Navigating Prostate Cancer Therapy. Nevin Murray MD Clinical Professor of Medicine, UBC Medical Oncologist, BCCA

Navigating Prostate Cancer Therapy Nevin Murray MD Clinical Professor of Medicine, UBC Medical Oncologist, BCCA

Disclosures In compliance with accreditation, we require the following disclosures to the session audience: Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board N/A N/A N/A N/A N/A AstraZeneca, Bristol Myers Squibb, Astellas AstraZeneca, Bristol Myers Squibb, Astellas Presentation includes discussion of the following off- label use of a drug or medical device: N/A

Prostate Cancer Demographics In Canada in 2015 24,000 new cases (#1 overall) 4,100 deaths (#3 in men) In B.C. in 2013 3,800 new cases (#1 overall) 600 deaths (#3 in men)

Prostate Cancer Screening Review of new studies Why does a clear consensus escape us? Randomized trials but no easy answer. Current recommendations And what to do in Family Medicine

Summary Gary Larson Far Side

The evidence Comes from 2 Randomized Studies Europe - ERSPC USA - PLCO NEJM March 2009

ERSPC European Randomized Screening Trial of Prostate Cancer 162,400 men in core group 55-69 years Median follow-up 11 years Control group not screened Screened group: PSA every 4 years x 2 PSA threshold 3ng/ml (2.5-4ng/ml) DRE dropped control screened Positive diagnosis rate 6% 9.6% (63% increase) Schroder et al. N Engl J Med, 360,(13), 2009 & March 2012

Results: ERSPC trial Large stage shift (% of positive) control screened High risk 13% 8% Metastases 8.2% 3% (48% decrease) Non-palpable (T1c) 41% 54% (31% increase) Schroder NEJM March 2009 & March 2012, Supplemental material on line, adjusted for null stage

Update: ERSPC trial And this translates into a reduction in prostate cancer deaths Screened 0.4% (n=299) Control 0.5% (n=462) RR 0.79 p=0.001 Schroder: NEJM March 15, 2012

Update: ERSPC trial NNInvite 781 (was 1440) NNDiagnose 27 (was 48) In those actually screened Mortality reduction ratio 0.71 But no hint of an overall survival benefit Mortality ratio 0.99 [CI 0.97-1.01] Schroder EAU Paris 2012

Update: PLCO trial Prostate Cancer Mortality Cumulative number of deaths Screened Control Study year of death Redrawn from Andriole JNCI On line 2012

Why the differences? In the US the baseline opportunistic screening rate was 45% in the prior 3 years (lifetime rate unknown) rising to 52% in the control arm by year 6 and 86% in the screening arm So it was a trial of more screening versus ~50% screening

Indicative of an underlying problem PSA is not a great test! Significant overlap No level free of cancer risk Holmström,BMJ 2009;339:b3537

PSA: No safe level Thompson. JCO VOLUME 23 NUMBER 32 NOVEMBER 10 2005

PSA screening in Family Practice 93% are screening Bluman et al Primary Care Physician Education and Engagement in the Promotion of Recommended Cancer Screening in BC Report On Province-wide Cancer Screening Needs Assessment UBC Division of Continuing Professional Development, Faculty of Medicine & The BC Cancer Agency Widely available through Google search

What is the BCCA policy? May 2012 We recommend: Considering PSA Testing Start age: asymptomatic men 50-55 years estimated life expectancy > 10 years well informed about the risks of over-diagnosis and over-treatment BCCA web site: Google BCCA PSA Screening http://www.bccancer.bc.ca/hpi/cancermanagementguidelines/genitourinary/prostate/psascreening/recommendations.htm

1: Asymptomatic men 50-55 years Tempting to get a baseline level at 45-50 But not evidence based Costly Many false positives Possibly indicated in the high risk Family history African ethnicity

2: Well informed about the risks of over-diagnosis and over-treatment This is really difficult It is impossible to do properly in 5 minutes Is it actually required ethically? Do we do this for cholesterol testing? An easy out to say no! Most authorities say it is required Patient information brochures are available And should be read before the blood is drawn Wolf AM, Wender RC, Etzioni RB, et al. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin. 2010 Mar- Apr;60(2):70-98.

Minimum components of consent Risks of PSA testing False negative and false positive PSA results A low PSA test does not mean that a person does not have prostate cancer, and a high PSA does not necessarily mean a person does have prostate cancer. Biopsy Pain and very rarely infection. Distress and anxiety Being diagnosed with prostate cancer is associated with anxiety. Over-diagnosis and treatment Over-diagnosis refers to the detection of cancers that would not otherwise have become clinically apparent. This could result in treatment of a prostate cancer that may not have been a problem for a man in his lifetime The risks of treatment such as radiation and surgery include urinary problems and incontinence, sexual dysfunction, and bowel problems. BCCA web site: Google BCCA PSA Screening http://www.bccancer.bc.ca/hpi/cancermanagementguidelines/genitourinary/prostate/psascreening/recommendations.htm

Minimum components of consent Benefits Early detection of prostate cancer can save lives. Early detection and treatment of prostate cancer can avert future prostate cancer-related problems. BCCA web site: Google BCCA PSA Screening http://www.bccancer.bc.ca/hpi/cancermanagementguidelines/genitourinary/prostate/psascreening/recommendations.htm

How to do it: If the patient wants it Every 4 years starting 50-55 (45 if high risk) Any PSA that is high (age-adjusted) needs 1. Checking 2. Then referral to a Urologist Or abnormal DRE Refer to a Urologist Stop when life expectancy <10 years

Summary Small decrease in prostate cancer mortality At a cost of probable overall net harm Patients should be informed of its availability And make their own decision With your guidance Watch out for normal PSA s that are high for age >1 ng/ml in 40 s >2 ng/ml in 50 s Refer promptly if abnormal PSA Those with <10 yr life expectancy should not be screened

Localized Prostate Ca BCCA Promotes Active Surveillance Monitoring of low risk cancer with intervention if the cancer progresses to intermediate risk Low risk: PSA 10 and Gleason score 6 Of BCCA patients referred to Rad Onc last year 1/3 had low risk prostate cancer 2/3 of these had no immediate treatment 2/3 of those will avoid treatment for 5 years

LOW RISK RESULTS Weighted >40 months follow-up or less than 100 patients Treatment Success % PSA Progression Free 100 90 80 70 60 HDR Proton EBRT/IMRT 11/16/2015 Update of BJU Int, 2012, Vol. 109(Supp 1) 68 51 50 97 92 96 6625 110 46 22 8 4 75 13 201 81 37 44 62 48 3 6 86 69 41 82 33 60 203 71 65 85 39103 98 84 3172 29 101 89 99 61 93 18 88 19 24 38 102 47 105 54 73 78 2 40 26 20258 1100 7656 7 87 77 70 80 41 15 45 57 74 79 10959 90 17 53 63 11314 11435 32 10 1128 67 429495 36 43 64 55 12 83 107 106 9 7 34 Years from Treatment 91 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Prostate Cancer Results Study Group Numbers within symbols refer to references 20 11 27 Prostate Cancer Center of Seattle 5 LDR Brachy 16 Surgery 111 115 52 104 108 + Seeds & ADT EBRT & ADT EBRT & Seeds Robot RP Seeds Surgery EBRT CRYO HIFU Protons Hypo EBRT HDR 24

Management Objective of Metastatic Cancer incurable. Prostate Cancer Have patient live as well as possible, and as long as possible in co-existance with metastatic prostate cancer. Use available systemic therapy cost-effectively at appropriate time, keeping side effects to a minimum.

THE EFFECTS OF CASTRATION ON ADVANCED CARCINOMA OF THE PROSTATE GLAND CHARLES HUGGINS, M.D.; R. E. STEVENS, Jr., M.D.; CLARENCE V. HODGES, M.D. Arch Surg. 1941;43(2):209-223. In this paper evidence is presented that significant improvement often occurs in the clinical condition of patients with far advanced cancer of the prostate after they have been subjected to castration. Conversely, the symptoms are aggravated when androgens are injected. We believe that this work provides a new concept of prostatic carcinoma. Charles B. Huggins Nobel Prize in Physiology or Medicine 1966

The Predominate Sources of Androgen ~90% androgen synthesis Testes In healthy men, ~90% of circulating androgens are synthesized in the testes ~10% androgen synthesis Adrenal Gland ~10% of circulating androgens are secreted by the adrenals DHT is the primary androgen in prostatic tissue Hoimes CJ, et al. Ther Adv Med Oncol. 2010;2:107-123. 27

Androgens Drive Prostatic Tumor Growth LHRH therapy or orchiectomy may be used to suppress testicular sources of androgen LHRH therapy or orchiectomy Adrenal Gland Prostatic Tumor Tissue Treatment with LHRH therapy or orchiectomy is used to induce regression of prostate tumor tissue and cause cell death; however, it is rarely curative Hoimes CJ, et al. Ther Adv Med Oncol. 2010;2:107-123. 28

Primary Androgen Deprivation Therapy Orchiectomy Cheap Permanent Medical vs surgical side effects similar LHRH Agonists Injections every one to six months. Requires biclutamide x 1 month to avoid flare. Home Care programs. Intermittent strategy LHRH Antagonists Monthly injections. Works faster. No flare or need for biclutamide for this purpose.

Intermittent ADT PR.7: Non-Metastatic PR.8: Metastatic JM Crook et al, NEJM367:895, 2013; M. Hussain et al, NEJM, 368:1314, 2013

Many options currently available to inhibit extragonadal androgen production or androgen receptors Biclutamide, nilutamide, flutamide Prednisone 10 mg daily Dexamethasone 2 mg daily Clinical Impact? But... 2 nd Line Hormone Therapy PSA response rate 20-30% TTP/duration of response 3-6 months Survival and clinical benefit have never been well defined Are we changing natural history? Well tolerated, inexpensive Some very good PSA and symptomatic responses Appropriate for patients with minimal symptoms, no visceral metastases and chemotherapy-ineligible Big Guns kept in reserve for when really needed.

Defining The Patient Population: Castration Resistant Prostate Cancer Aka: Hormone Refractory, Androgen Independent Prostate Cancer Clinical Trials Working Group: Castrate level of testosterone (<50 ng/dl/1.7 nmol/l) Nodal or visceral progression Bone Progression: appearance of 2 or more new lesions Heterogenous Group No clinical metastases Clinical metastases Asymptomatic Symptomatic PSA Rise Biochemical Clinical Metastases Symptomatic Disease Death 36+ Months 18-24+ Months 12-18 Months

Prostate Cancer Before 1996 Localized Local Relapse Treat with curative intent Failed Localized Therapy Hormone Therapy (incurable) Death Biochemical Progression A whole lot of nothing Metastatic HRPC (asympt.) prednisone Metastatic HRPC (sympt)

Systemic Therapies

Cytotoxic Therapy for Castration-Resistant Prostate Cancer

Assessing Response to Chemotherapy Most men with metastatic prostate cancer have bone metastases. Soft Tissue Disease on CT Scan Lymph nodes, liver, lung. Necessary to rely on surrogate endpoints to assess response decline in serum PSA, LDH. improvement in pain QOL

Timing of Chemotherapy Many patients who have disease progression following androgen-deprivation therapy do not immediately require cytotoxic chemotherapy Not for PSA relapse only Not for clinically silent metastatic disease Performance status reserve required Consider PSA doubling time in borderline case

TAX-327 Stratification: Pain level PPI 2 or AS 10 vs. PPI < 2 or AS < 10 KPS 70 vs. 80 R A N D O M I Z E Docetaxel 75 mg/m 2 q3 wks + Prednisone 5 mg bid Docetaxel 30 mg/m 2 wkly 5 of 6 wks + Prednisone 5 mg bid Mitoxantrone 12 mg/m 2 q3 wks + Prednisone 5 mg bid Overall Survival Tannock et al., NEJM, 2004 (slide courtesy of Dr. K. Chi)

TAX-327 Overall Survival Probability of Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median survival Hazard (mos) ratio P-value Combined: 18.2 0.83 0.03 D 3 wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone 0 6 12 18 24 30 Tannock et al., NEJM, 2004 (slide courtesy of Dr. K. Chi)

STRATIFICATION Extent of Mets -High vs Low Age 70 vs < 70yo ECOG PS - 0-1 vs 2 CAB> 30 days -Yes vs No SRE Prevention -Yes vs No Prior Adjuvant ADT 12 vs > 12 months NEJM, 373: 737, 2015 R A N D O M I Z E ARM A: ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles ARM B: ADT (androgen deprivation therapy alone) Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks Evaluate every 12 weeks ADT allowed up to 120 days prior to randomization. Intermittent ADT dosing was not allowed Standard dexamethasone premedication but no daily prednisone High volume: visceral metastases and/or 4 or more bone metastases (at least 1 beyond pelvis and vertebral column) Follow for time to progression and overall survival Chemotherapy at investigator s discretion at progression

CHAARTED: Overall Survival

Summary Addition of docetaxel x 6 cycles to initial ADT improves overall survival in patients with metastatic disease: a new standard of care Recommended in patients with high volume metastases ( 4 bone mets with 1 outside spine/pelvis or visceral mets) or poor prognosis Consider in patients with non-high volume disease/good prognosis but risk vs. benefit ratio needs to be considered Do not consider in patients without metastatic disease

2 nd Line Chemotherapy Patients are older, and generally more symptomatic The expectation is for short duration of survival, so emphasis on QOL and symptom management is paramount Consider repeat docetaxel for good responders Cabizitaxel in robust patients Mitoxantrone weak

Abiratirone acetate Enzalutamide New Pills for CRPC

Mechanism of Action: Abiratirone Inhibits Androgen Production at Multiple Sites Zytiga inhibits the CYP17 enzyme complex that is required for testosterone biosynthesis in all three sites: Testes Adrenal Gland Prostate Tumor Tissue Testes LHRH Therapy Orchiectomy Prostatic Tumor Tissue Abiraterone acetate Adrenal Gland

Sites of Abiratirone Acetate Action in Steroidogenesis Pathway Cholesterol Pregnenolone Aldosterone Abiraterone CYP17A1 17OH- Pregnenolone CYP17A1 Cortisol DHEA Androstenedione Testosterone DHT

Mechanism of Action: Effect on Adrenal Function Blocking the CYP17 enzyme also causes decreased cortisol levels This Leads to ACTH increase Resulting in excess aldosterone (Mineralocorticoids) Can cause hypertension, hypokalemia and fluid retention Prednisone X Co-administration of a corticosteroid suppresses ACTH drive, resulting in a reduction in the incidence and severity of mineralocorticoid adverse reactions

Abiratirone : Need for Prednisone Low-dose steroid replacement reduces mineralocorticoid-related toxicity Cholesterol No Prednisone Prednisone Pregnenolone Progesterone DOC Corticosterone Aldosterone SALT Mineralocorticoids T CYP17 17α-hydroxylase T Abiraterone HTN Low K+ 17α-OHpregnenolone 17α OHprogesterone 11-Deoxycortisol Cortisol SUGAR Glucocorticoids T CYP17 C17,20-lyase T Abiraterone DHEA Androstenedione Testosterone DHT SEX Androgens Estradiol Source: Attard et al. J Clin Oncol. 2008;26:4563-4571; Ryan et al. J Clin Oncol. 2010;28:1481-1488.

COU-AA-301 Study Design Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada) 1195 patients with progressive, mcrpc Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel Randomised 2:1 Stratification by: ECOG performance status (0-1 vs. 2) Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs. 4-10 [present]) Prior chemotherapy (1 vs. 2) Type of progression (PSA only vs. radiographic progression with or without PSA progression) Abiraterone acetate 1000 mg daily Prednisone 5mg twice daily Placebo daily Prednisone 5mg twice daily T R E A T U N T I L P R O G R E S S I O N Primary endpoint: OS (25% improvement; HR 0.8) de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Abiraterone Acetate Improves Overall Survival in mcrpc 100 Hazard ratio = 0.646 (0.54-0.77) P < 0.0001 Survival (%) 80 60 40 20 Placebo: 10.9 months (95% CI, 10.2-12.0) AA Placebo Abiraterone acetate: 14.8 months (95% CI, 14.1-15.4) 0 0 3 6 9 12 15 18 Time to Death (Months) AA 797 736 657 520 282 68 2 0 Placebo 398 355 306 210 105 30 3 0 21 V2.0 de Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO) Scher et al. J Clin Oncol 2011; 29(7S):Abstract 4 (Oral presentation at ASCO GU )

Novel Study Design: Co-primary End Points Patient Population Progressive mcrpc without prior chemotherapy; Asymptomatic or mildly symptomatic R A N D O M I Z E D 1:1 a a Stratification by ECOG PS 0 vs 1. Study COU-AA-302 Abiraterone 1000 mg daily + Prednisone 5 mg BID (actual n = 546) Placebo daily + Prednisone 5 mg BID (actual n = 542) Co-primary end points: rpfs (central review) OS Secondary end points: Time to opiate use Time to initiation of chemotherapy Time to ECOG PS deterioration Time to PSA progression Exploratory end points: HR-QoL (FACT-P, BPI- SF) BID, twice daily; rpfs, radiographic progression free survival; OS, overall survival; HR-QoL, Health-related quality of life; FACT-P, Functional Assessment of Cancer Therapy-Prostate; BPI-SF, Brief Pain Inventory-Short Form; ECOG PS, Eastern Cooperative Oncology Group performance status; PSA, prostate-specific antigen. Rathkopf D, ASCO GU 2013, Oral Presentation/ Abstract 5

MDV3100: Enzalutamide AR antagonist 8 fold higher affinity than bicalutamide NO DNA binding NO partial agonist activity Chen et al Lancet Oncol. 2010

AFFIRM: A Phase 3 Trial of Enzalutamide vs. Placebo in Post-Chemotherapy Treated Castration-Resistant Prostate Cancer (CRPC) TOC Scher HI, et al. N Engl J Med. 2012;367:1187-97. For Educational Purposes Only Not For Promotional Use

AFFIRM Overall Survival TOC HR = 0.63 (95% CI: 0.53, 0.75); p < 0.001 37% Reduction in Risk of Death Overall Survival, % Placebo: 13.6 months (95% CI: 11.3, 15.8) Enzalutamide: 18.4 months (95% CI: 17.3, NYR) No. at Risk Enzalutamide Placebo Months NYR: not yet reached Scher HI, et al. N Engl J Med. 2012;367:1187-97. For Educational Purposes Only Not For Promotional Use

AFFIRM Adverse Events TOC Any Grade Enzalutamide (n = 800) Placebo (n = 399) Frequent Adverse Events More Common with Enzalutamide* Grades 3 Enzalutamide (n = 800) Placebo (n = 399) Fatigue 34% 29% 6% 7% Diarrhea 21% 18% 1% <1% Hot Flash 20% 10% 0% 0% Musculoskeletal pain 14% 10% 1% <1% Headache 12% 6% <1% 0% Adverse Events of Special Interest Any Cardiac Disorders 6% 8% 1% 2% Myocardial Infarction <1% <1% <1% <1% LFT Abnormalities 1% 2% <1% <1% Seizure <1% 0% <1% 0% *Adverse events that occurred in >10% of patients in the enzalutamide group and that occurred in the enzalutamide group at a rate that was at least 2% points higher than that in the placebo group. Grade 4 and 5 events were not observed. Abnormalities on liver-function testing (LFT) included hyperbilirubinemia and increased levels of AST or ALT Scher HI, et al. N Engl J Med. 2012;367:1187-97. For Educational Purposes Only Not For Promotional Use

PREVAIL: A Safety and Efficacy Study of Oral Enzalutamide in Chemotherapy-Naïve Patients With Progressive Metastatic Prostate Cancer Enrollment Complete n = 1680 mcrpc asymptomatic or mildly symptomatic progression after ADT R 1:1 Enzalutamide 160 mg qd Placebo qd PREVAIL is a phase 3, randomized, double-blind, placebo-controlled trial Co-primary endpoints: overall survival and progression-free survival Planned Evaluations Overall survival / Radiographic PFS Time to first SRE Initiation of cytotoxic chemotherapy QoL (FACT-P, EQ-5D) PSA progression Pain palliation (BPI-SF) Safety (AEs, vital signs, physical exam, lab evaluations, ECG) Pharmacokinetics Long-term follow-up (radiographic PFS, SREs, additional therapies for prostate cancer, OS) Subgroups www.clinicaltrials.gov (NCT01212991) 58

Abiraterone vs. Enzalutamide Sequencing Study A phase 2, randomized, multicenter study Whole Blood: cfdna Collection RNA Collection Whole Blood: cfdna Collection RNA Collection Whole Blood: cfdna Collection RNA Collection R A N D O M I S E n = 59 n = 59 1 ST LINE THERAPY 2 ND LINE THERAPY ARM A ABIRATERONE + PREDNISONE ENZALUTAMIDE ARM B P S A P R O G R E S S I O N ARM A CROSS-OVER TO ENZALUTAMIDE CROSS-OVER TO ABIRATERONE + PREDNISONE ARM B CONTINUE UNTIL CLINICAL PROGRESSION CONTINUE UNTIL CLINICAL PROGRESSION ClinicalTrials.gov: NCT02125357

Radium-223 Ca Ra Radium-223 α-particles cause double-strand DNA breaks in nearby tumor cells Limited penetration of α-particles (~ 2-10 cell diameters) results in localized area of effect

ALSYMPCA: Study Design PATIENTS STRATIFICATION TREATMENT Confirmed symptomati c CRPC 2 Bone metastases No known visceral metastases Postdocetaxel, unfit for docetaxel, or refused docetaxel a Total ALP: <220 U/L vs 220 U/L Bisphosphonate use: Yes vs no Prior docetaxel: Yes vs no R A N D O M I Z E 2:1 N = 921 6 Injections at 4-week intervals Radium 223 dichloride (50 kbq/kg IV) + Best standard of care b Placebo (saline) + Best standard of care b 136 Centers in 19 countries Planned follow-up is 3 years ALP, alkaline phosphatase; ALSYMPCA, ALpharadin in SYMptomatic Prostate CAncer; CRPC, castration-resistant prostate cancer; IV, intravenous. a Unfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable. b Best standard of care is defined as a routine standard of care at each center, eg, local external beam radiation therapy, corticosteroids, antiandrogens, estrogens (eg, stilbestrol), estramustine, or ketoconazole. From supplementary appendix. Parker C, et al. N Engl J Med. 2013;369:213-223

Radium-223: ALSYMPCA Trial C. Parker et al, NEJM, 369:213, 2013

An Evolution - Not a Revolution Class The Old The New Hormones/AR-Axis Keto +/- Prednisone Bicalutamide Abiraterone acetate Enzalutamide Bone targeted Zoledronic acid Denosumab Chemotherapy Docetaxel Mitoxantrone Docetaxel Cabazitaxel Radiopharmaceuticals Strontium-89 Samarium-153 Radium-223

The Disease Continuum in Prostate Cancer & Current Treatments Death PSA Local Therapy 1 st Line Hormonal Therapy/ Castration 2 nd line Hormonal Therapies Bicalutamide Flutamide Nilutamide, etc. Asymptomatic Enzalutamide Abiraterone Docetaxel + Prednisone Enzalutamide Cabazitaxel + Prednisone Abiraterone plus Prednisone Radium 223 Symptoms TOC Non-Metastatic Castration Sensitive Time Metastatic Castration Resistant For Educational Purposes Only Not For Promotional Use 65

Prostate Cancer