Con$nuing Care for Your Pa$ents with Metasta$c CRPC

27 th Annual InternaAonal Prostate Cancer Symposium Update January 26, 2017 Con$nuing Care for Your Pa$ents with Metasta$c CRPC Michael S. Cookson, MD, MMHC Professor and Chair Department of Urology University of Oklahoma Health Science Center

Overview IntroducAon Urologists as the Primary Caregiver Establishing a MulAdisciplinary CRPC Clinic Evidenced Based TherapeuAc OpAons Conclusions

Lesson #1 The Urologist should be the primary caregiver for men with Prostate Cancer This includes paaents as they progress through the disease spectrum and especially those with CRPC

Urologist as the Primary Caregiver PaAents progress through disease spectrum, but should not have to progress through specialists! Role of the Urologist Diagnose and treat prostate cancer Understand the progression of the disease Understand the management of the progression Coordinate the care between specialists

Lesson #2 Establish, organize and manage a MulAdisciplinary CRPC Clinic that incorporates your available resources and works best for your clinical healthcare environment

MulAdisciplinary CRPC Clinic In response to the changing landscape, clinicians are altering care delivery to incorporate these treatments Even with guidelines, the breadth of treatment opaons allows for alternaave views on Aming and sequencing of agents One approach includes Shared Pa$ent Care in a MDC Reports from MDCs show high paaent saasfacaon rates, improved classificaaon of disease and clinical outcomes Studies of other tumors have also provided evidence that a MDC approach may impact paaent survival

Models for Establishing a MulAdisciplinary CRPC Clinic ALL- IN- ONE MDC

MulAdisciplinary CRPC Clinic CriAcal step is determining clinic structure Established clinics show an all- in- one approach may be most efficient, paracularly from paaent point of view Discuss treatment with specialists on the same day Decreases Ame and travel burden on paaents while improving communicaaon; potenaally increasing acceptance into clinical trials

MulAdisciplinary CRPC Clinic However, Ame and space limitaaons may prevent widespread use of the all- in- one model Furthermore the all- in- one clinic may reduce producavity and have financial disincenaves Obstacles to implemenang a MDC at a single locaaon can be managed by a virtual MDC

MulAdisciplinary CRPC Clinic Two alternaave approaches to the all- in- one MDC are the same day/different clinic and the different day/ different clinic models For providers with clinic locaaons in proximity, paaents can be evaluated on the same day between the clinics Care may then be coordinated through group meeang, tumor boards or messaging among providers

Models for Establishing a MulA- Disciplinary CRPC Clinic Virtual MDC Models 1. Same day/different clinic 2. Different day/different clinic

MDC CRPC: Key Ingredients PaAent Navigator Physician Assistants and/or Nurse PracAAoners Weekly meeangs w/ MulAD specialist: Tumor Boards Shared EMR (if possible) PCP to manage comorbid condiaons SupporAve care, nutriaonists, and pain management

Lesson #3 Offer Evidence Based TherapeuAc OpAons for paaents with metastaac CRPC GUIDELINES (AUA, NCCN, EAU)

mcrpc Changing Landscape Surgery / Radiation Asymptomatic/Minimally symptomatic Traditional Androgen Deprivation Therapy Symptomatic Local Therapy Androgen Deprivation Antiandrogen AAW Therapies After LHRH Agonists and Antiandrogens Chemotherapy Radium-223 Abiraterone or Enzalutamide Postchemotherapy Death Sipuleucel-T Docetaxel Cabazitaxel Radiation Therapy Prostate Cancer. NCCN Guidelines. v3.2016, AUA CRPC Guidelines, 2016.

CLINICAL GUIDANCE Since the approval of docetaxel in 2004, the first drug to offer survival benefits for CRPC paaents, five addiaonal agents have demonstrated a survival benefit and have now been approved on the basis of randomized clinical trials. Abiraterone Cabazitaxel Enzalutamide Radium 223 Sipuleucel- T

TREATMENT EVOLUTION 2004: Docetaxel Tannock et al. (TAX 327) 2010: Cabazitaxel de Bono et al. (TROPIC) 2012: Enzalutamide Scher et al. (AFFIRM) 2013: Radium 223 Parker et al. (ALSYMPCA) 2005 2007 2009 2011 2013 2014 While the greater availability of treatment agents benefits paaents, the mulaple opaons and sequencing of medicaaons complicates clinical decision- making. 2010: Sipuleucel- T Kantoff et al. (IMPACT) 2011: Abiraterone de Bono et al. (COU- AA- 301) 2013: Abiraterone Ryan et al. (COU- AA- 302) 2014: Enzalutamide Beer et al. (PREVAIL)

INDEX PATIENTS To assist in clinical decision- making, six index pa$ents were developed represen$ng the most common clinical scenarios that are encountered in clinical prac$ce These index pa$ents were created based on the following: 1. Presence or absence of metasta$c disease 2. Degree and severity of symptoms 3. Pa$ents performance status (ECOG scale) 4. Prior docetaxel chemotherapy

INDEX PATIENTS 1. Asymptoma$c non- metasta$c CRPC 2. Asymptoma$c or minimally- symptoma$c, mcrpc without prior docetaxel 3. Symptoma$c, mcrpc with good performance status and no prior docetaxel 4. Symptoma$c, mcrpc with poor performance status and no prior docetaxel 5. Symptoma$c, mcrpc with good performance status and prior docetaxel 6. Symptoma$c, mcrpc with poor performance status and prior docetaxel

INDEX PATIENT 1 Asymptoma$c non- metasta$c CRPC (M0) Clinicians should recommend observa2on with con2nued androgen depriva2on to pa2ents with non- metasta2c CRPC. (Recommenda*on; Evidence Level Grade C) Clinicians may offer treatment with first- genera2on an2- androgens (flutamide, bicalutamide and nilutamide) or first- genera2on androgen synthesis inhibitors (ketoconazole+steroid) to select pa2ents who are unwilling to accept observa2on. (Op*on; Evidence Level Grade C) Clinicians should NOT offer systemic chemotherapy or immunotherapy to pa*ents with outside the context of a clinical trial. (Recommenda*on; Evidence Level Grade C)

INDEX PATIENT 2 Asymptoma$c or minimally symptoma$c, metasta$c mcrpc (M1) without prior docetaxel chemotherapy Clinicians should offer abiraterone + prednisone, enzalutamide, docetaxel or sipuleucel- T to pa*ents with good performance status. [Standard; Evidence Level Grade A (abiraterone+prednisone and enzalutamide) / B (docetaxel and sipuleucel- T)] Clinicians may offer first- genera*on an*- androgen therapy, ketoconazole + steroid or observa*on who do not want or cannot have one of the standard therapies. (Op*on; Evidence Level Grade C)

ABIRATERONE: COU- 302 COU- AA- 302: 1,088 men with mcrpc who had not received prior chemotherapy Prednisone 5mg twice daily plus 1,000mg abiraterone daily OR placebo ParAcipants receiving abiraterone had staasacally significantly bemer radiographic progression- free and overall survival (HR = 0.53, p<0.001 and HR= 0.75, p= 0.01, respecavely) Ryan et al. NEJM 2013

ABIRATERONE: COU- 302 Ryan et al. Lancet Oncology 2015

ENZALUTAMIDE: PREVAIL The Phase III PREVAIL trial evalua$ng enzalutamide versus placebo in 1,717 chemotherapy- naive men with asymptoma$c or mildly symptoma$c mcrpc (including some with visceral metastases) was stopped a`er a planned interim analysis conducted when 540 deaths had been reported Enzalutamide (160mg/day) Placebo Overall survival HR 0.706, 95% CI [0.60-0.84] P<0.001 Radiographic progression- free survival HR 0.186, 95% CI [0.15-0.23] Beer T, et al. NEJM 2014

ENZALUTAMIDE: PREVAIL Pa$ent Popula$on: 1717 men with progressive mcrpc Asymptoma$c/ mildly symptoma$c Chemotherapy- naïve Steroids allowed but not required Prior an$androgens allowed but not required Pa$ents with visceral disease (liver and/or lung) allowed R A N D O M I Z E D 1:1 Enzaluta mide 160 mg/day n = 872 (ADT was maintained) Placebo n = 845 (ADT was maintained) Coprimary Endpoint s: rpfs Overall survival ADT=androgen deprivaaon therapy. Beer T, et al. NEJM 2014

ENZALUTAMIDE: OVERALL SURVIVAL ENZALUTAMIDE: PREVAIL PREVAIL: Co- Primary Endpoints PFS 81% decreased risk of progression or death OS 29% decreased risk of death Armstrong AJ. ASCO 2014, abstract 5007. *Median OS follow-up: ~22 months

DOCETAXEL: TAX- 327 TAX- 327 included 1,006 men with mcrpc and good performance status 5 mg prednisone twice daily plus docetaxel 75mg every three weeks OR docetaxel 30mg weekly for five of every six weeks OR mitoxantrone 12mg every three weeks PaAents who received docetaxel every three weeks showed significantly bemer survival than those receiving mitoxantrone (HR= 0.76, p= 0.009). Tannock et al. NEJM 2004

TAX- 327 OVERALL SURVIVAL 1.0 0.8 Docetaxel q3w Docetaxel q1w Mitoxantrone Propor$on alive 0.6 0.4 0.2 Median OS Hazard ratio P value Doc q3w 19.2 0.79 0.004 Doc weekly 17.8 0.87 0.086 Mitoxantrone 16.3 0 0 1 2 3 4 5 6 7 Time (years) Berthold DR et al. J Clin Oncol 2008;26:242 245

SIPULEUCEL- T: IMPACT The IMPACT trial included 512 men with asymptoma$c or minimally symptoma$c mcrpc and good func$onal status PaAents received either sipuleucel- T or placebo on a 2:1 basis. Compared to placebo, sipuleucel- T was associated with a relaave reducaon of 22% in the risk of death (HR= 0.78, p= 0.03). Some have criacized the IMPACT trial, noang that it failed to show an advantage for acave agent in the trial s second endpoint (progression- free survival). Kantoff et al. NEJM 2010

SIPULEUCEL- T: IMPACT Median Survival: Sipuleucel- T (n=341) 25.8 Mos. HR = 0.775 (95% CI: 0.614, 0.979) Survival Benefit = 4.1 months P = 0.032 (Cox Model) Placebo (n=171) 21.7 Mos. Kantoff et al. NEJM 2010

INDEX PATIENT 3 Symptoma$c, mcrpc with good performance status and no prior docetaxel chemotherapy Clinicians should offer abiraterone + prednisone, enzalutamide or docetaxel to pa*ents with symptoma*c, mcrpc with good performance status and no prior docetaxel chemotherapy. [Standard; Evidence Level Grade A (abiraterone + prednisone and enzalutamid/ B (docetaxel)] Clinicians may offer ketoconazole + steroid, mitoxantrone or radionuclide therapy to pa*ents who do not want or cannot have one of the standard therapies. [Op*on; Evidence Level Grade C (ketoconazole) /B (mitoxantrone) / C (radionuclide therapy)]

INDEX PATIENT 3 Symptoma$c, mcrpc with good performance status and no prior docetaxel chemotherapy Clinicians should offer radium- 223 to pa2ents with symptoms from bony metastases from mcrpc with good performance status and no prior docetaxel chemotherapy and without known visceral disease. (Standard; Evidence Level Grade B) Clinicians should NOT offer treatment with either estramus*ne or sipuleucel- T to pa*ents with symptoma*c, mcrpc (Recommenda*on; Evidence Level Grade C)

RADIUM- 223 PaAents 1,2 StraAficaAon 2 Treatment 1,2 N=921 Prior docetaxel: Radium Ra223 Yes vs No dichloride (50 kbq/ CRPC with Current kg) + best standard 6 injec$ons at symptomaac bisphosphonate of care 4- week (n=614) intervals bone metastases use: Yes vs No Placebo (saline) + No known Total alkaline best standard of 136 centers in 19 countries visceral phosphatase care (n=307) metastases Included paaents with malignant (ALP): <220 lymphadenopathy U/L up to 3cm 1 Best standard of care included: vs >220 U/L local external beam radiaaon therapy (EBRT), coracosteroids, anaandrogens, estrogens, 1. Radium estramusane, RA 223 dichloride injecaon; or ketoconazole 2. Parker C, al. N 1 Engl J Med. 2013;369:213-223.

RADIUM- 223 radium Ra 223 dichloride* Radium Ra 223 dichloride median OS: 14.9 months (95% Cl: 13.9-16.1) Placebo* Placebo median OS: 11.3 months (95% Cl: 10.4-12.8) radium Ra 223 614 578 504 369 277 178 105 60 41 18 7 1 0 0 dichloride placebo 307 288 228 157 105 67 39 24 14 7 4 2 1 0 30% reducaon in the risk of death vs placebo (HR=0.695) *Plus best standard of care; *95% Cl: 0.581-0.832 for the exploratory updated analysis.

INDEX PATIENT 5 Symptoma$c, mcrpc with good performance status and prior docetaxel chemotherapy Clinicians should offer treatment with abiraterone + prednisone, cabazitaxel or enzalutamide. If the pa*ent received abiraterone + prednisone or enzalutamide prior to docetaxel chemotherapy, he should be offered cabazitaxel. [Standard; Evidence Level Grade A (abiraterone) /B (cabazitaxel) /A (enzalutamide)]

CABAZITAXEL An open- label, randomized Phase III trial included 755 pa$ents who had received prior docetaxel 25mg cabazitaxel intravenously with oral prednisone every three weeks 12mg mitoxantrone intravenously with oral prednisone every three weeks Cabazitaxel demonstrated improved overall survival (15.1 months v. 12.7 months) and improved progression- free survival (2.8 months v. 1.4 months). de Bono et al. Lancet 2010

CABAZITAXEL HR = 0.70 (95% CI: 0.59, 0.83) P < 0.0001 30% reduc$on in rela$ve risk of death Cabazitaxel Median Survival: 15.1 Mos. Mitoxantrone Median Survival: 12.7 Mos. de Bono et al. Lancet 2010

Post Chemotherapy Clinical Trials Trial/ Agent/ Date Approved Mechanism Comparator Survival (months) Hazard Ratio P-value Reference AFFIRM Enzalutamide Androgen Receptor Signaling Inhibitor Placebo 18.4 vs. 13.6 0.631 <0.0001 de Bono et al, ASCO 2012 COU-AA-301 Abiraterone + prednisone 2011 CYP17 Inhibitor Placebo + prednisone 14.8 vs. 10.9 0.646 <0.0001 de Bono et al, NEJM 2011 TROPIC Cabazitaxel + prednisone 2010 Cytotoxic Mitoxantrone + prednisone 15.1 vs. 12.7 0.70 <0.0001 de Bono et al, Lancet 2010 Radium 223* Alpha-particle emitting radionuclide Placebo 14.9 vs 11.3 0.69 0.0018 Parker et al, ESMO 2011 *Radium-223 trial included chemotherapy-ineligible men Visceral disease allowed

Future DirecAons: M0 CRPC Many clinical trials currently underway

M0 CRPC - PROSPER: Enzalutumide Recrui$ng N = 1560 Patients with nonmetastatic CRPC No prior chemotherapy R 2:1 Enzalutamide 160 mg qd + ADT n = 1040 Placebo+ ADT n = 520 P3, multinational, randomized, placebocontrolled study Primary endpoint: Metastasis-free survival* * Defined as the *me from randomiza*on to radiographic progression or death on study CRPC = castra*on- resistant prostate cancer; EQ- 5D- 5L = European quality of life- 5 dimensions- 5 levels; FACT- P = func*onal assessment of cancer therapy- prostate; PSA = prostate- specific an*gen; QLQ- PR25 = quality of life ques*onnaire- prostate 25; R = randomized Planned Evaluations Metastasis-free survival Overall survival Time to pain progression Time to opiate use for prostate cancer pain Time to first use of cytotoxic chemotherapy Time to first use of new antineoplastic therapy PSA response rates Time to PSA progression Time to functional status deterioration as assessed by the FACT-P global score Quality of life as assessed by the EQ-5D-5L health questionnaire and QLQ-PR25 module Safety www.clinicaltrials.gov (NCT02003924)

N=1200 M0 CRPC; ECOG 0 or 1 M0 CRPC - SPARTAN: ARN- 509 Recruiting No prior treatment with second generaaon hormonal agents, radiopharmaceuacal agents, chemotherapy, or other invesagaaonal agents, or history of or predisposiaon to seizure R 2:1 ARN- 509 240 mg/d + ADT Placebo + ADT Primary Endpoint Metastasis Free Survival (MFS) Key Secondary Endpoints Overall Survival (OS) Time to symptomaac radiographic progression Time to iniaaaon of cytotoxic chemotherapy Radiographic Progression Free Survival (rpfs) Time to metastasis QOL: change in FACT- P and EQ- 5D quesaonnaire scores Adverse events (MedDRA) PharmacokineAcs www.clinicaltrials.gov (NCT1946204)

M0 CRPC - ARAMIS: ODM-201 Recruiting N=1500 M0 CRPC, prostate- specific anagen doubling Ame of 10 months and PSA > 2 ng/ml, ECOG 0-1 No prior treatment with: second generaaon androgen receptor inhibitors, other invesagaaonal AR inhibitors, or CYP17 enzyme inhibitor or prior chemotherapy or immunotherapy R 2:1 ODM-201 300 mg bid + ADT Placebo + ADT Primary Endpoint Metastasis- Free Survival Key Secondary Endpoints OS Time to first symptomaac skeletal event Time to iniaaaon of chemotherapy Time to pain progression www.clinicaltrials.gov (NCT02200614)

SPECTRUM OF DISEASE

Conclusions Urologists should be the Primary Caregiver for men with Advanced Prostate Cancer Establishing a MulAdisciplinary CRPC Clinic is an essenaal component to care delivery Evidenced Based TherapeuAc OpAons exist, and familiarity and use will enhance outcome