Have we optimized the use of Androgen Receptor pathway targeted drugs in Castrate-Resistant Prostate Cancer?

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1 Have we optimized the use of Androgen Receptor pathway targeted drugs in Castrate-Resistant Prostate Cancer? Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

2 Disclosure Participation to advisory boards/honorarium for: Amgen, Astellas, Astrazeneca, Bayer, Clovis, Curevac, Essa, Genentech, Janssen, MSD, Orion, Sanofi

3 Androgen Receptor is still expressed in CRPC Xenograft model of MDA PCa 2b prostate cancer cells in SCID mice Prostate cancer in intact animal After castration Castration-resistant Androgen Receptor Navone N and Fizazi K, unpublished data

4 Targeting the AR pathway Adrenals Abiraterone Orteronel Galeterone ODM-204 Androgen Receptor inhibitors: -Bicalutamide -Enzalutamide -ODM-201 -ARN 509 -Galeterone -ODM-204 -EPI drugs DNA Testosterone/ Other androgens Cell division Testis Castration (alhrh or Surg.) Autocrine secretion Abiraterone Orteronel Galeterone ODM-204

5 Survival (%) Proportion of Overall Survival 4 new active drugs in 4 years for post-docetaxel CRPC! Cabazitaxel, De Bono J, Lancet 2010 Abiraterone, Fizazi K, Lancet Oncol MTX+PRED CBZ+PRED Time (months) Enzalutamide, Scher HI, NEJM Placebo: 13.6 months (95% CI: ) Duration of overall survival (months) Enzalutamide: 18.4 months (95% CI: 17.3 NYR) % Radium-223, Parker J, NEJM Placebo Median OS 11.3 mo Radium-223 Median OS 14.9 mo

6 b Abiraterone: CYP17 blockade inhibits androgen synthesis

7 Abiraterone post-chemotherapy: COU-301 Patients Progressive mcrpc patients (N = 1195) Failed 1 or 2 chemotherapy regimens R A N D O M I Z E D 2:1 AA 1000 mg daily Prednisone 5 mg BID n = 797 Placebo daily Prednisone 5 mg BID n = 398 Efficacy end points Primary end point: Overall survival (25% improvement; HR=0.8) Secondary end points: TTPP rpfs PSA response Stratification by: Performance status 0-1 vs 2 Worst pain BPI short form; 0-3 (absent) vs 4-10 (present) Prior chemotherapy 1 vs 2 Type of progression PSA only vs radiographic (with or without PSA) de Bono JS, et al. N Engl J Med, 2011

8 COU-301: Abiraterone prolongs survival in post-docetaxel mcrpc patients Fizazi K, et al. Lancet Oncol. 2012;13:

9 Abiraterone-Prednisone: Adverse events of special interest All Grades AA (n=791) Grades 3/4 All Grades Placebo (n=394) Grades 3/4 Fluid retention 31% 2% 22% 1% Hypokalemia 17% 3% 8% 1% Hypertension 10% 1% 8% <1% Cardiac disorders a 13% 3% 11% 2% LFT abnormalities 10% 3% 8% 3% Fizazi K, et al. Lancet Oncol.2012;13: de Bono et al. N Engl J Med 2011; 346:

10 Randomisation 1:1 Abiraterone in asymptomatic mcrpc: the COU-302 Phase III study Co-primary endpoints Patients Progressive chemonaïve mcrpc Asymptomatic or mildly symptomatic Abiraterone acetate + prednisone (n = 546) Placebo + prednisone (n = 542) Radiographic progression-free survival Overall survival Secondary Time to opiate use (cancerrelated pain) Time to initiation of chemotherapy Time to ECOG-PS deterioration Time to PSA progression Stratification by ECOG performance status 0 vs. 1 Ryan C, et al. American Society of Clinical Oncology Congress 2012; Abstract LBA4518.

11 Overall Survival (%) COU-302: Abiraterone in docetaxel-naïve CRPC patients Radiographic progression-free survival (rpfs) Overall survival (Final analysis) HR 0.43 (95% CI: ; P < ) HR (95% CI): 0.81 ( ) p Value: Abiraterone, 34.7 mos AA + P PL + P Abiraterone acetate Control Prednisone, 30.3 mos Abiraterone acetate Placebo Time to Death (Months) Ryan C, et al. N Engl J Med 2013 Ryan C et al., Lancet Oncol 2015

12 Cou-302: Safety Profile Abiraterone (n = 542) % Prednisone (n = 540) % All Grades Grade 3/4 All Grades Grade 3/4 Fluid retention/edema Hypokalemia Hypertension Cardiac disorders Atrial fibrillation ALT increased AST increased ALT, alanine aminotransferase; AST, aspartate aminotransferase September 2014, Madrid, Spain esmo.org

AFFIRM: Enzalutamide in mcrpc patients post-chemotherapy AFFIRM is a phase III randomised, double-blind, placebo-controlled trial mcrpc 1 2 prior chemotherapy regimens* (n = 1,199) R 2:1 Enzalutamide

13 AFFIRM: Enzalutamide in mcrpc patients post-chemotherapy AFFIRM is a phase III randomised, double-blind, placebo-controlled trial mcrpc 1 2 prior chemotherapy regimens* (n = 1,199) R 2:1 Enzalutamide 160 mg qd (n = 800) Placebo per qd (n = 399) * 1 docetaxel (glucocorticoids were allowed but not required) Recruitment in 156 centres from 15 countries across 5 continents between September 2009 and November 2010 Scher HI et al. N Engl J Med 2012; 367(13): mcrpc, metastatic castrate-resistant prostate cancer; qd, once per day; R, randomisation

14 Survival (%) AFFIRM: Overall survival HR = 0.63 (95%CI: ); p< % reduction in risk of death Enzalutamide: 18.4 months (95% CI: 17.3 NYR) Placebo: 13.6 months (95% CI: ) 4.8 month difference in median overall survival N o at risk: Enzalutamide, n = Placebo, n = Duration of overall survival (months) Scher HI et al. N Engl J Med 2012; 367(13): CI, confidence interval; HR, hazard ratio; NYR, not yet reached

15 AFFIRM: Summary of adverse events Adverse events, n (%) Total events (all grades) Enzalutamide (n = 800) Placebo (n = 399) Grade 3 events Enzalutamide (n = 800) Placebo (n = 399) 1 Adverse event 785 (98) 390 (98) 362 (45) 212 (53) Any serious adverse event 268 (34) 154 (39) 227 (28) 134 (34) Discontinuation due to adverse event 61 (8) 39 (10) 37 (5) 28 (7) Adverse event leading to death 23 (3) 14 (4) 23 (3) 14 (4) Adverse events of interest, n (%) Fatigue 269 (34) 116 (29) 50 (6) 29 (7) Cardiac disorder (any) 49 (6) 30 (8) 7 (1) 8 (2) Myocardial infarction 2 (<1) 2 (<1) 2 (<1) 2 (<1) LFT abnormality* 8 (1) 6 (2) 3 (<1) 3 (<1) Seizure 5 (<1) 0 5 (<1) 0 LFT, liver function test *abnormalities on LFT included hyperbilirubinaemia and increased levels of aspartate aminotransferase or alanine aminotransferase The adverse event reporting period for the Enzalutamide group was more than twice that for the placebo group Scher HI et al. N Engl J Med 2012; 367(13):

Radiographic Progression-Free Survival (%) Prevail: Enzalutamide in docetaxel-naïve mcrpc patients 100 Hazard Ratio: 0.186 (95% CI: 0.15,0.23) P < 0.

16 Radiographic Progression-Free Survival (%) Prevail: Enzalutamide in docetaxel-naïve mcrpc patients 100 Hazard Ratio: (95% CI: 0.15,0.23) P < Enzalutamide Placebo Radiographic Progression-Free Survival (Months) 832 Placebo Beer T, N Engl J Med 2014; 371:

17 Prevail: safety of Enzalutamide pre-docetaxel Enzalutamide (n=871) All Grades (%) Grade 3 events (%) Placebo (n=844) Enzalutamide (n=871) Placebo (n=844) Fatigue Back pain Constipation Arthralgia Cardiac AEs Hypertension ALT increased Seizure

18 Comparison between 302 & PREVAIL Overall Study Design COU-AA-302 PREVAIL Number of pts 1,088 1,717 Conditions Treatment Primary endpoints Secondary endpoints Design Locations Progressive chemo-naïve mcrpc Asymptomatic/mildly symptom No visceral mets AA+ Prednisone Prednisone rpfs OS Time to opiate use Time to initiation of chemotherapy Time to ECOG-PS deterioration TTPP multicenter, randomized, doubleblind, placebo-controlled 151 sites in 12 countries (USA EU Australia Canada) Progressive chemo-naïve mcrpc Asymptomatic/mildly symptom Visceral mets allowed ENZA (Steroid is allowed) Placebo (Steroid is allowed) rpfs OS Time to initiation of chemotherapy Time to 1st SRE multicenter, randomized, doubleblind, placebo-controlled 207 sites in 22 countries (USA EU Australia Canada Asia including Japan ) Stratification ECOG PS 0 vs. 1

19 Short response to ADT predicts poor response to Enzalutamide (post-docetaxel) PSA decrease 50% PFS 8% 58% P<0.001 TTCRPC Loriot Y et al., Eur J Cancer 2015

20 Treatment decision making in CRPC: several obvious situations History of seizure Enzalutamide Visceral metastases Radium-223 Patient too old/sick Taxanes Contra-indication to steroids (severe diabetes, etc) Abiraterone

21 Drug-drug interactions with enzalutamide Enzalutamide = powerful CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer: Avoid Cabazitaxel, Be careful with many drugs (zolpidem, fentanyl, clopidrogel, lovastatin, triazolam, amiodarone, etc) CYP2C8 induces Enzalutamide metabolism into its active metabolite and its elimination: Avoid CYP2C8 inhibitors (gemfibrozil) and inducers (rifampicine) Avoid any drug that increases the risk of seizure (anti-depressors, neuroleptics, tramadol)

22 Drug-drug interactions with abiraterone Abiraterone = CYP 2C8 inducer (ex: pioglitazone, anti-diabetes: AUC increased x 1.5) Abiraterone= CYP 2D6 inhibitor (ex: dextromethorphan: AUC is increased x 3, thioridazine=melleril) Abiraterone is a substrate of CYP 3A4: theoretically, be careful with strong CYP3A4 inducers (rifampicine). No effect of ketoconazole

23 How to best treat mcrpc? Earlier treatment? Sequential treatments? Combinations? Personalized treatments?

24 How to best treat mcrpc? Ealier treatment Sequential treatments Combinations Personalized treatments

25 Who Dies of Prostate Cancer? Upfront localized cancer 44% of deaths Metastases Death De novo metastases 56% of deaths Patrikidou A. Prostate Cancer Prostatic Dis. 2014;17:

Randomization 1:1 LATITUDE: study design Randomized, double-blind, active-controlled, multicentre, phase 3 study

Presence of measurable visceral lesion ADT + abiraterone Abiraterone 1000 mg QD + Prednisone 1,000 mg 5 q.d. mg QD + ADT + prednisone 5 mg q.

OS Secondary: rpfs Time to next skeletalrelated event Time to PSA progression mhnpc, metastatic hormone naive prostate

26 Randomization 1:1 LATITUDE: study design Randomized, double-blind, active-controlled, multicentre, phase 3 study Patients de novo mhnpc Meets at least 2 of 3 highrisk criteria Gleason score 8 Presence of 3 lesions on bone scan Presence of measurable visceral lesion ADT + abiraterone Abiraterone 1000 mg QD + Prednisone 1,000 mg 5 q.d. mg QD + ADT + prednisone 5 mg q.d. Placebo 1000 mg QD + Placebo 5 mg QD + ADT ADT + placebos q.d. Efficacy endpoints Primary: Primary OS endpoints rpfs OS Secondary: rpfs Time to next skeletalrelated event Time to PSA progression mhnpc, metastatic hormone naive prostate cancer; q.d., once daily; rpfs, radiographic progression-free survival. Fizazi K, N Engl J Med 2017; 377:

27 LATITUDE: Abiraterone in mcspc 38% risk reduction of death 53% risk reduction of progression/death Overall survival rate at 3 years: ADT + AA + P: 66% ADT + placebos: 49% Median follow-up: 30.4 months Fizazi K, N Engl J Med 2017; 377:

28 EMA approval

29 Stampede Abiraterone James ND, N Engl J Med 2017

30 LATITUDE: Prespecified Secondary and Exploratory End Points ADT+AA+P (n = 597) ADT+place bos (n = 602) Hazard Ratio (95% CI) P Value* Secondary end points Time to pain progression mo NR ( ) < Time to PSA progression mo ( ) < Time to next symptomatic skeletal event mo NR NR 0.70 ( ) Time to chemotherapy mo NR ( ) < Time to subsequent prostate cancer therapy mo NR ( ) < Exploratory end point Patients with a PSA response (decline 50% from baseline) % ( ) * < Fizazi K, N Engl J Med 2017; 377:

31 Patients without worst fatigue progression (%) Mean change from baseline in worst fatigue score (BFI) Addition of Abiraterone to ADT significantly improved fatigue: PROs from LATITUDE 35% Risk Reduction for Worst Fatigue Progression Mean Change From Baseline Differed from Cycle 5 Onward ADT + AAP, NR 0.2 Worse 60 ADT + Placebos, NR HR 0.65 (95% CI, ) P = Better Patients at risk ADT + AAP Months Cycle* ADT + Placebos ADT + AAP ADT + Placebos *1 cycle = 28 days. PRO, patient reported outcomes. Chi K, et al. Data presented at ESMO 2017 (abstract 7830).

32 An indirect comparison to determine the relative efficacy of Abiraterone vs Docetaxel in mhspc Posterior Density: OS - Main Analysis Posterior Density: rpfs - Main Analysis HR (95% CrI): 0.85 (0.63, 1.14) P (HR < 1) = 86.7% HR (95% CrI): 0.71 (0.49, 1.02) P (HR < 1) = 96.8% Analyses suggest that ADT + AAP has greater reduction in risk of progression and death vs ADT + Doc CrI, credible interval; P, Bayesian probabilities. Feyerabend S, et al. Data presented at ESMO 2017 (abstr 803P).

33 Abiraterone or docetaxel? Direct comparison from STAMPEDE Favours SOC+AAP Favours SOC+DocP Head-to-head data in 566 pts (Nov-2011 to Mar-2013) Failure-free survival Progression-free survival Metastatic progression-free survival Strong evidence favouring AAP Weak evidence favouring AAP Symptomatic skeletal events Cause-specific survival Overall survival No good evidence of a difference Proportionately different time spent in each disease state Hazard ratio Toxicity profiles quite different and well known Sydes M, et al. Data presented at ESMO (abstract LBA31).

34 PEACE-1: European Phase III Trial in de novo Metastatic Prostate Cancer (revised design) SOC Patients with newly diagnosed (castration-naïve) metastatic CaP 1156 pts planned R A N D O M I Z E D SOC + Abiraterone 1000 mg Prednisone 5 mg BID SOC + Local radiotherapy Co-primary endpoints: OS and PFS (HR: 0.75) SOC + Local radiotherapy + Abiraterone-Pred Standard of Care (SOC)= Androgen deprivation therapy (ADT) +/- docetaxel (Stratification) ClinicalTrials.gov. Identifier: NCT Study sponsor: Unicancer

function Stratification Comorbidities Volume of disease Study site Bone anti-resorptive

35 ENZAMET Screening Randomisation 1:1 Enzalutamide 160mg/daily + LHRHA (or orchidectomy) until progression Eligibility Metastatic prostate cancer Starting 1 st line ADT Adequate organ function Stratification Comorbidities Volume of disease Study site Bone anti-resorptive therapy Use of early docetaxel Non-steroidal anti-androgen + LHRHA (or orchidectomy) until progression

36 Who Dies of Prostate Cancer? Upfront localized cancer 44% of deaths Metastases Death De novo metastases Patrikidou A. Prostate Cancer Prostatic Dis. 2014;17:

37 Phase III trials in M0 CRPC Atrasentan (n=941) Zibotentan (n=1421) Denosumab (n=1432) Miller K, Prostate Cancer Prostatic Dis 2013; 16: Nelson JB, Cancer 2008; 113: Smith MR, Lancet 2012; 379: 39-46

38 PROSPER Trial Design: Enzalutamide in M0 CRPC Hussain M et al. ASCO Poster TPS5094

39 AR targeting works!

Proliferation VCaP IC50 (nm) enzalutamide 78 155 400 ARN-509 53 168 300

induction with therapeutic doses Fizazi K et al.

Clegg et al, Cancer Research 2012; Forster at al, Prostate 2011 ** Rat

40 ODM-201 has a unique profile enzalutamide 19%* ODM main metabolite 3% ** ARN %* Compound AR affinity Ki (nm) Antagonism WT AR IC50 (nm) Proliferation VCaP IC50 (nm) enzalutamide ARN ODM ORM (main metabolite) No CYP inhibition or induction with therapeutic doses Fizazi K et al., ECC2013 poster E *Refs. Clegg et al, Cancer Research 2012; Forster at al, Prostate 2011 ** Rat autoradiography (QWBA confirms brain/plasma ratio of 14C-ODM-201 related radioactivity was , indicating negligible penetration to the brain

41 ODM-201 and ARN-509 (AR inhibitors): PSA response ARN-509 ODM-201 No chemotherapy Chemotherapy Smith MR et al. ASCO GU 2013, Abstract # LBA 7 Fizazi K, Lancet Oncol 2014; 15:

42 How to best treat mcrpc? Earlier treatment Sequential treatments Combinations Personalized treatments

43 Should We Keep Using Old Hormonal Manipulations Before Using Next-generation AR-Targeting Drugs?

TERRAIN Study Design Patient population 375 men with progressive mcrpc

steroids TERRAIN trial: NCT01288911 R A N D O M I Z E D 1:1 ENZA 160 mg/day n

Radiographic progression (central review) Skeletal-related event Change in

planned at 220 progression events with 85% power to detect a target hazard

67 (assuming a median PFS of 9 months vs 6 months 1 ) The data cutoff date

44 TERRAIN Study Design Patient population 375 men with progressive mcrpc Asymptomatic/mild ly symptomatic Chemotherapy naive No requirement for steroids TERRAIN trial: NCT R A N D O M I Z E D 1:1 ENZA 160 mg/day n = 184 BIC 50 mg/day n = 191 Primary endpoint Progression-free survival (PFS) Radiographic progression (central review) Skeletal-related event Change in new antineoplastic therapy Death Statistical design The final analysis was planned at 220 progression events with 85% power to detect a target hazard ratio of 0.67 (assuming a median PFS of 9 months vs 6 months 1 ) The data cutoff date was 19 October 2014, with 240 events for the primary efficacy endpoint Secondary endpoints PSA response Time to PSA progression Shore ND, Lancet Oncol 2016; 17:

45 Patients without PFS event (%) Progression-Free Survival in TERRAIN ENZA Patients at risk BIC Patients at risk Median (95% CI): 5.8 months (4.8, 8.1) Median (95% CI): 15.7 months (11.5, 19.4) Time (months) ENZA BIC Hazard ratio (95% CI): 0.44 (0.34, 0.57); P < Shore ND, Lancet Oncol 2016; 17:

46 Percentage Change in PSA from Baseline PSA Response by Week 13 with ENZA or BICA ENZA BIC BICA ENZA PSA response: 21% Observations PSA response: 82% Shore ND, Lancet Oncol 2016; 17:

47 STRIVE trial: Enzalutamide vs Bicalutamide in early CRPC n=396 pts (M0=139; M1=257 Composite PFS: HR= 0.24 (95% CI, 0.18 to 0.32; P <.001) Median PFS: 19.4 months Enza vs 5.7 months Bica Penson DP, J Clin Oncol 2016; 34:

48 Patients without degradation (%) Terrain: Quality of life Patients at risk : Enzalutamide Bicalutamide Time to QoL deterioration (FACT-P) Time (months) Bicalutamide : Median = 8.5 mo (IC95% : ) Enzalutamide : Median = 13.8 mo (IC95% : ) HR=0.64 (IC95% : ) ; p= Shore N. et al, Lancet Oncol 2016; 17:

49 CRPC progressing on abiraterone or enzalutamide: How to treat?

50 Cross-resistance between abiraterone and enzalutamide Author ENZ ABI Year published N pts Duration of 2 nd treatment PSA 50% Median PFS Loriot et al mo 8% 2.7 mo Noonan et al wks 3% 3.6 mo ABI ENZ Schrader et al mo 29% - Badrising et al mo 21% - Bianchini et al mo 23% - Schmid et al mo 10% - Brasso et al mo 18% - Zhang T et al. Expert Opin Pharmacotherap 2014;16:1-9

51 Réduction maximale du PSA (%) Docetaxel post-abiraterone (COU-302) PSA response rate=47% TTP: 7.6 months Flaig T, ASCO GU 2016 De Bono J, Eur Urol 2016

52 Cabazitaxel post-abiraterone (and post-docetaxel) n=79 pts PSA response>30%: 62% PSA response>50%: 35% PFS: 4.4 mo OS: 11 mo In vitro: Caba active against both enza-s and enza-r cells PSA response Al Nakouzi N, Eur Urol 2015; 68:

53 A proposed decision tree for metastatic CRPC Majority of patients (If drug availaible) mcrpc - Cancer progression - Testo<0.50 ng/ml (2017) Abiraterone or Enzalutamide Patients who experience progression after a short ADT period Progression: Docetaxel (Switch to Enza?) (Radium-223?) Docetaxel Progression: Cabazitaxel Radium-223 Denosumab (or ZA), Vit D/Calcium, Supp. care Progression: consider: Cabazitaxel Abiraterone Enzalutamide Radium-223 mcrpc patient initially treated with ADT + Docetaxel??? Fizazi K, Eur J Cancer 2016; 66:

54 Decrease Increase PSA response for CRPC pts treated with docetaxel according to primary treatment for M1 Decrease Increase Best PSA variation (%) during the treatment (n= 80) Best PSA variation (%) during the treatment (n= 29) Docetaxel for CRPC if upfront ADT alone Docetaxel for CRPC if upfront ADT+Doce Lavaud P, Eur Urol 2017

55 PSA response for CRPC pts treated with abiraterone/enzalutamide when treated upfront with ADT+Docetaxel for M1 Best PSA variation (%) during the treatment (n= 15) 100 Decrease Increase Lavaud P, Eur Urol 2017

56 How to best treat mcrpc? Earlier treatment Sequential treatments Combinations Personalized treatments

57 Combining drug X to docetaxel: a failing strategy so far Doc + Oblimersen Doc + DN-101 Doc + Bevacizumab Doc + VEGF-Trap Doc + Lenalidomide Doc + Atrasentan Doc + Zibotentan Doc + GVAX Doc + Dasatinib Doc + Custirsen Negative Phase III trials

58 PSA change (%) PSA Change (%) Abiraterone + Enzalutamide Phase I-II trial PSA 50 decline in 78% 30% Redunction: of patients 87%(52/60) (47 out of 60) PSA 90 decline in 50% Redunction: of patients 77%(46/60) (30 out of 60) 90% Redunction: 47%(28/60) PSA 0.1 ng/ml in 13% of patients (8 out of 60) Exploratory: association of lack of PSA decline with resistance (p=0.008) Efstathiou E, ASCO 2014

59 Current combination strategies (ongoing Phase III) Abiraterone + Enzalutamide (US) Abiraterone + ARN-509 (ACIS) Abiraterone + Radium-223 (ERA) Enzalutamide + Radium-223 (PEACE-3)

60 How to best treat mcrpc? Earlier treatment Sequential treatments Combinations Personalized treatment

61 Success stories of Personalized Medicine Breast cancer: Trastuzumab in HER2 + tumors (Slamon, N Engl J Med 2001, 344: ) Colo-rectal cancer: Cetuximab in K-ras wt tumors (Karapetis CS, N Engl J Med 2008; 359: ) Wild type K-ras Mutated K-ras Non-small cell lung cancer: Crizotinib in Alk+ tumors (Shaw AT, ESMO 2012, Abstr 2862) PFS Crizotinib Chemotherapy

62 AR splice variants Nuclear localization domain N-Terminal Domain DNA binding domain Ligand Binding domain AR splice variants (V7) Splice variant -> AR constitutively active (no need for androgens)

63 PSA change, % * * * * CTCs: AR-V7 is a promising predictor of treatment response Abiraterone Enzalutamide Taxanes PSA response rate: AR-V7 positive: 0% (95% CI: 0-46%) AR-V7 negative: 68.0% (95% CI: 46-85%) P= AR-V7 positive * * * AR-V7 negative PSA response rate: AR-V7 positive: 0% (95% CI: 0-26%) AR-V7 negative: 52.6% (95% CI: 29-76%) P= Docetaxel, n=30 Cabazitaxel, n=7 PSA response rate: AR-V7 positive: 41% (95% CI: 18-67%) AR-V7 negative: 65% (95% CI: 41-85%) P=0.19 Antonarakis ES et al. N Engl J Med 2014;371: ; Antonarakis ES et al. JAMA Oncol 2015; 1:582-91

64 AR gains and mutations are associated with primary resistance to next generation AR axis targeted agents (Abiraterone) Romanel A, Science Trans Med 2015

65 Association between AR aberrations (cfdna) and PFS on Enzalutamide Wyatt AW, JAMA Oncol 2016

66 Zhao et al., JAMA Oncol 2017

68 Conclusion Sequential treatment still routinely used for CRPC, combination remains experimental The field is changing in 2017: M1 CSPC: Abiraterone M0 CRPC: Enzalutamide Cross-resistance between Abi and Enza (20% responders) but Taxanes still active after abi/enza Biomarkers clearly emerging

Have we optimized the use of Androgen Receptor pathway targeted drugs in Castrate-Resistant Prostate Cancer?

Have we optimized the use of Androgen Receptor pathway targeted drugs in Castrate-Resistant Prostate Cancer? Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France Disclosure Participation to