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, Bayer, BMS, Ipsen, Janssen, Takeda, Novartis, 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mice Prostate cancer in intact animal After castration Castration-resistant Androgen Receptor Navone N and Fizazi K, unpublished data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 Cell division Testis Castration (alhrh or Surg.) Autocrine secretion Abiraterone Orteronel Galeterone ODM-204

5 4 new active drugs in 4 years for post-docetaxel CRPC! Cabazitaxel, De Bono J, Lancet 2010 Abiraterone, Fizazi K, Lancet Oncol 2012 Proportion of Overall Survival MTX+PRED CBZ+PRED Time (months) Enzalutamide, Scher HI, NEJM 2012 Survival (%) 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 Abiraterone in asymptomatic mcrpc: the COU-302 Phase III study Co-primary endpoints Patients Progressive chemo-naïve mcrpc Asymptomatic or mildly symptomatic Randomisation 1:1 Abiraterone acetate + prednisone (n = 546) Placebo + prednisone (n = 542) Radiographic progressionfree 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.

COU-302: Abiraterone in docetaxel-naïve CRPC patients Radiographic progression-free survival (rpfs) Overall survival (Final analysis) HR 0.43 (95% CI: 0.35 0.52; P < 0.

11 COU-302: Abiraterone in docetaxel-naïve CRPC patients Radiographic progression-free survival (rpfs) Overall survival (Final analysis) HR 0.43 (95% CI: ; P < ) AA + P PL + P Abiraterone acetate Control Overall Survival (%) Abiraterone acetate Placebo 0 0 HR (95% CI): 0.81 ( ) p Value: Prednisone, 30.3 mos Abiraterone, 34.7 mos 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

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 AFFIRM: Overall survival HR = 0.63 (95%CI: ); p< % reduction in risk of death Enzalutamide: 18.4 months (95% CI: 17.3 NYR) Survival (%) 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):

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

16 Prevail: Enzalutamide in docetaxel-naïve mcrpc patients Radiographic Progression-Free Survival (%) 100 Hazard Ratio: (95% CI: 0.15,0.23) P < Enzalutamide Placebo 0 3 Radiographic 6 Progression-Free 9 12 Survival (Months) Placebo Beer T, N Engl J Med

17 Prevail: safety of Enzalutamide pre-docetaxel All Grades (%) Grade 3 events (%) Enzalutamide (n=871) 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 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

20 Short response to ADT predicts poor response to Enzalutamide (post- docetaxel) PSA decrease 50% PFS % 58% P< < 12 mths 12 mths TTCRPC Loriot Y et al., Eur J Cancer 2015

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

24 TERRAIN Study Design Patient population 375 men with progressive mcrpc Asymptomatic/mildly symptomatic Chemotherapy naive No requirement for steroids TERRAIN trial: NCT Statistical design R A N D O M I Z E D 1:1 ENZA 160 mg/day n = 184 BIC 50 mg/day n = 191 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 Primary endpoint Progression- free survival (PFS) Radiographic progression (central review) Skeletal- related event Change in new antineoplastic therapy Death Secondary endpoints PSA response Time to PSA progression 1. Kucuk O, et al. Urology. 2001;58: Heidenreich A. EAU Abstract 234.

25 Progression- Free Survival in TERRAIN Patients without PFS event (%) 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 < Heidenreich A. EAU Abstract 234.

80 60 40 20 0-20 - 40-60 - 80 ENZA BIC PSA

26 PSA Response by Week 13 with ENZA or BIC Percentage Change in PSA from Baseline ENZA BIC PSA response: 21% PSA response: 82% Observations

27 CRPC pre- treated by abiraterone or enzalutamide: How to treat?

7 months Only 1 partial response (8%) 30 pts progressing on enzalutamide and docetaxel PSA

28 Sequential use of Enzalutamide and Abiraterone: probably not a good option for most patients 38 pts progressing on enzalutamide and docetaxel PSA decrease 50% in 8% Median PFS: 2.7 months Only 1 partial response (8%) 30 pts progressing on enzalutamide and docetaxel PSA decrease 50% in 3% Median PFS: 3.5 months No objective response Loriot Y et al. Ann Oncol 2013 Noonan KL et al. Ann Oncol 2013

29 Enzalutamide post-abiraterone (and post-docetaxel) n=39 pts PSA resp: 13% PFS=2.8 months n=35 pts PSA resp: 29% PFS<4 months 1 partial resp (3%) n=61 pts PSA resp: 21% PFS=4 months Bianchini D Eur J Cancer 2014 Schrader AJ, Eur Urol 2014; 65: 30-6 Badrising S, Cancer 2014; 120:

30 Taxane post-abiraterone (COU-302) De Bono J, ASCO GU 2015

31 Cabazitaxel post-abiraterone 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 n= 41 pts (abi or enza) PSA response>50%: 39% PFS: 4.6 mo OS: 15.8 mo Al Nakouzi N, Eur Urol 2014 Pezaro CJ, Eur Urol 2013

32 Other drugs targeting the AR axis?

33 Failure of Orteronel (CYP17 inh) in CRPC PFS, Post-docetaxel OS, Post-docetaxel PFS, Pre-docetaxel OS, Pre-docetaxel Fizazi K, J Clin Oncol 2015 Saad F, Lancet Oncol 2015

34 ARN-509 (AR inhibitor) Next generation AR inhibitor Phase II - 47 pts CRPC M1 Recommended dose = 240 mg/d Fatigue grade 3 (2%), GI grade 1-2 No epilepsy reported PSA response (decrease > 50%) % Variation PSA depuis l inclusion weeks 24 weeks Smith MR et al. ASCO GU 2013, Abstract # LBA 7

35 ODM- 201 has a unique profile F 3 C NC O N S N Enzalutamide (MDV-3100) F O HN F 3 C NC N O N N S ARN-509 F O HN (R) n G (R) n O F X Y D Z N (R) n A (R) n R E General chemical structure for ODM-201 and backups (R) n 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) *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 No CYP inhibition or induction with therapeutic doses Fizazi K et al., ECC2013 poster E

36 ODM-201 (AR inhibitor) Phase I: PSA response By dose By prior chemotherapy 100 mg 200 mg 300 mg 500 mg 700 mg Po s t ab i Po s t ab i No chemotherapy Chemotherapy Fizazi K, et al. Lancet Oncol 2014; 15:

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

38 Response to Abiraterone or Enzalutamide by AR-V7 status Antonarakis E, NEJM 2014

39 AR splice variants: Toward N-term targeting drugs? Nuclear localization domain N-Terminal Domain DNA binding domain Ligand Binding domain N-term targeted agent (Epi-506) Splice variant -> AR constitutively active (no need for androgens)

40 Combination of AR pathway targeting drugs in mcrpc?

41 Abiraterone + Enzalutamide Phase I- II trial PSA 50 decline in 78% 30% of Redunction: patients 87%(52/60) (47 out of 60) PSA 90 decline in 50% of Redunction: 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) PSA change (%) Exploratory: association of lack of PSA decline with resistance (p=0.008) Efstathiou E, ASCO 2014

42 ACIS: Abiraterone + ARN- 509 in chemo- naïve CRPC Patient Characteristics mcrpc ECOG 0 or 1 Testosterone levels of < 50 ng/dl (BY: GnRHa or surgical castration) Pain score 3 (BPI- SF Q3) N ~ 960 1:1 Stratification factors: Baseline ECOG 0 vs. 1 Region (NA, EU, ROW) Presence/absence of visceral disease Abi + P + ARN-509 Abi + P + placebo Test PSA90 Abi/ARN vs Abi (n~200) Is PSA90 positive? YES: Continue to n~960 NO: Stop study Primary Endpoint: rpfs* Secondary Endpoints: 1.OS 2.Time to pain progression 3.Time to opiate use 4.Time to chemotherapy 5.Time to ECOG deterioration *rpfs definition as PREVAIL and COU-AA-302

43 Earlier use of AR pathway targeting drugs? De Novo metastatic prostate cancer (M1)?

44 Latitude: Phase III Trial of Abiraterone in patients with de novo metastatic prostate cancer Metastatic prostate cancer At least 2 poor-risk factors: Visceral mets >2 bone mets Gleason score > 7 Max: 3 months previous ADT R A N D O M I Z E D Androgen deprivation therapy (ADT) ADT + Abiraterone 1000 mg Prednisone 5 mg Primary endpoint: OS (HR: 0.80) 1270 pts planned Recruitment completed in 2014

45 PEACE-1: European Phase III Trial of Abiraterone and local RXT in patients with de novo metastatic prostate cancer Androgen deprivation therapy (ADT) Patients with newly diagnosed (hormone naïve) metastatic CaP 916 patients planned R A N D O M I Z E D ADT + Abiraterone 1000mg Prednisone 5mg BID ADT + Local radiotherapy Co-primary endpoints: OS and PFS (HR: 0.75) ADT + Local radiotherapy + Abiraterone-Pred Study sponsor: Unicancer NCT

46 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

47 Earlier use of AR pathway targeting drugs? Non metastatic castrate- resistant prostate cancer (M0 CRPC)?

48 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

49 ARAMIS Study Design: ODM-201 in High-Risk M0 CRPC Similar design: Prosper (Enza) and Spartan (ARN-509) Estimated Enrollment: 1,500 M0 CRPC PSA doubling time of 10 months ECOG PS R 1 ODM x 300mg BID Placebo Primary endpoints: Metastasis-free survival Key secondary endpoints: OS Time to first SSE Time to initiation of first cytotoxic chemo Time to pain progression Clinical Trials.gov NCT

50 Conclusion AR targeting a demonstrated active strategy in CRPC (Abiraterone, Enzalutamide) Better understanding of the biology: Next generation active compounds (ODM-201, etc) Emerging biomarkers (AR V7) New indications currently being explored (M0 CRPC, M1 HSPC) What registration endpoint for the new comers?

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