Recommendation TP biopsy Collaborative Group PLCO against PSA-based MDACC MDACC screening

2006 2009 2012 2013 2014 2015 2016

MDACC = The University of Texas MD Anderson Cancer Center; ERSPC = European Randomized Study of Screening for Prostate Cancer; PLCO = Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; USPSTF = U.S. Preventive Services Task Force; PIVOT = Prostate Cancer Intervention versus Observation Trial; TP = transperineal; TCGA = The Cancer Genome Atlas (Molecular Taxonomy of Primary Prostate Cancer); ProtecT = Prostate Testing for Cancer and Treatment trial. Use of Imaging in Prostate Cancer

• CT, Bone scan – Display anatomic detection of • Multiparametric magnetic resonance imaging – Improve staging (ECE, SVI) • Multiparametric magnetic resonance imaging (combined with fusion biopsy) – Improve accuracy of detection for clinically significant tumors (GS>3+3) • Molecular imaging based on positron-emission tomography – Detect recurrent disease – Detect metastatic disease

Use of Multiparametric MRI in Active Surveillance

MDACC Active Surveillance Case • 07/10/10—initial biopsy; Gleason score (GS), 6; 1.5 mm RA • 10/13/10—enrolled in active surveillance trial • 10/13/10—study entry biopsy; ntp • 08/12/11—1-yr biopsy, GS 7 (3+4), 2.5 mm RA

T2WI DWI DCE-MRI T2WI A large anterior Image of restricted Rapid Right obturator gland tumor visible diffusion achieved enhancement with lymph node with a T2 weighted with diffusion- dynamic contrast- biopsy confirmed image weighted imaging enhanced MRI N1 disease

MRI, magnetic resonance imaging Mechanism and Diagnostic Efficacy of PET Radioligands for Prostate Cancer Imaging

Lindenberg et al., JAMA Onc, 2017 Prostate Cancer Molecular Imaging

• Non-specific tumor imaging agents – Fludeoxyglucose* PET/CT (* FDA approved) • Glucose analogue • Poor sensitivity – 11C-choline* PET/CT (* FDA approved) • Incorporation into lipids • Biochemical relapse with negative conventional imaging (e.g., CT and bone scan)

Hubert Chuang, MD Prostate Cancer Molecular Imaging

• ProstaScint – mAb against prostate-specific membrane antigen – Imaging with negative or equivocal conventional imaging • Lymph node metastases in high-risk patients • Biochemical recurrence – Multiday imaging

Hubert Chuang, MD PSMA Imaging

• Prostate-specific membrane antigen (PSMA) – Also known as • Folate hydrolase I (FOLH1) • Glutamate carboxypeptidase II (GCPII) – Expressed on virtually all prostate cancer cells – Increased expression with • Higher grade tumors • Metastatic disease • Hormone-refractory prostate cancer

Hubert Chuang, MD Overdiagnosis, Tumor Heterogeneity, and Life Expectancy Patients C and D cannot wait long. Patients A and B can wait. Patient A was spared unnecessary treatment. Prostate Cancer Intervention vs. Observation Trial (PIVOT) Death from Any Cause

Death from Prostate Cancer

Wilt et al., NEJM, 2012 Incidence of Cancer, Metastatic at First Presentation, in United States, 1975–2012 Clinical States Framework for Clinical Practice, Clinical Research, and Biomarker Development in Prostate Cancer

Danila et al., CCR, 2011 Potential Use of Molecular Imaging Within Clinical States Framework

Volume of Met Disease

+ Bone mets

Predictive marker of response to: Risk Androgen deprivation therapy? + LNs Chemotherapy? Targeted therapy? stratification Immunotherapy?

Danila et al., CCR, 2011 Prostate Cancer Clinical States

Castration-Sensitive Prostate Cancer

Clinically localized disease Nonmetastatic, Clinical metastases: biochemical relapse noncastrate

Surgery No standard therapy Hormone therapy Radiation Hormone therapy +/-Chemotherapy Active surveillance Castration-Resistant Prostate Cancer

Metastatic, Metastatic, Metastatic after Nonmetastatic chemotherapy-naïve chemotherapy-naïve docetaxel asymptomatic symptomatic treatment

No standard therapy Sipuleucel-T (2010) Docetaxel (2004) Enzalutamide (2012) Second-line hormones Second-line hormones Radium-223 (2013) Abiraterone (2011) (Docetaxel) Cabazitaxel (2010) Abiraterone (2015) Radium-223 Enzalutamide (2014) Natural History of PSA Recurrence After Radical Prostatectomy • A retrospective review of a large single-institution surgical series • Detectable PSA > 0.2 ng/mL • Median follow-up, 5.3 years • Median time to metastases, 8 years • Median time to death, 5 years • No hormones until bone scan • Predictors of time to metastatic disease: Gleason score, time to PSA recurrence, PSA doubling time

Pound et al., JAMA, 1999 PSA Recurrence After Radical Prostatectomy: Risk of Prostate Cancer–Specific Mortality

Freedland et al., JAMA, 2005 Upfront Chemotherapy for Metastatic Hormone-Sensitive Prostate Cancer GETUG-AFU 15 CHAARTED STAMPEDE Charac- Gravis et al., 2014 Sweeney et al., 2015 James et al., 2015 teristics 2004–2008 2006–2012 2005–2013 Institution Multiple—Europe Multiple—US Multiple—UK and Switzerland

Patients Histologically confirmed mPCa with either path dx or High-risk, locally advanced disease adenocarcinoma with clinical dx with elevated PSA or metastatic prostate cancer proven metastases; Prior ADT allowed up to 24 starting long-term HT for first time Karnofsky ≥ 70 mo if progressed >12 mo after completing therapy Current Adt allowed if begun within 120 days of randomization Patient Median age, 64 Median age, 63 Median age, 65 Characteris- 32% ADT+d recurrent 65% high-volume metastatic 61% metastatic disease tics from after treatment for local disease 14% N+ XM0 Table 1 disease vs. 24% ADT only 85% white 22% N0M0 54% node disease 81% 70% had ECOG 0 93% dx w/in 6 mo rand bone disease 60% Gleason ≥ 8 PSA (median), 65 ng/mL No mention of nodal vs. 73% no prior local therapy PSA recurrence vs. visceral metastases 75% Gleason ≥ 8 —Continued—

Gravis et al., Eur J Cancer 2014;50:953–962; Sweeney et al., NEJM 2015; 373:737–746; James et al., Lancet 2016;387:1163–1177. Upfront Chemotherapy for Metastatic Hormone- Sensitive Prostate Cancer—Continued

GETUG-AFU 15 CHAARTED STAMPEDE Charac- Gravis et al., 2015 Sweeney et al., 2015 James et al., 2015 teristics 2004–2008 2006–2012 2005–2013 Treatments ADT, ADT+D ADT, ADT+D SOC, SOC+D, SOC+ZA, SOC+D+ZA

Docetaxel 75 mg/m2 for nine 3- 75 mg/m2 for six 3-week 75 mg/m2 for six 3-week dose week cycles cycles cycles

Docetaxel Premedication with 8 mg Premedication with 8 mg Prednisone 10 mg daily supportive dexamethasone or eq dexamethasone x 3 meds GCSF added after four treatment-related deaths

Design Minimization 1:1 Stratified randomization 1:1 Stratified randomization 2:1:1:1 Stratification Prior ADT Age (<70 vs. ≥70); ECOG ≤1 Age factors Chemotherapy for local vs. 2); Combined use of ZA or WHO PS disease or rising PSA denosumab (Y/N); Duration Metastatic site Glass risk groups of prior ADT (<12 vs. ≥12 LHRH analogues mo); metastases (high vs. low Plan for radiotherapy volume) —Continued— Upfront Chemotherapy for Metastatic Hormone- Sensitive Prostate Cancer—Continued

GETUG-AFU 15 CHAARTED STAMPEDE Charac- Gravis et al., 2015 Sweeney et al., 2015 James et al., 2015 teristics 2004–2008 2006–2012 2005–2013 N 385 790 2962 Primary end Overall survival Overall survival Overall survival point Median 50 months 28.9 months 42 months follow-up Analyses Cox PH model adjusted Cox PH model, stratified by Cox model of log-rank and unadjusted strata test, adjusted for treatment effects stratification factors Results ADT, HR = 1.01 ADT+D, HR = 0.61; P <0.001 SOC+D HR = 0.76; P = 54.2 mo ADT vs. 57.6 mo vs. 44 mo 0.003 (77 vs. 67 mo) 58.9 mo ADT+D SOC+ZA, HR = 0.93; P = 0.44 SOC+D+ZA, HR = 0.81; P = 0.02. Abbreviations: mPCa, metastatic prostate cancer; path dx, diagnosis by pathology; clinical dx, clinical diagnosis; PSA, prostate- specific antigen; ADT, androgen-deprivation therapy; HT, hormone therapy; D, docetaxel; ECOG, Eastern Cooperative Oncology Group; Gleason, Gleason score; dx, diagnosis; SOC, standard of care; ZA, zoledronic acid; meds, medications; eq, equivalent; GCSF, granulocyte colony–stimulating factor; chemo, chemotherapy; Y/N, yes or no; mets, metastases; WHO PS, World Health Organization performance scale; LHRH, luteinizing hormone–releasing hormone; Cox PH, Cox proportional hazards. Upfront Chemotherapy for Metastatic Hormone-Sensitive Prostate Cancer

GETUG 15 CHAARTED STAMPEDE

HR for death in the HR for death in the HR for death in the combination group, 1.01; combination group, 0.61; combination group, 0.76; 95% CI, 0.75 to 1.36; 95% CI (0.47 to 0.80; 95% CI 0.63 to 0.91; P = 0.955 P<0.001) P = 0.003 Biological Framework for Clinical Research and Biomarker Development in Castration-Resistant Prostate Cancer

Logothetis et al., Cancer Discovery, 2013 Immune Therapy in Cancer Not New

• Pasteur, Koch, Chekhov, and others observed cancer response in patients with erysipelas in 1800s. • In 1893 William Coley induced complete remission in a patient with a solid tumor by using killed bacteria/bacterial lysates (Coley’s toxins). Used until 1963 in USA. showed interest in Coley’s toxins in 2005.

• Established immunotherapy has been around for decades as a vaccine and as cytokines and used Dr. William Coley principally in tumors in which they could trigger an immune response: • Vaccine • From 1970s to present, instillation of BCG for superficial bladder cancer • Cytokines • In 1986, Interferon-alpha was first approved for hairy cell leukemia and later for melanoma, etc. • Interleukin-2 in kidney and melanoma in1992.

Modern Immune Therapy Generating Excitement

Pooled Overall Survival— Ipilumumab in Melanoma: 10-year Follow-Up

Ipilumumab 1. Prolonged overall survival in melanoma And in other ? 2. Durable responses 3. Better tolerated than chemotherapy 4. Rapidly evolving therapies

Schadendorf, J Clin Oncol, 2015 Mechanism of Immune Checkpoint Inhibitors

• Cancer cells develop many mutations that can make them appear foreign to the

Key Attributes of the • T cells can Immune System recognize, attack and kill these • Specificity • Memory “foreign” cancer • Adaptive cells

Drake CG, Urology 2013 Dynamic Allocation Modular Sequential Trial

PI: Ana Aparicio, MD Summary

• We are in a transformative time with explosive technologic advances. – We cannot let limitations of technology drive clinical management. Overdiagnosis/overtreatment/undertreatment – Always need to keep in mind patient benefit. • Imaging as a marker: – Potential to reach high sensitivity and specificity – Reflects biology – Provides noninvasive longitudinal assessment of tumor Thank you!