Reviewed by Dr. Nimira Alimohammed (Staff Oncologist, University of Calgary) and Dr. Scott Berry (Staff Oncologist, University of Toronto) in 2016

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1 PROSTATE CANCER Updated January 2016 by Dr. Kristy Wassn (PGY-5 Medical Onclgy Resident, University f Trnt) and August 2017 by Dr. Jenny K (Staff Onclgist, Abbtsfrd Cancer Centre, BCCA) Reviewed by Dr. Nimira Alimhammed (Staff Onclgist, University f Calgary) and Dr. Sctt Berry (Staff Onclgist, University f Trnt) in 2016 A) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: 99 per 100,000. Mst cmmn cancer amng men (excluding nn-melanma skin cancers), accunts fr 24% f all new male cancer cases in Canada. - Mrtality: 3rd leading cause f cancer death in men in Canada (17 deaths per 100,000). RISK FACTORS - Envirnmental/Chemical/Infectins: cnsumptin f a diet rich in red meat and saturated fat appears t increase risk, particularly f aggressive disease. - Genetic: increasing age is the mst imprtant risk factr, higher incidence in Nrth American blacks cmpared with ther ethnic grups and ften has a mre aggressive curse, risk increased twfld in men with ne r mre affected first-degree relatives, BRCA1 and BRCA2 carriers have an increased risk (1.8- and 4.7-fld). PREVENTION & SCREENING - Preventin: Finasteride and Dutasteride (5-AR inhibitrs) have been shwn t decrease the risk f prstate cancer, but with with an elevated rate f high-grade prstate cancers and n change in verall survival. - Screening: Serum PSA screening is f unknwn value as a ppulatin screening test. RCTs have shwn a small reductin in prstate-cancer mrtality, but harms assciated with screening, including ver-diagnsis and treatment are cmmn. - Evidence fr: The Eurpean Randmized Study f Screening fr Prstate Cancer (ERSPC) Study i fund a 20% reductin in prstate cancer death screening men aged 55-69, with an abslute risk reductin 0.71 deaths per 1000 men. T prevent 1 death: 1410 men need t be screened fr 9 years and 48 additinal cases diagnsed and treated. - Evidence against: The Prstate, Lung, Clrectal, Ovarian (PLCO) trial ii fllwed 77,000 men between 55 and 74 fr 13 years and fund the death rate frm prstate cancer was lw and did nt differ between the screened and cntrl (unscreened) grups. - Cancer Care Ontari des nt supprt an rganized, ppulatin-based screening prgram fr prstate cancer. - BCCA, Alberta Cancer Guidelines recmmend that fit men between the ages f 50 and 75 years with at least 10 years life expectancy shuld be made aware f the availability f PSA as a detectin test fr prstate cancer, as well as the ptential benefits and risks f early detectin, s they can make an infrmed decisin as t whether t have the test perfrmed. - Canadian Task Frce recmmends against PSA screening fr prstate cancer (CMAJ 2014). Ref. 1) Schrder F et al. N Engl J Med Mar 26;360(13): ) Andrile GL et al. N Engl J Med Mar 26;360(13):1310. B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - Lcalized disease - vast majrity - present with an abnrmal digital rectal examinatin (DRE) r PSA screening - Lcally advanced disease - lwer urinary symptms: hesitancy, weak stream, frequency, ncturia, incmplete bladder emptying - Metastatic disease - cnstitutinal symptms, bny pain

2 INVESTIGATIONS - Histry and Physical including DRE - Labratry: PSA, CBC, Calcium prfile, Creatinine, ALP and LFTs - Transrectal bipsy - typically cre - Radilgy: CT chest/abd/pelvis and bne scan in intermediate/high risk - If symptms r signs f crd cmpressin: MRI whle spine PATHOLOGY & MOLECULAR BIOLOGY - Mst cmmn histlgy is adencarcinma (>95%) - Gleasn Scre = sum f tw mst cmmn tumur patterns, mst cmmn stated first - Other: sarcmatid, endmetriid - Transitinal cell carcinma shuld be treated as a urthelial cancer - Sarcmas are rare and shuld be treated per sarcma guidelines STAGING - TNM T1: clinically inapparent tumur nt palpable r visible by imaging T1a: Tumr incidental histlgic finding in 5% r less f tissue resected T1b: Tumr incidental histlgic finding in mre than 5% f tissue resected T1c: Tumr identified by needle bipsy (eg, because f elevated PSA) T2: tumur cnfined within the prstate T2a: tumur invlves ne lbe T2b: tumur invlves bth lbes T3: tumur extends thrugh the prstatic capsule T3a: extracapsular extensin (unilateral r bilateral) T3b: tumur invades seminal vesicle(s) T4: tumur is fixed r invades adjacent structures ther than seminal vesicles: bladder neck, external sphincter, rectum, levatr muscles, and/r pelvic wall N1: reginal lymph nde metastasis (pelvic ndes belw the bifurcatin f the cmmn iliac arteries) M1a: nn-reginal lymph nde(s), M1b: bne(s), M1c: ther site(s) with r withut bne disease Stage 1: T1aN0M0 + Gleasn scre 2-4 Stage 2A: T1aN0M0 + Gleasn scre 5-6, T1b-T1cN0M0 any Gleasn Stage 2B: T2N0M0 any Gleasn Stage 3A: T3N0M0 any Gleasn Stage 4: T4N0M0 any Gleasn, anytn1m0 any Gleasn, anyt anyn M1 any Gleasn - Lw Risk: PSA 10 ng/ml + Gleasn 6 + Stage T1/T2a - Intermediate Risk: neither lw r high risk, any f: PSA 10-20, Gleasn 7, Stage 2B - High Risk : any f PSA > 20 ng/ml r Gleasn 8 r Stage T3a r wrse C) TREATMENT I) LOCALIZED Prstate Cancer - Bttm Line General Apprach: Lw Risk ptins: Active Surveillance (CCO & ASCO guideline preference; see belw), Prstatectmy, EBRT, brachytherapy Intermediate Risk ptins: Prstatectmy, EBRT + brachytherapy bst r brachytherapy alne. EBRT + shrt-term Andrgen Deprivatin Therapy (ADT; 4-6 mnths) ptin fr nn-brachy/nn-surgical patients High Risk ptins: EBRT + brachytherapy bst mnths ADT r Prstatectmy. EBRT + lng-term ADT ptin fr nn-brachy/nn-surgical patients Prstatectmy and RT have nt been cmpared head t head 3 RCTs shw brachy bst > EBRT fr intermediate and high risk patients (+/- ADT)

3 Adjuvant ADT fllwing EBRT - multiple randmized trials have demnstrated imprvement in cancer-specific and verall survival with adjuvant ADT fllwing EBRT in high-risk disease (RTOG 86-10, EORTC 22863, RTOG 85-31). 3 years was fund t be superir t 6 mnths f ADT but 18 mnths = 36 mnths (Quebec PCS3 study). Adjuvant ADT in intermediate risk is less clear fr brachytherapy patients but data supprts 4-6m ADT with EBRT. The RTOG 0815 trial has recently clsed in which adjuvant 6m ADT is being investigated with mdern high-dse radiatin (data wn t be avail until at least 2021). Neadjuvant ADT with Radical Prstatectmy has been explred in ver 20 trials and althugh several studies demnstrated a reductin in the rate f psitive surgical margins, this did nt translate t imprvements in bichemical prgressin free survival r verall survival and is nt currently recmmended. Adjuvant r Neadjuvant Chemtherapy - Clinical trials currently nging: RTOG 0521 EBRT (72-75 Gy) + ADT x 2 years +/- adjuvant Dcetaxel - presented at ASCO Fr high-risk, lcalized PCa, adjuvant Dcetaxel imprved OS frm 89% t 93% at 4 years. CALGB Phase III trial f neadjuvant dcetaxel plus ADT fllwed by radical prstatectmy versus immediate radical prstatectmy Adjuvant Radiatin: patients with adverse histlgic features (extracapsular extensin, seminal vesicle invlvement, psitive margins, r lymph nde invlvement) shuld be referred t radiatin nclgy fr cnsideratin f adjuvant RT (CCO, ASCO & AUA guidelines) Salvage RT: persistent elevatin r rising PSA after surgery shuld be referred t radiatin nclgy fr cnsideratin f adjuvant RT (> 0.2 ng/ml) (CCO, ASCO & AUA guidelines). 2 years f bicalutamide 150mg fund t imprve OS and MFS in salvage raditherapy setting (RTOG 9601) If age r cmrbidity preclude definitive therapy in men with intermediate r high-risk prstate cancer, systemic therapy with ADT may be useful as a palliative apprach, althugh this has been assciated with shrter verall survival than definitive therapy. - Active Surveillance: bservatin rather than immediate therapy in lw-risk patients as a means f aviding ver-treatment. Trnt prspective chrt prtcl: serum PSA at three mnth intervals, with a PSA dubling time f three years r less as a criterin fr active interventin; repeat prstate bipsy is perfrmed at ne year then repeated every fur t five years t lk fr evidence f bilgic prgressin t Gleasn 4+3 r higher. - Prgnsis: lw risk disease: 10-year prstate cancer survival rates >99%; intermediate risk 95-98%; high risk lcalized disease 80-90%. - Surveillance after definitive treatment: serum PSA every 3-6 mnths fr the first 2 years then q6m thereafter. Bipsies dne at 1y then q3y. Rle f MR-guided bipsies has been investigated (ASIST - results expected late 2016) II) Hrmne-Sensitive Metastatic Prstate Cancer I) Bttm Line General Apprach: Initial ptins include Andrgen Deprivatin Therapy (ADT) r cmbined Chemhrmnal Therapy (ADT + 6 cycles f Dcetaxel) I) ADT = lwering serum teststerne t castrate levels (<1.7 nml/l r <50 ng/dl). Surgical rchiectmy (castratin) and Medical rchiectmy with GnRH agnist r GnRH antagnist are equally effective. Anti-andrgens (ie Bicalutamide) are ften cmbined with GnRH agnists at the start f therapy fr 2-4 weeks t prevent symptm flare due t transient increase in teststerne. Several meta -analyses have shwn small imprvements in OS with cmplete andrgen blckade (GnRHa + anti-andrgen) but with increased txicity. II) Early vs Delayed ADT meta-analysis shwing n significant OS benefit t early ADT, hwever, hetergeneus ppulatin and n prgnstic factrs incrprated int studies. III) Intermittent vs Cntinuus ADT - cntrversial. INT-0162 Phase III trial shwing intermittent ADT is NOT nn-inferir t ADT with respect t OS. IV) Side effects f ADT: vasmtr symptms, decreased libid, decreased muscle mass, decreased energy, metablic syndrme, stepenic effects V) Calcium and Vitamin D shuld be given t all men n ADT

4 VI) Bichemical prgressin n standard ADT is treated with secndary hrmnal manipulatins: additin f bicalutamide and bicalutamide withdrawal. Steridal anti -andrgens (ie ketcnazle) are nt as cmmnly used since the develpment f abiraterne and enzalutamide. VII) 3 Phase III RCT (CHAARTED, Stampede (ASCO 2015), GETUG-AFU 15) have evaluated early Dcetaxel in cmbinatin with ADT in metastatic castrate sensitive prstate cancer. CHAARTED and Stampede shwed imprved PFS and OS with early Dcetaxel + ADT cmpared t ADT alne (*GETUG-AFU 15 did nt shw a statistically significant increase in OS). Median OS in the lw-vlume disease subgrup has nt been reached and additinal fllw-up is required. Stampede has nt yet been published. VIII) 2 Phase III RTCs (LATITUDE, STAMPEDE) have been published t shw OS benefit f abiraterne/prednisne added t ADT within 3 mnths f initiatin f ADT (see belw fr details). N data n dcetaxel vs. abiraterne/prednisne in this setting. II) Prgnsis: mnths with ADT alne vs 57 mnths with cmbined chemhrmnal therapy shrter with high vlume disease, see CHAARTED III) Imprtant Phase III clinical trials: CHAARTED: Chemhrmnal Therapy in Metastatic Hrmne-Sensitive Prstate Cancer Reference: Sweeney et al. NEJM 2015;373:737. Regimen Andrgen Deprivatin Therapy (ADT) with LHRHa alne vs ADT + Dcetaxel 75 mg/m2 n day 1 every 3 weeks x 6 cycles Mechanism f Actin f Experimental Primary Endpint Inclusin/Exclusin Dcetaxel: inhibits plymerizatin f tubulin therefre inhibiting DNA, RNA and prtein synthesis. OS Pathlgical diagnsis f prstate cancer r clinical scenari cnsistent Radigraphic evidence f metastatic disease ECOG 0-2 Prir adjuvant ADT allwed if 24 ms and cmpleted 12 ms prir ADT cmmenced within 120 days f randmizatin Size (N) 790 Results Survival: mos 57.6 ms vs 44.0 ms, HR 0.61 Subgrup with high vlume disease: mos 49.2 ms vs 32.2 ms HR 0.60 Subgrup with high vlume disease: mos nt reached in lw vlume grup Decrease in PSA t 0.2ng/ml at 12 ms: 27.7% vs 16.8% Time t develpment f castratin-resistant PCa: 20.2 ms vs 11.7 ms Txicity Grade 3 r 4 neutrpenia 32%, febrile neutrpenia 3% Cmmn txicities include fatigue, n/v/d, neurpathy (30%), edema Cnclusin Other Cmments Six cycles f dcetaxel at the beginning f ADT fr metastatic prstate cancer resulted in significantly lnger verall survival than that with ADT alne. high vlume disease defined as visceral mets r 4 bny mets with 1 utside axial skeletn

5 GETUG-AFU 15: Andrgen-deprivatin therapy alne r with dcetaxel in nn-castrate metastatic prstate cancer: a randmized, pen-label Phase 3 trial. Reference: Gravis et al. Lancet Oncl 2013;14:149. Regimen Mechanism f Actin f Experimental Primary Endpint Inclusin/Exclusin Andrgen Deprivatin Therapy (ADT) with LHRHa alne r rchiectmy vs ADT + Dcetaxel 75 mg/m2 n day 1 every 3 weeks x 9 cycles Dcetaxel: inhibits plymerizatin f tubulin therefre inhibiting DNA, RNA and prtein synthesis. OS Histlgically cnfirmed adencarcinma f the prstate Radigraphic evidence f metastatic disease Karnfsky PS 70% ADT cmmenced within 2 mnths f enrlment Prir neadjuvant r adjuvant therapy cmpleted 12 mnths prir Size (N) 385 Results Survival: mos 62 ms vs 49 ms, HR 0.88 ( ) NS bichemical PFS: 22.9 ms vs 12.9 ms, HR 0.67 Median time t subsequent treatment: 20 ms vs 15.4 ms Fall in PSA 50% at 6 mnths: 94% vs 85% Txicity Neutrpenia 21%, febrile neutrpenia 3%, abnrmal LFTs 2% Cnclusin Other Cmments Dcetaxel shuld nt be used as part f first-line treatment fr patients with nn-castrate metastatic prstate cancer. Additin f dcetaxel, zledrnic acid, r bth t fi rst-line lng-term hrmne therapy in prstate cancer (STAMPEDE): survival results frm an adaptive, multiarm, multistage, platfrm randmised cntrlled trial James Lancet Vlume 387, N , p , 19 March 2016 Regimen Standard f care was hrmne therapy fr at least 2 years; raditherapy was encuraged fr men with N0M0 disease t Nvember, 2011, then mandated; raditherapy was ptinal fr men with nde-psitive nn-metastatic (N+M0) disease. Stratified randmisatin (via minimisatin) allcated men 2:1:1:1 t standard f care nly (SOC-nly; cntrl), standard f care plus zledrnic acid (SOC + ZA), standard f care plus dcetaxel (SOC + Dc), r standard f care with bth zledrnic acid and dcetaxel (SOC + ZA + Dc). Zledrnic acid (4 mg) was given fr six 3-weekly cycles, then 4-weekly until 2 years, and dcetaxel (75 mg/m2) fr six 3- weekly cycles with prednislne 10 mg daily. Primary Endpint OS Inclusin/Exclusin men with high-risk, lcally advanced, metastatic r recurrent prstate cancer wh are starting first-line lng-term hrmne therapy Size (N) N=2962 Results Median age was 65 years (IQR 60 71) (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0.

6 165 (6%) men were previusly treated with lcal therapy, and median prstate-specific antigen was 65 ng/ml (IQR ). Median fllw-up was 43 mnths (IQR 30 60). There were 415 deaths in the cntrl grup (347 [84%] prstate cancer). Median verall survival was 71 mnths (IQR 32 t nt reached) fr SOC-nly, nt reached (32 t nt reached) fr SOC + ZA (HR 0 94, 95% CI ; p=0 450), 81 mnths (41 t nt reached) fr SOC + Dc (0 78, ; p=0 006), and 76 mnths (39 t nt reached) fr SOC + ZA + Dc (0 82, ; p=0 022). There was n evidence f hetergeneity in treatment effect (fr any f the treatments) acrss prespecified subsets. Grade 3 5 adverse events were reprted fr 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Dc, and 269 (52%) receiving SOC + ZA + Dc. Subgrup analysis, OS - M0 HR 0.95 (crsses 1) - M1 HR 0.76 (significant) Cnclusin Zledrnic acid shwed n evidence f survival imprvement and shuld nt be part f standard f care fr this ppulatin. Dcetaxel chemtherapy, given at the time f lng-term hrmne therapy initiatin, shwed evidence f imprved survival accmpanied by an increase in adverse events. Dcetaxel treatment shuld becme part f standard f care fr adequately fit men cmmencing lng-term hrmne therapy. Abiraterne plus Prednisne in Metastatic, Castratin-Sensitive Prstate Cancer (LATITUDE) Fizazi N Engl J Med 2017; 377: Regimen Andrgen-deprivatin therapy plus abiraterne acetate (1000 mg daily, given nce daily as fur 250-mg tablets) plus prednisne (5 mg daily) (the abiraterne grup) r andrgen-deprivatin therapy plus dual placebs (the placeb grup). Primary Endpint OS Radigraphic PFS Inclusin/Exclusin Patients with newly diagnsed, metastatic, castratin-sensitive prstate cancer starting ADT <3m All the patients had high-risk, metastatic, castratin-sensitive prstate cancer, as dcumented by a psitive bne scan r metastatic lesins at the time f diagnsis n cmputed tmgraphy (CT) r magnetic resnance imaging (MRI), accrding t Respnse Evaluatin in Slid Tumrs (RECIST), versin 1.1. In additin, the patients were required t have at least tw f the three fllwing high-risk factrs assciated with pr prgnsis: a Gleasn scre f 8 r mre (n a scale f 2 t 10, with higher scres indicating mre aggressive disease), at least three bne lesins, and the presence f measurable visceral metastasis. Size (N) N=1199 Results After a median fllw-up f 30.4 mnths at a planned interim analysis (after 406 patients had died), the median verall survival was significantly lnger in the abiraterne grup than in the placeb grup (nt reached vs mnths) (hazard rati fr death, 0.62; 95% cnfidence interval [CI], 0.51 t 0.76; P<0.001). The median length f radigraphic prgressin-free survival was 33.0 mnths in the abiraterne grup and 14.8 mnths in the placeb grup (hazard rati fr disease prgressin r death, 0.47; 95% CI, 0.39 t 0.55; P<0.001). Significantly better utcmes in all secndary end pints were

7 bserved in the abiraterne grup, including the time until pain prgressin, next subsequent therapy fr prstate cancer, initiatin f chemtherapy, and prstate-specific antigen prgressin (P<0.001 fr all cmparisns), alng with next symptmatic skeletal events (P=0.009). These findings led t the unanimus recmmendatin by the independent data and safety mnitring cmmittee that the trial be unblinded and crssver be allwed fr patients in the placeb grup t receive abiraterne. Txicity Similar t knwn S/E f abiraterne/prednisne Rates f grade 3 hypertensin and hypkalemia were higher in the abiraterne grup. Cnclusin The additin f abiraterne acetate and prednisne t andrgendeprivatin therapy significantly increased verall survival and radigraphic prgressin-free survival in men with newly diagnsed, metastatic, castratin-sensitive prstate cancer. Abiraterne fr Prstate Cancer Nt Previusly Treated with Hrmne Therapy (STAMPEDE) James N Engl J Med 2017; 377: Regimen ADT alne r ADT plus abiraterne acetate (1000 mg daily) and prednislne (5 mg daily) (cmbinatin therapy) Lcal raditherapy was mandated fr patients with nde-negative, nnmetastatic disease and encuraged fr thse with psitive ndes. Fr patients with nnmetastatic disease with n raditherapy planned and fr patients with metastatic disease, treatment cntinued until radilgic, clinical, r prstate-specific antigen (PSA) prgressin; therwise, treatment was t cntinue fr 2 years r until any type f prgressin, whichever came first. Primary Endpint OS Inclusin/Exclusin Eligible patients had prstate cancer that was newly diagnsed and metastatic, nde-psitive, r high-risk lcally advanced (with at least tw f fllwing: a tumr stage f T3 r T4, a Gleasn scre f 8 t 10, and a PSA level 40 ng per milliliter) r disease that was previusly treated with radical surgery r raditherapy and was nw relapsing with high-risk features (in men n lnger receiving therapy, a PSA level >4 ng per milliliter with a dubling time f <6 mnths, a PSA level >20 ng per milliliter, ndal r metastatic relapse, r <12 mnths f ttal ADT with an interval f >12 mnths withut treatment). Patients were intended fr treatment with lng-term ADT that started n lnger than 12 weeks befre randmizatin. There were n age restrictins. Patients with clinically significant cardivascular disease (e.g., severe angina, recent mycardial infarctin, r a histry f cardiac failure) were excluded. Size (N) N=1917 Results There were 248 treatment-failure events in the cmbinatin grup as cmpared with 535 in the ADT-alne grup (hazard rati, 0.29; 95% CI, 0.25 t 0.34; P<0.001); the hazard rati was 0.21 in patients with nnmetastatic disease and 0.31 in thse with metastatic disease. Fr OS, M0 HR 0.75, crsses 1; M1 -HR 0.61, significant mfu 40m There were 184 deaths in the cmbinatin grup as cmpared with 262 in the ADT-alne grup (hazard rati, 0.63; 95% cnfidence interval [CI], 0.52 t 0.76; P<0.001); the hazard rati was 0.75 in patients with nnmetastatic disease and 0.61 in thse with metastatic disease.

8 Restricted mean failure-free survival time: 43.9 mnths in the cmbinatin grup and 30.0 mnths in the ADT-alne grup in the first 54 mnths after randmizatin, a difference f 13.9 mnths (95% CI, 12.3 t 15.4). The effect f abiraterne n failure-free survival was nted in all subgrups The 3-year prgressin-free survival was 80% in the cmbinatin grup and 62% in the ADT-alne grup (hazard rati fr clinical r radilgic prgressin r death frm prstate cancer, 0.40; 95% CI, 0.34 t 0.47; P<0.001) FFS M0 HR 0.21; M1 HR 0.31 Bth significant Txicity Grade 3 t 5 adverse events ccurred in 47% f the patients in the cmbinatin grup (with nine grade 5 events) and in 33% f the patients in the ADT-alne grup (with three grade 5 events). Cnclusin Amng men with lcally advanced r metastatic prstate cancer, ADT plus abiraterne and prednislne was assciated with significantly higher rates f verall and failure-free survival than ADT alne.

9 III) Castrate-Refractry Metastatic Prstate Cancer (mcrpc) I) Bttm Line General Apprach: I) Treatment ptins fr mcrpc include taxane chemtherapy (Dcetaxel, Cabazitaxel), antiandrgens Abiraterne Acetate and Enzalutamide and Radium st line ptins include Dcetaxel, Abiraterne, Enzalutamide and Radium-223. Pst-Dcetaxel ptins include Abirterne, Enzalutamide, Radium-223 and Cabazitaxel. II) Palliative raditherapy is als frequently used fr cancer-related pain frm bne metastases III) New treatment ptins were develped in parallel and the ptimal sequencing f treatments is unknwn but f increasing imprtance. Currently, decisins are based n patient factrs (cmrbidities, perfrmance status, cancer-related symptms, cntraindicatins) and disease factrs (site f disease: lymph nde r bne nly sites vs visceral metastases, duratin f respnse t ADT and aggressiveness: rate f prgressin/de nv metastatic disease/high Gleasn scre) IV) Abiraterne and Enzalutamide shw decreased rates f PSA respnse when used subsequent t the ther indicative f crss resistance. V) Use f bisphsphates (Zledrnic Acid) r Densumab decreases skeletal related events but des nt imprve OS r QOL. 1) Saad et al. J Natl Cancer Inst 2004; 96: ) Fizazi et al. Lancet 2011; 377:

10 II) Prgnsis: 35 mnths with mst recent trials vs 16 mnths withut treatment in TAX327 (Mitxantrne des nt imprve OS) III) Imprtant Phase III Clinical Trials TAX 327: Dcetaxel plus Prednisne r Mitxantrne plus Prednisne fr Advanced Prstate Cancer. Reference: Tannck IF et al. NEJM 2004;351:1502. Regimen Mechanism f Actin f Experimental Up t 10 cycles f Dcetaxel (75 mg/m2 n day 1 every 3 weeks) OR up t 5 cycles f weekly Dcetaxel (30 mg/m2 n day 1, 8, 15, 22, 29 f a 6 week cycle) plus plus prednisne 5mg BID vs. Mitxantrne (12 mg/m2 n day 1 every 3 weeks) plus prednisne 5mg BID Dcetaxel: inhibits plymerizatin f tubulin therefre inhibiting DNA, RNA and prtein synthesis. Primary Endpint OS Inclusin/Exclusin N prir cyttxic treatment Karnfsky PS >/= 60% Disease prgressin n hrmnal treatment Size (N) 1006 Results Survival: mos 18.9 ms in q3 weekly Dcetaxel vs 16.5 ms in Mitxantrne, n significant imprvement with weekly Dcetaxel PSA Respnse: 45%, 48% Dcetaxel vs 32% Mitxantrne (p<0.01) QOL: Imprved QOL with bth Dcetaxel grups vs Mitxantrne Pain: decreased with q3 weekly Dcetaxel Txicity Grade 3 r 4 neutrpenia 32%, febrile neutrpenia 3% Cmmn txicities include fatigue, n/v/d, neurpathy (30%), edema Cnclusin Dcetaxel q3 weeks (but nt weekly Dcetaxel) plus prednisne led t superir survival and imprved rates f respnse in terms f pain, serum PSA level, and quality f life, as cmpared with mitxantrne plus prednisne. This is the first study t shw a survival benefit in mcrpc. Other Cmments (e.g. any criticisms abut the study)

11 Pst-Dcetaxel AFFIRM: Increased Survival with Enzalutamide in Prstate Cancer after Chemtherapy. Reference: Scher HI et al. NEJM 2012;367:1187. Regimen Mechanism f Actin f Experimental Primary Endpint Inclusin/Exclusin Enzalutamide (MDV3100) 160mg PO daily vs. placeb Enzalutamide: andrgen receptr antagnist, inhibits translcatin f AR int cell nucleus and inhibits AR binding t DNA OS Castrate levels f teststerne (<50 ng/ deciliter [1.7 nml/ liter]) Previus treatment with Dcetaxel ECOG 0-2 Disease prgressin (radigraphic r rising PSA n 3 ccasins) Size (N) 1199 Results Survival: mos 18.4 ms vs 13.6 ms, HR 0.63 PSA Respnse: increased with Enzalutamide (54% vs 2%) ORR: increased with Enzalutamide (29% vs 4%) QOL: increased with Enzalutamide (43% vs 18%) time t first skeletal event: increased with Enzalutamide (16.7 ms vs 13.3 ms) time t PSA prgressin: increased with Enzalutamide 8.3 ms vs 3.0 ms PFS: increased with Enzalutamide 8.3 ms vs 2.9 ms Txicity Seizure 0.6% Cmmn: fatigue, diarrhea, ht flashes, headache, MSK pain Cnclusin Enzalutamide significantly prlnged survival in men with metastatic castratin resistant prstate cancer after chemtherapy. Other Cmments interactins

12 COU-AA-301: Abiraterne and Increased Survival in Metastatic Prstate Cancer. Reference: de Bn et al. NEJM 2011;364:1995. Regimen Abiraterne 1000mg PO daily + prednisne 5mg BID vs. placeb + prednisne 5mg BID Mechanism f Actin f Experimental Primary Endpint Inclusin/Exclusin Abiraterne: irreversible and specific inhibitr f CYP17 (inhibits andrgen synthesis) OS Castrate levels f teststerne (<50 ng/ deciliter [2 nml/ liter]) Previus treatment with Dcetaxel ECOG 0-2 Disease prgressin (radigraphic r rising PSA n 2 ccasins) Size (N) 1195 Results Survival: mos 14.8 ms vs 10.9 ms, HR 0.65 PSA Respnse: increased with Abiraterne (29% vs 6%) ORR: increased with Abiraterne (14% vs 3%) Rate f pain palliatin: increased with Abiraterne (44% vs 27%) Time t first skeletal event in 25%: increased with Abiraterne (9.9 vs 4.9 ms) Time t PSA prgressin: 10.2 ms vs 6.6 ms PFS: 5.6 ms vs 3.6 ms Txicity Cmmn: fatigue, back pain, nausea, cnstipatin, bne pain - similar frequency as placeb Hypkalemia (17%), fluid retentin (31%), hypertensin (10%), cardiac events (13%), AST/ALT elevatin (10%, same as placeb) Cnclusin Abiraterne abiraterne acetate prlnged verall survival amng patients with metastatic castratin-resistant prstate cancer wh previusly received chemtherapy. Other Cmments (e.g. any criticisms abut the study)

13 TROPIC: Prednisne plus cabazitaxel r mitxantrne fr metastatic castratin-resistant prstate cancer prgressing after dcetaxel treatment: a randmised pen label trial. Reference: de Bn et al. Lancet 2010;376:1147. Regimen Mechanism f Actin f Experimental Primary Endpint Inclusin/Exclusin Up t 10 cycles f Cabazitaxel (25 mg/m2 q21 days) + prednisne 10mg daily vs. Mitxantrne (12mg/m2 q 21days) + prednisne 10mg daily. Prphylactic GCSF allwed after 1st ccurrence f febrile neutrpenia r neutrpenia greater than 7 days Cabazitaxel: inhibits plymerizatin f tubulin therefre inhibiting DNA, RNA and prtein synthesis. OS Previus treatment with Dcetaxel Disease prgressin (radigraphic r rising PSA n 2 ccasins) ECOG 0-2 Onging castratin by rchiectmy r LHRHa >/= Grade 2 peripheral neurpathy excluded Size (N) 755 Results Survival: mos 15.1 ms vs 12.7 ms, HR 0.7 PSA Respnse: increased with Cabazitaxel (39.2% vs 17.8%) ORR: increased with Cabazitaxel (14% vs 4%) Time t PSA prgressin: 8.8 ms vs 5.4 ms mpfs: 2.8 ms vs 1.4 ms Rate f pain palliatin: n difference Time t pain prgressin: n difference Txicity Grade 3 r 4 neutrpenia 82%, febrile neutrpenia 8%, diarrhea 6% Cmmn txicities include haematlgic, diarrhea, fatigue, n/v Cnclusin Cabazitaxel plus prednisne imprves verall survival in patients with metastatic castratin-resistant prstate cancer whse disease has prgressed during r after dcetaxel-based therapy. Other Cmments (e.g. any criticisms abut the study)

14 ALSYMPCA: Alpha emitter Radium-223 and Survival in Metastatic Prstate Cancer Reference: Parker et al. NEJM 2013;369:213. Regimen Mechanism f Actin f Experimental Primary Endpint Inclusin/Exclusin Up t 6 injectins f Radium kBq/kg n Day 1 every 4 weeks vs. Placeb Radium-223: targeted alpha emitter that selectively binds t areas f increased bne turnver in bne metastases and induces dublestranded DNA breaks OS Castrate levels f teststerne (<50 ng/ deciliter [1.7 nml/ liter]) 2 r mre bne metastases N visceral metastases, lymph nde mets <3cm Symptmatic disease: regular use f analgesics r radiatin fr cancer-related bne pain in previus 12 weeks Previus treatment with Dcetaxel, nt a candidate fr Dcetaxel r declined Dcetaxel** PSA f at least 5ng/ml and with 2 cnsecutive increases ECOG 0-2 Size (N) 921 Results Survival: mos 14.9 ms vs 11.3 ms, HR 0.7 Time t first skeletal event: 15.6 ms vs 9.8 ms, HR 0.66 Time t an increase in ALP: 7.4 ms vs 3.8 ms Time t an increase in PSA: 3.6 vs 3.4 ms PSA respnse: 16% vs 6% 30% reductin in ALP: 47% vs 3% Nrmalizatin f ALP: 34% vs 1% Imprved QOL: 25% vs 16% Txicity Cnclusin The number f patients experiencing an adverse event was cnsistently lwer in the Radium-223 grup than in the placeb grup fr all adverse events N clinically meaningful differences in the frequency f hematlgic adverse events were bserved between grups. Radium-223 significantly prlnged verall survival in patients wh had castratin-resistant prstate cancer previusly treated with (r ineligible fr) Dcetaxel and symptmatic bne metastases Other Cmments **nly ~60% were pst-dcetaxel, thers were nn -Dcetaxel

15 Pre-Dcetaxel COU-AA-302: Abiraterne in Metastatic Prstate Cancer withut Previus Chemtherapy. Reference: Ryan et al. NEJM 2013;368:138 and Ryan et al. Lancet Oncl 2015;16:152. Regimen Abiraterne 1000mg PO daily + prednisne 5mg BID vs. placeb + prednisne 5mg BID Mechanism f Actin f Experimental Primary Endpint Inclusin/Exclusin Abiraterne: irreversible and specific inhibitr f CYP17 (inhibits andrgen synthesis) OS* Radigraphic PFS *c-primary endpints Castrate levels f teststerne (<50 ng/ deciliter [1.7 nml/ liter]) Disease prgressin (radigraphic r rising PSA n 2 ccasins) Chemtherapy-naive ECOG 0-1 N symptms r mild symptms n BPI-SF Pts with visceral metastases excluded Pts treated with ketcnazle > 7 days were excluded Size (N) 1088 Results mpfs: 16.5 vs 8.3 ms, HR 0.53 Survival: mos 34.7 ms vs 30.3 ms, HR 0.81 PSA Respnse: 62% va 24% ORR: 36% vs 16% Time t initiatin f cytxic chemtherapy: 25.2 ms vs 16.8 ms Time t piate use fr cancer-related pain: 33.4 ms vs 23.4 ms Time t decline in ECOG PS: 12.3 ms vs 10.9 ms Time t PSA prgressin: 11.1 ms vs 5.6 ms Txicity Cnclusin Fatigue, arthralgia, peripheral edema - mre cmmn than placeb Hypkalemia (17%), fluid retentin (28%), hypertensin (22%), cardiac events (19%), AST/ALT elevatin (8%) Abiraterne imprved radigraphic PFS, verall survival, and delayed clinical decline, time t initiatin f chemtherapy and time t piate use in patients with metastatic castratin-resistant prstate cancer. Other Cmments (e.g. any criticisms abut the study)

16 PREVAIL: Enzalutamide in Metastatic Prstate Cancer befre Chemtherapy Reference: Beer et al. NEJM 2014;371:424. Regimen Mechanism f Actin f Experimental Primary Endpint Inclusin/Exclusin Enzalutamide (MDV3100) 160mg PO daily vs. placeb Enzalutamide: andrgen receptr antagnist, inhibits translcatin f AR int cell nucleus and inhibits AR binding t DNA OS* Radigraphic PFS* c-primary endpints Castrate levels f teststerne (<50 ng/ deciliter [1.7 nml/ liter]) Disease prgressin (radigraphic r rising PSA n 2 ccasins) N prir cyttxic chemtherapy, ketcnazle r abiraterne ECOG 0-1 N symptms r mild symptms n BPI-SF Pts with visceral metastases eligible Histry f seizure r cnditin predispsing t seizure excluded Size (N) 1717 Results Survival: 12-mnth OS 72% vs 63%, HR 0.71 PFS: 12-mnth Radigraphic PFS 65% vs 14%, HR 0.19 PSA Respnse: 78% vs 3% ORR: 59% vs 5% Time t initiatin f cytxic chemtherapy: 28 ms vs 10.8 ms Time t PSA prgressin: 11.2 ms vs 2.8 ms Time t first skeletal-related event: 31.1 mst vs 31.3 ms Time t decline in FACT-P glbal scre: 11.3 ms vs 5.6 ms Txicity Cnclusin Cmmn: fatigue, hypertensin Enzalutamide significantly decreased the risk f radigraphic prgressin and death and delayed the initiatin f chemtherapy in men with metastatic prstate cancer. Other Cmments

17 Other References 1) Canadian Cancer Statistics ) UpTDate 3) Alberta Cancer Guidelines 4) BC Cancer Agency Clinical Practice Guidelines