SEQUENCING IN METASTATIC PROSTATE CANCER TREATMENT

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1 SEQUENCING IN METASTATIC PROSTATE CANCER TREATMENT Eleni Maragkouli, Medical Oncologist Oncology Department The University of Thessaly, Medical School University Hospital of Larissa, Greece

2 Tumour volume and activity PROSTATE CANCER DRUG DEVELOPMENT Chemotherapy Docetaxel or abiraterone acetate (AA) + ADT for mhspc Castration M0 CRPC (enzalutamide? ARN509?) AA 2013 Enzalutamide 2014 Sipeuleucel-T Radium 223 Docetaxel AA 2011 Cabazitaxel 2010 Radium 223 Enzalutamide 2012 Image from

3 DOCETAXEL PLUS PREDNISONE OR MITOXANTRONE PLUS PREDNISONE For advanced prostate cancer N=1006 men with chemotherapy-naive mcrpc randomly assigned to docetaxel (75 mg/m 2 q3w), docetaxel (30 mg/m 2 weekly) or mitoxantrone (12 mg/m 2 q3w). All patients received prednisone 5 mg orally bd KaplanMeier estimates of the probability of overall survival in the three groups Response to treatment, as measured by decreases in pain, PSA level, and tumour burden and improvements in the QoL HR for death=0.76 (95% CI, ; p=0.009) OS = +2,9 m Docetaxel improved rates of response in terms of pain, serum PSA level, and quality of life From N Engl J Med, Tannock IF, et al., Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer, 351, Copyright 2004 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

4 THIS IS ALL EFFECTIVE IN THE POST-DOCETAXEL SETTING P, prednisone; CI, confidence interval; mths, months. 1. Bahl A, et al., Ann Oncol 2013;24: Open Access article distributed under CC-BY-NC Licence ( 2. Reprinted from Lancet Oncol 13, 10, Fizazi K, et al., Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study , Copyright 2012, with permission from Elsevier; 3. From N Engl J Med, Scher H, et al., Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy, 367, Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society ; 4. From N Engl J Med, Parker C, et al., Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer, 369, Copyright 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

5 BUT ALSO EFFECTIVE PRE-DOCETAXEL COU-AA PREVAIL 2 ORR: 62% 1. From N Engl J Med, Ryan CJ, et al., Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy, 368: Copyright 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society; 2. From N Engl J Med, Beer TM, et al., Enzalutamide in Metastatic Prostate Cancer before Chemotherapy, 371: Copyright 2014 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

6 ALGORITHM SEQUENCING IN mcrpc

7 WHICH DRUG FOR WHICH PATIENT

8 THERE ARE NO PROSPECTIVE SEQUENCING OR HEAD-TO-HEAD STUDIES TO GUIDE OUR TREATMENT CHOICE IN mcrpc

9 REGIMEN SEQUENCING Laboratory parameters PSA doubling time, LDH, ALP Clinical Parameters Symptomatic or asymptomatic disease Response to previous chemo or hormone, lines of therapy Radiographic parameters High or low volume disease Presence of visceral disease Other parameters Other medical history Disease characteristics (SCPC, anaplastic features) BIOMARKERS? Other?

10 PATIENT AND (ONLY INDIRECTLY) TUMOUR CHARACTERISTICS INFLUENCING TREATMENT DECISIONS Based on Level I evidence and adverse events Performance status symptomatic disease Comorbidities Based on retrospective experience, Phase 2 results Time to CRPC Prior therapy exposure and response Tumour characteristics

11 SHORT RESPONSE TO FIRST ADT (1 YEAR) MAY PREDICT POOR RESPONSE TO AR-TARGETED THERAPIES AR-targeted agents 1 Retrospective analysis in 108 patients with metastatic PCa Poor response to subsequent hormone therapies (including abiraterone, enzalutamide) if time to CRPC with first ADT <16 months Docetaxel patients with mcrpc in 2 prospective databases High Gleason score and visceral metastases more common if early CRPC ( 1 year) Good response to docetaxel irrespective of time to CRPC Duration of response <16 mo 16 mo Duration of response 1yr >1yr PSA 50% 18% 58% Median TTP 3 mo 5 mo PSA 50% 67% 81% Median TTP 6.1 mo 7.1 mo 1. Loriot Y, et al., ASCO GU 2012 (abstract 213); 2. Huillard, ASCO 2013 (abstract 5075).

12 SEQUENTIAL ADMINISTRATION OF NEW AGENTS 1 Few clinical trials Retrospective uncontrolled post-hoc analysis (inherent bias) Small sample size Short follow-up Evaluation of objective responses not always comparable Evaluation of cumulative results and not patients individual data Prognostic variables that may influence the clinical outcomes Not always available OS since the first initiation of docetaxel never reported Maines F, et al., Crit Rev Oncol Hematol 2015;96:498506

13 PRE- AND POST-DOCETAXEL SETTING OF ABI AND ENZA COMPARISON OS in favour for ENZ both in chemotherapy pretreated (HR 0.85) and naïve (HR 0.90) patients OS identical in pts with visceral disease and >75 ys OS relatively (ns) better with ENZ in pts without visceral disease It is a not direct comparison! ENZ provides a significantly longer time without PSA progression ENZ provides a significantly better radiographic PFS Zhang W, et al., Asian J Androl 2017;19: Open access article distributed under the terms of the CC BY-NC-SA 3.0 License (

14 SEQUENTIAL ADMINISTRATION OF NEW AGENTS 2 A comprehensive review of genomic landscape, biomarkers and treatment sequencing in castration-resistant prostate cancer Reprinted from Cancer Treat Rev, 48, Seisen T, et al., A comprehensive review of genomic landscape, biomarkers and treatment sequencing in castration-resistant prostate cancer, 2533., Copyright2016, with permission from Elsevier.

15 HETEROGENEITY OF CLINICAL TRIALS Reprinted from Crit Rev Hem Oncol 96, 2015, Maines F, et al., Sequencing new agents after docetaxel in patients with metastatic castration-resistant prostate cancer, , Copyright 2015, with permission from Elsevier.

16 WHAT ABOUT EARLIER CHEMOTHERAPY? What if we start having patients that have already received chemotherapy and have hormonosensitivity? Things are changing, since they may have to go directly to second-line chemotherapy with cabazitexel when disease progresses, or try a re-challenge with docetaxel

17 THE FIRST DATA How should we treat castration-resistant prostate cancer patients who have received androgen deprivation therapy (ADT) plus docetaxel upfront for hormone-sensitive disease? Retrospective analysis of the GETUG-AFU 15 Phase 3 trial Study design Lavaud P, et al., ESMO 761P, Courtesy of Dr Lavaud.

18 PSA RESPONSE FOR CRPC PATIENTS Treated with docetaxel (first- or second-line) according to time of relapse after upfront ADT+D treatment (cut-off 13.6 months) Treated with abiraterone or enzalutamide (first- or second-line): Patients treated with upfront ADT+D Lavaud P, et al., ESMO 761P, Courtesy of Dr Lavaud.

19 KAPLANMEIER CURVES FOR bpfs Survival after first-line docetaxel treatment for CRPC in patients treated for mhspc with upfront ADT and ADT-D bpfs after docetaxel for first-line CRPC was 6 months (95% CI ) in the ADT arm and 4.1 months (95% CI ) in the ADT+D arm When used for first-line or secondline CRPC treatments, nextgeneration AR axis-targeted agents (abiratone or enzalutamide) were associated with a PSA decline of more than 50% in 10/12 (83%) evaluable patients in the ADT control arm and 10/17 (59%) in the ADT+D arm Median OS for CRPC 27.5 mo for ADT vs mo for ADT+D Lavaud P, et al., ESMO 761P, Courtesy of Dr Lavaud

20 THERE ARE MORE CONSIDERATIONS

21 ARE WE EVALUATING DISEASE PROPERLY? Upfront metastatic, high-volume bone (lytic?), visceral, high GS Anaplastic phenotype? PSA high or low? PSA decline CTCs? Methodology of disease measurement Search of biomarkers (clinical, pathological, molecular, to better identify patients that may be helped by early chemotherapy)

22 WHAT IS EXTENSIVE DISEASE? We need a more precise identification of disease distribution or volume to better identify those who most benefit from chemotherapy 4 lesions 4 lesions <4 lesions Presented By Michael Morris at 2014 ASCO Annual Meeting. J Clin Oncol 32:5s, 2014 (suppl; abstr 5022)

23 OS (%) Survival (%) DIFFERENT APPROACHES OF DISEASE VOLUME Disease extent is a powerful prognostic factor for OS 1. First report on disease extent and OS Minimal: Spine, pelvis and/or lymph nodes versus Extensive: Ribs, long bones and/or visceral organs (liver, lung) 2. S8894 Bilateral orchiectomy ± flutamide Flutamide, extensive disease Placebo, extensive disease Minimal: 51 mo Extensive: 27.5 mo Flutamide, minimal disease Placebo, minimal disease Months of follow-up 3. S9346 Survival by disease extent for CAD arm only 4. MDACC High volume: 3 bone metastases or visceral disease At risk Death Median (years) Extensive Minimal Low: 7.8 yrs High: 3.1 yrs Years since randomisation 1. Crawford ED, et al., N Engl J Med. 1989;321(7):4194; 2. rom N Engl J Med, Eisenberger MA, et al., Bilateral Orchiectomy with or without Flutamide for Metastatic Prostate Cancer, 339, ; Copyright 1998 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society; 3. Hussain M, et al., N Engl J Med 2013;368(14):131425; 4. Millikan RE, et al., J Clin Oncol. 2008;26(36):

24 BONE METASTASES Definition low volume disease Imaging Modality Dependent Patient with prostrate cancer 1 Patient with breast cancer Bone scan F-choline-PET >20 NaF-PET This meta-analysis indicated that MRI was better than choline PET/CT and BS on a per-patient basis (pooled sensitivities) 3 Choline PET/CT 0.91 (95% (CI): ) MRI 0.97 (95% CI: ) BS 0.79 (95% CI: ) BS + SPECT NaF-PET WBMR_DWI BS, bone scintigraphy. 1. Kjölhede H, et al., BJU Int 2012;110:15016; 2. Jambor I, et al., Prospective evaluation of planar bone scintigraphy, SPECT, SPECT/CT, 18F-NaF PET/CT and whole body 1.5T MRI, including DWI, for the detection of bone metastases in high risk breast and prostate cancer patients: SKELETA clinical trial. Acta Oncol 2016;55:5967, copyright Acta Oncologica Foundation reprinted by permission of (Taylor & Francis Ltd, on behalf of Acta Oncologica Foundation; 3. Shen G, et al., Skeletal Radiol 2014;43:

25 IS PFS A SURROGATE FOR OS? N x Age % M at presentation High risk / Strata? Chemo at PD Control arm F/up Difference of PFS / OS CHAARTED % 65% / YES 40% (60%?) 29 mos YES / YES GETUG % 48% / NO 63% 85% 83 mos YES / NO STAMPEDE %?? / NO 44% 43 mos YES / YES

26 FOLLOW-UP? SUBSEQUENT TREATMENTS? Consider the total treatment given to patients in each arm of the study: Intent-to-treat GETUG-15 CHAARTED ADT + D ADT ADT + D ADT Total enrolled Total failed 142 (74%) 146 (81%) 145 (36%) 174 (44%) Post-prot. docetaxel 54 (28%) 120 (62%) 49 (12%) 129 (32%) Post-prot. cabazitaxel 3 (2%) 2 (1%) 43 (11%) 29 (7%) Post-prot. ABI or placebo 19 (10%) 21 (11%) 92 (23%) 79 (20%) Post-prot. ENZ or placebo 9 (5%) 7 (4%) 0 0 Post-prot. sipuleucel-t (8%) 20 (8%) Non-life prolonging 106 (55%) 131 (69%) 49 (12%) 129 (32%) Courses life prolonging rx. 277 (144%) 150 (78%) 603 (151%) 255 (65%) Taxane only 249 (130%) 122 (63%) 489 (123%) 158 (40%) Presented By Howard Scher at 2015 ASCO Annual Meeting

27 DOCETAXEL (DOC) POST AR INHIBITION WITH AA Baseline characteristics and outcome measures DOC post-αa 1 (n=86) DOC post-aa 2 (n=38) DOC post-αa 3 (n=23) DOC post-αa 4 (n=23) DOC post-αa 5 (n=365) Median age, years (range) 71 (5285) 71 (4687) ECOG performance status % 9% 68% 29% Gleason score 8 43% 37% 74% PSA (median, ng/ml) Metastatic sites, % Bone Lymph node Visceral Efficacy endpoints 50% PSA, % 30% PSA, % Median OS, months Median PFS, months Response, % Suggestion of lower efficacy of subsequent taxanes 1. Mezynski J, Ann Oncol 2012;23:2943-7; 2. Azad AA, The Prostate 74: (2014); 3. Aggarwal R, Clin Genitourin Cancer Oct;12(5):e167-72; 4. Suzman DL, Prostate 2014 Sep;74(13): ; 5. Flaig TW, et al., ASCO 2015 Abstr. 168.

28 IMPACT OF PRIOR RESPONSE TO AA ON DOCETAXEL EFFICACY 86 patients (37 docetaxel naïve) PSA response rates were not linked to prior response to AA No differences in patients receiving docetaxel for PSA response rates Median PFS Median OS Azad AA, et al., A retrospective, Canadian multi-center study examining the impact of prior response to abiraterone acetate on efficacy of docetaxel in metastatic castration-resistant prostate cancer. Prostate 2014;74: Wiley Periodicals, Inc.

29 CABAZITAXEL POST-(DOC+AR- INHIBITION) Baseline characteristics and outcome measures CABA post-doc-aa/enz 1 (n=37) CABA post-doc-aa 2 (n=24) CABA post-doc-aa 3 (n=79) Median age, years (range) ECOG performance status PSA (median, ng/ml) Metastatic sites % Bone Lymph node Visceral Efficacy endpoints 50% PSA, % 30% PSA, % Median OS, months Median PFS, months Response % % NR CABA post-doc-aa 4 (n=65) % in TROPIC TRIAL Pezzaro CJ, et al., Eur Urol 2014;66:459465; 2. Sella A, et al., Clin Genitourin Cancer 2014;12(6):42832; 3. Al Nakouzi N, et al., Eur Urol 2014;68(2):22835; 4. Caffo O, et al., J Clin Oncol 2014;32:Abstract 5089.

30 AA POST-ENZ IN mcrpc POST-CHEMO Baseline characteristics and outcome measures AA post-enz 1 (n=30) AA post-enz 2 (n=38) AA post-doc 3 (n=103) Median age, years (range) 70 (5684) 71 (5284) 67 (4585) ECOG performance status % 23% 68% 29% Gleason score 8 43% 37% PSA (median, ng/ml) ng/dl (3-3,000) Metastatic sites, % Bone Lymph node Visceral Efficacy endpoints 50% PSA, % 30% PSA, % Median OS, months Median PFS, months Response, n % 34% % PSA response: 38% 1. Noonan KL, et al., Ann Oncol 2013;24:18027; 2. Loriot Y, et al., Ann Oncol 2013;24:180712; 3. Demirci E, et al., J Clin Oncol 32, 2014 (suppl; abstr e16094).

31 ENZALUTAMIDE POST-AA IN mcrpc POST-CHEMO (1) Baseline characteristics and outcome measures ENZ post-aa 1 (n=79*) ENZ post-aa 2 (n=26) ENZ post-aa 3 (n=35) ENZ post-aa (n=150 ) ENZ post-aa 4 (n=24) ENZ post-aa (n=61) ENZ post-aa (n=23) Median age, years (range) 74 (5587) 72 (5688) 72 (6083) 70 (4490) 72 (5782) 69 (6474) 70 (5794) ECOG performance status % 77% 23% PSA (median, ng/ml) Metastatic sites % Bone Lymph node Visceral Efficacy endpoints 50% PSA, % 30% PSA, % Median OS, months Median PFS, months Response, n % 33% % 43% *75 post-abiraterone, 62 of whom received abiraterone as last treatment before enzalutamide, 122 patients had prior post-chemotherapy abiraterone and 28 received. pre-chemotherapy abiraterone. 1. Stevenson R, et al., J Clin Oncol 2014;32(Suppl 4): Abstract 125; 2. Vera-Badillo FE, et al., J Clin Oncol 2014;32(Suppl 4): Abstract 159; 3. Schmid SC, et al., Adv Ther 2014;31:23441; 4. Thomsen FB, et al., Scand J Urol 2013;48(3):268-75

32 ENZALUTAMIDE POST-AA IN mcrpc POST-CHEMO (2) Baseline characteristics and outcome measures ENZ post-aa 1 (n=35) ENZ post-cyp17i 2 (n=20) ENZ post-aa 3 (n=39) ENZ post-aa 4 (n=23) ENZ post-aa 5 (n=24) ENZ post-aa 6 (n=66) Median age, years (range) 70 (5781) 76 (6484) 70 (5485) 76 (6582) 72 (5782) 74.8 (5694) ECOG performance status % 35.8% 65.2% 34.8% 66.7% 33.3% PSA (median, ng/ml) Metastatic sites % Bone Lymph node Visceral Efficacy endpoints 50% PSA, % 30% PSA, % Median OS, months Median PFS, months Response, n Not reached % PSA response: 1254% 1. Schrader AJ, et al., Eur Urol 2014;65:306; 2. Bournakis E, et al., ECC Poster presentation P413; 3. Bianchini D, et al., Eur J Cancer 2014;50:7884; 4. Thomson D, et al., J Clin Oncol 2014;32(Suppl 4): Abstract 188; 5. Thomsen FB, et al., Scand J Urol 2013;48(3):268-75; 6. Scholz MC, et al., J Clin Oncol 2014;32(Suppl 4): Abstract 247.

33 COMPLETED RETROSPECTIVE STUDIES OF SEQUENCING AA AND ENZ Completed retrospective studies of sequencing AA and ENZ in patients with mcrpc In the post-chemotherapy setting Authors Year published No. of pts Duration of 2 nd treatment >50% decline in PSA Median PFS ENZ AA Loriot Y, et al months 3% 2.7 months Noonan KL, et al months 3% 3.8 months Schrader AJ, et al months 29% Badrising S, et al months 21% AA ENZ Bianchini D, et al months 23% Schmid SC, et al months 10% Brasso K, et al months 18% In the pre-chemotherapy setting Authors Year published No. of pts Duration of ENZ treatment >50% decline in PSA Median PFS ENZ AA Suzman DL, et al months 34% 4.1 months Azad AA, et al months 25% 4.6 months Analysis of patients who received AA followed by ENZ in pre-chemotherapy setting Median duration of ENZ therapy was around 4 months Similar to the low response rates detected in the post-chemotherapy sequencing studies, Suzman et al. found that only 34% of patients had >50% PSA decline on ENZ, whereas Azad et al. found that only 25% of patients had a >50% PSA decline on ENZ Zhang T, et al., Expert Opin Pharmacother. 2015;16(4):47385.

34 PSA change (%) ENZALUTAMIDE IN HEAVILY PRE-TREATED PATIENTS With bone mcrpc resistant to Androgen Biosynthesis Inhibitor (ABI) treatment The Hellenic experience of the Name Patient Access Program (NPAP) % PSA decline: 40% (8/20) 90% PSA decline: 5% (1/20) Bournakis E, et al., ESMO Poster presentation P413. Courtesy of Dr Bournakis.

35 ENZALUTAMIDE AS A FOURTH- OR FIFTH-LINE TREATMENT OPTION Retrospective study 47 patients mcrpc All patients were treated with D and AA 42 patients (89%) CAB Median age: 69 years (IQR, ) 79% had bone metastases; 55% had lymph node metastases; 17% had visceral metastases Median duration of ENZ treatment was 12.0 weeks (IQR, ) 11 patients (23%) responded to ENZ (maximum PSA decline 50%) Median OS: 40.1 weeks (95% CI, ) Median PFS: 12.1 weeks (95% CI, ) Median time to PSA progression:15.7 weeks (95% CI, ) ENZ is well tolerated and there is a 23% response rate in heavily pre-treated CRPC patients, which is comparable with third-line treatment outcomes Badrising SK, et al., Oncology 2016;91(5):26727

36 AA VS. ENZALUTAMIDE BEFORE AND AFTER DOCETAXEL EnzaAbi sequence (N=16) AbiEnza sequence (N=65) P- value Age (years), median Race, % Caucasian African-American Asian Metastatic disease at diagnosis, % PSA (ng/ml) at diagnosis, median Gleason score, % < Prior prostatectomy, % Prior ketoconazole, % Prior docetaxel, % ECOG PS, % 01 > Bone pain present, % Visceral disease present, % PSA (ng/ml), prior to first agent in sequence, median Alkaline phosphate (U/L), median Hb (g/dl), median Albumin (g/dl), median Number of bone lesions, % < Median PFS: 19.5 m (AA) vs. 13 m (ENZ) Median OS: 33.3 m (AA) vs. 30 m (ENZ) Median PSA-PFS: 29.5 m (AA) vs m (ENZ) Chance of achieving PSA response to both 1 st and 2 nd hormonal therapy is significantly higher in the AA ENZ group (33.8% vs. 6.3%) Maughan BL, et al., Comparing Sequencing of Abiraterone and Enzalutamide in Men With Metastatic Castration Resistant Prostate Cancer: A Retrospective Study. Prostate 2017;77(1): Wiley Periodicals, Inc.

37 RESISTANCE MECHANISMS Prognostic markers Multiple clinical nomograms CALGB: LDH, haemoglobin (Hb), albumin, alkaline phosphatase, PSA, VISCERAL metastases, pain/opioids, PS Neutrophil:Lymphocyte ratio CTC enumeration (CellSearch) cfdna quantification What about predictive markers? Can we interrogate tumour to assess response based upon MOA?

38 PRIMARY RESISTANCE 1. From N Engl J Med, de Bono JS, et al., Abiraterone and Increased Survival in Metastatic Prostate Cancer, 364: Copyright 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 2. From N Engl J Med, Scher H, et al., Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy;367: Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

39 AS SECOND-LINE CHEMO IN mcrpc PSA response rates for cabazitaxel (post-docetaxel) are quite similar pre- and post-abiraterone Post-abiraterone Pre-abiraterone Saad F, et al., Can Urol Assoc J.2016;10: Canadian Urological Association. With permission from Can Urol Assoc J.

40 Response rate (%) LDH??? Predictive markers of PSA response to AA in mcrpc PSA response according to total score Composite score Multivariable analyse Variable P Comparison OR 95% CI NLR vs 1 2 vs LDH vs Met extension vs Elevated LDH increases risk of non-response Leibowitz-Amit R and Templeton AJ, J Clin Oncol 2013;31(15S):322s(abs.5058).

41 PSA PFS PFS OS PSA PFS PFS OS CLINICAL OUTCOME OF TAXANE TREATMENT VS. AR-TREATMENT ACCORDING TO AR-V7 STATUS Adjusted p= No. at risk Time (months) Taxane ENZA or AA Adjusted p= Time (months) Adjusted p= Time (months) Taxane, AR-V7 positive ENZA or AA, AR-V7 positive Adjusted p= No. at risk Time (months) Taxane ENZA or AA Adjusted p= Time (months) Adjusted p= Time (months) Taxane, AR-V7 negative ENZA or AA, AR-V7 negative Cox model adjusting for: AR-FL level, prior use of ENZA/AA PSA response: 65% Taxane, 64% ENZA/AA, p=0.60, adjusted p=0.36 Antonarakis ES, et al.. JAMA Oncol 2015;1(5):58291

42 OUTCOMES: AR-V7 CONVERSIONS Outcome AR-V7 AR-V7 (n=36/42) AR-V7 AR-V7+ (n=6/42) AR-V7+ AR-V7+ (n=16) PSA response 68% (95% CI, 5281%) 17% (95% CI, 458%) 0% (95% CI, 019%) PSA PFS 6.1 months (95% CI, 5.9 mo NR) 3.0 months (95% CI, 2.3 mo NR) 1.4 months (95% CI, mo) PFS 6.5 months (95% CI, 6.1 mo NR) 3.2 months (95% CI, 3.1 mo NR) 2.1 months (95% CI, mo) Clinical outcomes of AR-V7 to AR-V7+ men were intermediate Antonarakis ES, ASCO 2014, A 5001.

43 AR-V7 AND EFFICACY OF TAXANE CHEMOTHERAPY IN PATIENTS WITH mcrpc N=37 patients, starting taxane Rx, prior AA/ENZA allowed, 1º: PSA response 17/37 (46%) AR-V7+ CTCs (25% in NO prior AA/ENZA, 50% in either, 53% in both) AR-V7+: Younger, GS >8, prior ENZA/AA, >bone, PSA, ALkP, AR-FL PSA responses (54%, 41% in AR-V7+, 65% in AR-V7), PSA PFS, PFS numerically better in AR-V, but NS AR-V7 : 11% +, 89% remained Low conversion rate with taxanes? AR-V7+ : 58%, 42% remained + CTC disappearance? If so, could taxane Rx restore sensitivity to secondary hormonal therapies? BUT clinical info is NOT supporting this now Compared with 62 patients from previous trial In AR-V7+ men, taxanes appear to be more efficacious than ENZA or AA (PSA response, PSA PFS, cpfs) In AR-V7 men, taxanes and ENZA or AA may have comparable efficacy Antonarakis ES, et al., JAMA Oncol 2015;1(5):58291

44 RESISTANT REVERSIONS THROUGH TIME POST TREATMENTS LINES Treatment (A) AR-V7 at BASELINE (n=15) Remained AR-V7 "Conversions" to AR-V7+ First-line ADT (n=2) 1 1 Abiraterone (n=4) 3 1 Enzalutamide (n=4) 1 3 Cabazitaxel (n=2) 0 Total (n=15) 7 8 (A) Number of baseline AR-V7 individuals that either remained AR-V7 or converted to AR-V7+ during treatment AR-V7+ may be associated with primary and acquired resistance to ENZA and AA Docetaxel If validated (n=3) AR-V7+ patients 0 could be steered 3 away from receiving AR-targeting drugs and could be offered alternative treatments Treatment (B) AR-V7+ at BASELINE (n=22) Remained AR-V7+ "Reversions" to AR-V7 First-line ADT (n=0) 0 0 Abiraterone (n=5) 4 0 Enzalutamide (n=4) 4 0 Docetaxel (n=9) 4 5 Cabazitaxel (n=4) 1 1 Total (n=22) 13 6 (B) Number of baseline AR-V7+ individuals that either remained AR-V7+ or reverted back to AR-V7 during treatment

45 CABAZITAXEL RETAINS ACTIVITY IN AR-V7+ Reprinted from European Urology 68(2015), Onstenk W, et al., Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR- V7 in Circulating Tumor Cells, , Copyright (2015), with permission from Elsevier.

46 CLINICAL CONCLUSIONS Detection of AR-V7 in CTCs from men with mcrpc is not associated with primary resistance to taxane agents AR-V7positive patients may retain sensitivity to taxanes In AR-V7positive men: Taxanes may be more efficacious than AR-directed therapies In AR-V7negative men: Taxanes may have comparable efficacy to AR-directed agents AR-V7 may be a treatment-selection marker in mcrpc

47 CTCs COLLECTIONS POST THERAPY LINES 161 patients Reproduced with permission from JAMA Oncol 2016;2(11): Copyright 2016 American Medical Association. All rights reserved.

48 LIQUID BIOPSY AND CELL-FREE DNA TO GUIDE THERAPY Compensate for the heterogeneity between different cancer foci Easier to obtain Can be repeated at different time points Stage dependent AR ON cells (PSA+ and PSMA) are mostly found in hormone-naïve patients changing to AR OFF after induction of androgen deprivation Transition from AR ON to AR mixed or AR OFF during treatment with AA was prognostic Detection of ARVs Hegemann M, et al., Liquid biopsy: ready to guide therapy in advanced prostate cancer? BJU International 2016;118(6): BJU International

49 LIQUID BIOPSY TO GUIDE THERAPY The blood of a proportion of patients can contain CTCs derived from the primary tumour and different metastatic sites (CellSearch) 75% of pts with advanced PrCa 5 CTCs in 7.5 ml has been validated as a prognostic marker in mcrpc receiving docetaxel or AA Increase in CTCs at any point under treatment was associated with reduced OS More prognostic than PSA CTCs with stem cell features contribute to metastases However, lack of sensibility within CRPC Scher HI, at al., Nat Rev Clin Oncol 2013;10:22534.

50 MUTATION GUIDED THERAPY Overall, 16 patients (33%) had tumour aberrations in DNA-repair genes. BRCA2 aberrations were detected in 7 patients Other: BRCA1 ATM Fanconi s anaemia genes CHEK2 Mateo J, et al., N Engl J Med 2015;373(18):

51 Platinum sensitivity? From N Engl J Med, Mateo J, et al., DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer, 373, Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

52 PLATINUM-BASED THERAPY IN HEAVILY PRETREATED mcrpc PATIENTS Platinum-based therapy plus oral cyclophosphamide is a tolerable and promising regimen for heavily pretreated poor PS mcrpc patients with some anaplastic disease features as opposed to best supportive care. Carboplatin seems to be more effective in terms of time to response and response rates Bournakis E, et al., Abstract Medical Oncology ESMO Reproduced courtesy of Dr Bournakis.

53 AT FIRST LINE IN SPECIAL POPULATIONS Cabazitaxel + carboplatin with G-CSF 1. Corn PG, et al., J Clin Oncol 2016;33 suppl; abstr 5010; 2. Corn PG, et al. J Clin Oncol 2016;34 suppl; abstr Courtesy of Dr PG Corn

54 Loriot Y, et al., Ann Oncol 2009;20(4):703-8; Rechon A, et al. Ann Oncol 2011;22(11): , both by permission of Oxford University Press on behalf of the European Society for Medical Oncology.

55 AA WITHDRAWAL TO AVOID RESISTANCE AA withdrawal seems to be a safe and promising choice for a carefully chosen cohort of mcrpc patients with common characteristics such as slow-rising PSA values, slow PSA-DT (>3 m) under treatment, asymptomatic status and no radiological progression. Probably, patients with bone metastases only or LN might be the ones to whom such a choice could apply Bournakis E, et al., Abstract Medical Oncology ESMO Reproduced courtesy of Dr Bournakis

56 WHAT MAY COME NEXT FOR TREATING M-PC? Molecular stratification Somatic and germline DNA analyses DNA repair defective mcrpc treatment with PARP inhibitors PTEN loss mcrpc combined AR and AKT blockade High mutational load mcrpc immunotherapy Better treatment of local disease for M1 at diagnosis patients Radiation? Surgery? Predictive biomarkers for established drugs Abiraterone and enzalutamide AR-aberrations Taxane therapy

57 SEQUENCING DECISIONS BASED ON OVERALL THERAPEUTIC PLAN In hormone sensitive patients new data arise

58 WHAT ABOUT EARLIER NEW AR-AGENTS? SUCH AS ABIRATERONE In hormone-naïve prostate cancer, AA + prednisolone improves Overall survival by 37% Failure-free survival by 71% Symptomatic skeletal events by 55% Treatment was well tolerated AA + prednisolone should be part of the standard of care for men starting long-term androgen-deprivation therapy Fizazi K, et al., N Engl J Med 2017;377(4):35260

59 STUDY DESIGN Patients Newly diagnosed adult men with high-risk mhnpc Meets at least 2 of 3 high-risk criteria Gleason score of 8 Presence of 3 lesions on bone scan Presence of measurable visceral lesion Stratification factors Presence of visceral disease (yes/no) ECOG PS (0, 1 vs. 2) R 1:1 ADT + AA 1000 mg QD + prednisone 5 mg QD (n=597) ADT + placebos (n=602) Efficacy end points Co-primary: OS rpfs Secondary: time to Pain progression PSA progression Next symptomatic skeletal event Chemotherapy Subsequent PC therapy Conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada Designed and fully enrolled prior to publication of CHAARTED/STAMPEDE results Fizazi K, et al., N Engl J Med 2017;377(4):35260

60 THE FIRST DATA Not reached 34.7 mo At a median follow-up of 30.4 months (48% of total deaths), the addition of AA and prednisone to ADT significantly improved OS, with a 38% reduction in the risk of death The 3-year OS rate was 66% in the ADT-AA-prednisone group compared with 44% in the ADT-placebos group From N Engl J Med, Fizazi K, et al., Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer, 377, 35260, Copyright 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

61 THE FIRST DATA How should we treat castration-resistant prostate cancer patients who have received androgen deprivation therapy (ADT) plus docetaxel upfront for hormone-sensitive disease? Retrospective analysis of the GETUG-AFU 15 Phase 3 trial Study design Lavaud P, et al., ESMO 761P, 2016.

62 CHAARTED Median overall survival ADT + DOC 57.6 mos ADT alone 44.0 mos Hazard Ratio 0.61 (95% CI ; p<0.0001) ADT: androgen deprivation therapy; DOC: docetaxel; OS: overall survival; mths: months From N Engl J Med, Sweeney C, et al., Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer, 373, Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

63 OVERALL SURVIVAL BY EXTENT OF METASTATIC DISEASE AT START OF ADT High volume Hazard Ratio 0.60 (95% CI ) P= Low volume ADT + DOC Not reached ADT alone 32.2 mths ADT + DOC 49.2 mths ADT alone Not reached Hazard Ratio 0.63 (95% CI ) P= month benefit in median OS (from 32.2 to 49.2 months) for high volume We projected 33 months in ADT arm with collaboration of SWOG9346 team ADT: androgen deprivation therapy; DOC: Docetaxel 75 mg/m 2 From N Engl J Med, Sweeney C, et al., Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer, 373, Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

64 CHAARTED: SUBGROUPS BENEFIT FROM DOCETAXEL 287/700 pts became CRPC: 50% docetaxel 28% AA or enzalutamide ADT: androgen deprivation therapy; DOC: Docetaxel 75 mg/m 2 From N Engl J Med, Sweeney C, et al., Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer, 373, Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

65 Overall survival NOT HIGH AND LOW BURDEN DISEASE OR OTHER PROGNOSTIC STRATIFICATION SOC Docetaxel: Survival SOC+Doc SOC SOC+DOC 405 deaths 165 deaths HR (95% CI) 0.76 (0.63, 0.91) P-value Median OS (95% CI) SOC: 67m (60, 91m) SOC+DOC: 77m (70, NR) Non-PH p-value 0.51 Restricted mean OS time SOC 58.8 m SOC+DOC 63.4 m Diff (95% CI) 4.6 m (1.8, 7.3 m) Time from randomisation (months) James N, et al., J Clin Oncol 2015;33(15_suppl): At risk (events) SOC 1184 (73) 1092 (130) 860 (89) 521 (59) 310 (33) 156 (17) 81 (2) 36 SOC+DOC 592 (33) 545 (51) 437 (32) 283 (19) 180 (12) 91 (12) 48 (6) 18

66 Reprinted from Eur Urol 69, 4, Tucci M, et al., Addition of Docetaxel to Androgen Deprivation Therapy for Patients with Hormone-sensitive Metastatic Prostate Cancer: A Systematic Review and Meta-analysis, Copyright 2015, with permission from European Association of Urology.

67 META-ANALYSIS No heterogeneity between trials 1 27% reduction in the risk of death in metastatic patients (HR 0.73; p=0.002) 1 33% reduction in the risk of death in metastatic patients with high volume metastatic disease (HR 0.67) 1 No significant interaction between docetaxel and the disease volume (p=0.5) 1 Low powered statistical calculation due to the low number of events and limited follow-up? 1 23% reduction in the risk of death 2 1. Tucci M, et al., Eur Urol 2016;69:56373; 2. Vale CL, et al., Lancet Oncol 2016;17(2):

68 Overall survival OS STAMPEDE ABIRATERONE PLUS PREDNISONE COMPARISON SOC + AAP 0.6 This represents a 37% improvement in survival Trt = SOC by KaplanMeier Trt = SOC + AAP by KaplanMeier HR % CI 0.52 to 0.76 p-value SOC by flexible parametric model SOC + AAP by flexible parametric model No. of pts (events) Time from randomisation (months) SOC 957 (37) 909 (88) 806 (92) 491 (36) 123 SOC + AAP 960 (26) 917 (63) 840 (67) 541 (25) 161 James ND, et al., N Engl J Med 2017;377:33851

69 OS STAMPEDE ABIRATERONE PLUS PREDNISONE COMPARISON SOC vs SOC+AAP Subgroup SOC-only Dths/N SOC+AAP Dths/N Interaction p-value Haz. Ratio (95% CI) Mets status M0 M1 44/ /502 34/ / (0.48, 1.18) 0.61 (0.49, 0.75) Nodal status N0 N+ NX 83/ /483 15/36 61/ /484 10/ (0.49, 0.96) 0.61 (0.48, 0.77) 0.68 (0.29, 1.57) Gleason Sum Score (cats) <= unknown 40/ /721 6/13 33/ /715 7/ (0.48, 1.23) 0.59 (0.48, 0.73) 0.47 (0.11, 1.91) Age at randomisation (cats) Under or over 180/596 82/ /603 74/ (0.40, 0.65) 0.94 (0.69, 1.29) WHO PS 0 vs /744 80/ /745 47/ (0.56, 0.87) 0.50 (0.35, 0.72) NSAID/Aspirin use No use Uses either 191/718 71/ /714 52/ (0.47, 0.74) 0.71 (0.50, 1.02) Is radiotherapy planned? No RT planned RT planned 226/561 36/ /564 24/ (0.51, 0.77) 0.64 (0.38, 1.08) Recurrent disease No Yes 254/919 8/38 171/900 13/ (0.50, 0.74) 0.94 (0.35, 2.52) Time period (co-recruiting arms) ABC-E-G /328 ABC-E-GH-- 17/49 A-----GH-- 123/580 95/330 10/47 79/ (0.53, 0.90) 0.60 (0.27, 1.33) 0.59 (0.44, 0.78) Overall 0.63 (0.52, 0.76) Favours: abiraterone SOC-only From N Engl J Med, James ND, et al., Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy, 377: Copyright 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

70 LATITUDE RESULTS Significantly significant 38% risk reduction of death [ADT+AA+Pred, not reached] [ADT+PBOs, 34.7 mo] Median follow-up: 30.4 mo OS rate at 3 years: ADT+AA+P: 66% ADT+PBOs: 49% No. events: 406 (48% of 852) ADT+AA+P: 169 ADT+PBOs: 237 Significantly significant 70% risk reduction of time to PSA progression [ADT+PBOs, 7.4 mo] [ADT+AA+Pred, 33.2 mo] These findings indicate that the addition of AA + P to ADT can potentially be considered a new standard of care for patients with high-risk, newlydiagnosed mcnpc From N Engl J Med, Fizazi K, et al., Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer, 377, 35260, Copyright 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

71 OS STAMPEDE ABIRATERONE PLUS PREDNISONE COMPARISON Overall survival by metastatic status pre-planned analysis SOC vs SOC+AAP Mets SOC-only SOC+AAP Mets * treatment interaction P-value 0.37 Haz. Ratio status Dths/N Dths/N (95% CI) M0 44/455 34/ (0.48, 1.18) M1 218/ / (0.49, 0.75) Overall 0.63 (0.52, 0.76) Favours: abiraterone 0.63 SOC-only No good evidence of heterogeneity by metastatic status From N Engl J Med, James ND, et al., Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy, 377: Copyright 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

72 WHAT MAY COME NEXT FOR TREATING HSPC? When In hormone-naïve prostate cancer, abiraterone acetate + prednisolone improves: Overall survival and failure-free survival Meets at least 2 of 3 high-risk criteria Gleason score of 8 Presence of 3 lesions on bone scan Presence of measurable visceral lesion is a possible option Who is the early-chemo candidate patient? Maybe when we have the clinical presentation of a more aggressive disease, such as multiple visceral lesions or rapidly progressive in restaging, before any treatment in hormone-naïve patients NOT really clear yet!

73 TAKE HOME MESSAGES mcrpc Ideal treatment sequence NOT known Resistance mechanisms and biomarkers, if better elucidated, could provide insight into treatment selection Upon clinical suspicion of anaplastic/nepc Short response (<1 year) to 1 st -line ADT, lack of undetectable PSA with 1 st ADT High Gleason score (810), short PSA doubling time (<46 mo) Visceral metastases, predominantly lytic bone metastases Disproportionally low PSA to tumour burden, presence of B symptoms See a medical oncologist and discuss it early SCPC and anaplastic IAC share neuroendocrine pathways and their reliance on AR is little, if any treatments aiming at AR are not efficacious

74 THANK YOU!