mcrpc in 2016 How to decide the optimal treatment? N. Mottet

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1 mcrpc in 2016 How to decide the optimal treatment? N. Mottet

2 Disclosures

3 Conflict of interest Chairman EAU PCa guidelines..... Therefore I'm 100% biased

4 Castrate-resistant prostate cancer (CRPC) Definition 3 main criteria: Castrate serum testosterone <50 ng/dl or 1.7 nmol/l Biochemical progression 3 consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with PSA >2 ng/ml + either OR Radiological progression Appearance of 2 lesions (bone scan) or soft tissue lesion enlargement RECIST EAU guidelines on prostate cancer, update 2016 Symptomatic progression alone to be questioned and not sufficient to define mcrpc

5 Phase III clinical trials in mcrpc Study Agents N Indication Inclusion criteria TAX Docetaxel/P vs mito/p 1006 mcrpc / IMPACT 2 Sipuleucel-T vs pbo 512 mcrpc (pre-doc) asympto COU-AA COU-AA Abiraterone/P vs P Abiraterone/P vs P mcrpc (pre-doc) mcrpc (post-doc) Asympto / no vis mets / PREVAIL 5 AFFIRM 6 Enzalutamide vs pbo Enzalutamide vs pbo mcrpc (pre-doc) mcrpc (post-doc) Asympto / vis mets (11%) / TROPIC 7 Cabazitaxel/P vs mito/p 755 mcrpc (post-doc) / ALSYMPCA 8 Radium-223 vs pbo 921 mcrpc No visc met 1. Tannock NEJM 2004; 2. Kantoff NEJM 2010; 3. Ryan Lancet Oncol 2015; 4. Fizazi Lancet Oncol 2012; 5. Beer N Engl J Med 2014; 6. Scher NEJM. 2012; 7. De Bono Lancet 2010; 8. Parker NEJM. 2013

6 Phase III clinical trials in mcrpc Study Agents N Indication HR OS (m) TAX Docetaxel/P vs mito/p 1006 mcrpc IMPACT 2 Sipuleucel-T vs pbo 512 mcrpc (pre-doc) COU-AA COU-AA Abiraterone/P vs P Abiraterone/P vs P mcrpc (pre-doc) mcrpc (post-doc) PREVAIL 5 AFFIRM 6 Enzalutamide vs pbo Enzalutamide vs pbo (or P) mcrpc (pre-doc) mcrpc (post-doc) TROPIC 7 Cabazitaxel/P vs mito/p 755 mcrpc (post-doc) ALSYMPCA 8 Radium-223 vs pbo 921 mcrpc Tannock NEJM 2004; 2. Kantoff NEJM 2010; 3. Ryan Lancet Oncol 2015; 4. Fizazi Lancet Oncol 2012; 5. Beer ASCO 2015; 6. Scher NEJM. 2012; 7. De Bono Lancet 2010; 8. Parker NEJM. 2013

7 Docetaxel rechallenge in mcrpc pts Small retrospective studies 1-6 In selected patients Good initial responders (PSA decrease 50%) 1-6 AND a progression-free interval ( 6 months) since last docetaxel administration 6 No survival benefit demonstrated 6 Increased toxicity with subsequent rechallenges 6 Asthenia and Peripheral neuropathy Eymard BJU Int 2010; 2. Ansari Oncol reports 2008; 3. Beer Cancer 2008; 4. Garmey Clin Adv Hematol Oncol 2008; 5. Loriot Eur J Cancer 2010; 6. Oudard BJU Int. 2014

8 Ongoing castration EAU guidelines on prostate cancer, update 2016

9 Primary resistance to AR-targeted agents Radiological progression-free survival (rpfs) ABI+P (COU-AA-301) 1 Primary resistance 1 out of 3 patients ENZ±P (AFFIRM) 2 Primary resistance 1 out of 4 patients 1. De Bono N Engl J Med 2011; 2. Scher N Engl J Med 2012

10 In 2016: tools for individualizing Mostly level 4 Consensus Dedicated consensus Fitzpatrick Eur J Cancer. 2014, Gillessen Ann Oncol PCa Guidelines Mottet [EAU] 2016, Cookson [AUA] 2015, Basch [ASCO] J Clin Oncol 2014, Parker [ESMO] Ann Oncol 2015

11 Baseline Gleason score: a predictive factor? Study Agent N Gleason HR for OS TAX327 1 DOC/P vs Mito/P 1006 Pre-docetaxel COU-AA Abi/P vs Pbo/P 1088 NOT predictive PREVAIL 3 ENZ/P vs Pbo 1717 Post-docetaxel COU-AA Abi/P vs Pbo/P 1195 <7 7 <8 8 <8 8 < Post-hoc analyses of TAX327, COU-AA-201 and COU-AA-302 trials; planned subgroup analyses of PREVAIL 1. Tannock NEJM 2004; 2. Fizazi ASCO 2014 (# 20); 3. Beer NEJM 2014

12 Response to first ADT: a predictive factor for Abi? Prior GnRH duration median (37 mths) Prior GnRH duration > median (37 mths) Prognostic NOT predictive Lowest quartile of priorgnrh duration ( 20 mths) Oudard ASCO 2014 (#14)

13 Response to first ADT: a predictive factor for Enza? Subgroup retrospective analysis (from AFFIRM) Loriot EJC 2015 Predictive? N = 57 treated with Enza N = 19 treated with placebo

14 Initial castration efficacy International consensus Response duration (<1 year) first line castration as treatment choice Healthy symptomatic, the recommendation is Le: 4 56%: Docetaxel upfront for the majority of pts 41% in a minority of selected cases Less clear if asymptomatic Gr: C 41 international experts consensus Gillessen Ann Oncol. 2015

15 Prediction of abiraterone efficacy Who are the responders? (defined as pts on drug for >4 months) Predictive Bone marrow biopsy - Intense AR nuclear expression - and CYP 17 expression YES Responders : 82% (12/13) p<0.001 NO Responders : 18% (2/12) Efstathiou J Clin Oncol 2011

16 Prediction of enzalutamide efficacy Phase II N = 60 mcrpc treated with enzalutamide Efstathiou Eur Urol 2015 Transiliac bone marrow biopsies (before treatment, at 8 weeks and at end of treatment) % of patients Predictive Primary resistance Moderate benefit (4-6 mths) Prolonged benefit (> 6 mths)

17 Overall survival, median (mths) Predictive of Docetaxel efficacy: Duration of first-line ADT Overall survival PSA response 50% by duration of first ADT *p < % * * 60% * 18.6 *p (log-rank) < PSA response rate, % Predictive? 40% 44% < 15 mths (median) 15 mths (median) < 15 mths (median) 15 mths (median) Docetaxel 3-weekly+P* (n=335) Mitoxantrone+P (n=337) Van Soest. ASCO 2015 (# 5043) 17

18 Radium-223 efficacy Alcaline phosphatses? Variable Subgroup N Hazard Ratio HR 95% CI Overall Survival Total ALP # < 220 U/L 220 U/L Current Use of Bisphophonates # Yes No Prior Use of Docetaxel # Yes No Predictive? Baseline ECOG Status 0 or Parker NEJM 2013 Favors Radium-223 Favors Placebo

19 mcrpc: primary / acquired resistance Chemotherapy candidates: (taxane, platine)... NO level 1 evidence.... Specially if no histological confirmation Anaplastic mcrpc Aparicio Clin Cancer Res 2013 mcrpc + 1 from Histology Small cell (pur / mixte) Only visceral metastases Maily lytic bone lesions N ( 5 cm) or prostate 5 cm, GS 8 PSA 10 ng/ml (before castration or at mcrpc progression) + 20 bone lesions Neuroendocrine histologic / serum marqueurs Castration efficacy 6 mo Better response and PFS if chemotherapy Caba + Carbo / to Caba only Gettys ASCO 2015

20 Once started, when to consider progression? PSA progression alone - A poor marker NOT to be used PCWG2 Scher JCO 2008 EAU guidelines Visceral disease may progress without PSA progression Pezaro Eur Urol PSA flare (< 10%): may occur. NOT linked to PFS Burgio Clin Genitourinary cancer 2016

21 The bone flare Quite frequent with systematic / early bone scan Up to 40%. Most with subsequent bone response Ryan Clin Cancer Research 2011 Bone progression definition: 2 new stops confirmed later!

22 In practice Switch only if unequivocal progression At least 2 criteria out of - PSA progression - Bone scan progression - CT progression - QoL / symptom progression Mottet EAU 2016 guidelines / Gillessen Ann Oncol 2015

23 Practical points Hormonal approach in the first line in the majority of patients with mcrpc Introduce treatment early in metastatic CRPC Do not act on PSA before 3 months if no clinical deterioration If PSA declines then rises and asymptomatic Re-image for new or progression of metastases If no new metastases continue abiraterone and re-image in 3 months OR consider chemotherapy

24 Poor response to ABI after ENZ? Author No prior ENZ De Bono 1 (COU-AA-302) ENZ àabi Year published N pts Median ABI duration â PSA 50% Median PFS mo 29% 5.6 mo Clear cross-resistance Loriot mo 8% 2.7 mo Noonan mo 3% 3.6 mo 1. NEJM 2011; 2. Ann Oncol 2013; 3. Ann Oncol 2013

25 Author No prior ABI Year published N pts Median ENZ duration â PSA 50% Median PFS Scher mo 54% 8.3 mo ABI à ENZ Poor response to ENZ after ABI? Schrader mo 29% - Thomsen mo 17% 2.8 mo Clear cross-resistance Badrising mo 21% 2.8 mo Bianchini mo 23% 2.8 mo Schmid mo 10% 3.1 mo Azad mo 22% 4.6 mo Brasso mo 18% - Joshua mo - - [1] AFFIRM trial; [2-8] retrospective mcrpc pts (post-doc); [9] compassionate program (75% prior ABI) 1. NEJM 2012; 2. Eur Urol 2014; 3. Scand J Urol 2014; 4. Cancer 2014; 5. Eur J Cancer Adv Ther 2014; 7. Eur Urol 2015; 8. K. Eur Urol 2014; 9. Prostate 2015

26 International consensus Abi after Enza OR Enza after Abi Primary resistance Not recommended (55%) or in a minority of selected cases (42%) Acquired resistance Not recommended (24%) or in a minority of selected cases (53%) 41 international experts consensus Gillessen Ann Oncol. 2015

27 Docetaxel refractory patients Retrospective N = 186 mcrpc 33 (17.7%) docetaxel refractory* Subsequent therapies: cabazitaxel Cabazitaxel AR-targeted agents (ABI or ENZ) Multivariate analysis OS benefit with cabazitaxel versus new AR-targeted agents Abiraterone Retrospective N = 44 mcrpc Treated with docetaxel ABI 7/44 patients docetaxel refractory No PSA, radiological or clinical response to ABI *Docetaxel refractoriness: progression occurring within 3 mths from docetaxel initiation and after adequate exposure to docetaxel (ie cumulative dose of 225 mg/m2). Di Lorenzo Eur Urol 2014

28 Contraindication mcrpc: what is trivial? Docetaxel Abiraterone Enzalutamide Baseline neutrophil count <1,500 cells/ml Severe liver impairment Severe liver impairment Special warning Docetaxel Abiraterone Enzalutamide Liver impairment severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and those with severe renal impairment History of seizures or other predisposing factors Severe neutropenia History of CV disease Renal impairment Severe fluid retention Moderate hepatic impairment Hepatic impairment Pulmonary symptoms

29 Finally the available tools The patient: symptoms, extend of disease, ability to receive a drug The disease: heterogeneous situations - NO one class fits all First line: "Simple situation": anaplastic disease Not evidence based, but rational: initial ADT efficacy Second line: initial treatment is the key selection point Second line HT after AA / Enza: a poor idea Doce refractory: AA / Enza: a poor idea More evidence / clear predictive factors are needed!

30 AND..... What will be the impact of Charteed / Stampede in mcrpc? To be determined!

31 FUTURE: key words Heterogeneity Individualize Combine H I C

32 Heterogeneity from the very beginning H RT Low/intermediate risk RP Low/intermediate risk RP Whole cohort (Low to high risk) Retrospective analysis: -Training cohort (Toronto): N=126 (low/intermediate-risk): RT -Validation cohorts: MSKCC (N=154) and Cambridge (N=117) (low to high-risk) PGA: percentage of genome alteration Lalonde E et al. Lancet Oncol 2015;15:

33 Lethal clones from the very beginning H Haffner MC et al. J Clin Invest 2013;123:

34 mcrpc: an heterogeneous situation H Meta-analysis of 5 phase III RCTs* based on individual patient data; N=3,993 men with mcrpc treated with docetaxel *TAK 327, SWOG 9916, CALGB 90401, ENTHUSE 33, SWOG 0421 Pooled HR for death Metastatic site HR (95% CI) P Lung vs. non-visceral 1.3 ( ) <0.001 Liver vs. lung 1.4 ( ) <0.001 Halabi S. J Clin Oncol 2016;doi /JCO (epub) LN: lymph node; RCT: randomized controlled trial

35 Inter-patient genomic heterogeneity Robinson D et al. Cell 2015;161: H

36 mcrpc: metastases heterogeneity New findings H/I N=132 patients progressing with AR-targeted agents Biopsy of metastases (laser microdissection) 73% single histologic subtype 34% adenocarcinoma 26% intermediate atypical carcinoma 13% small cell neuroendocrine carcinoma 24% mixed histology low PSA (Not AR-driven?) N=79 Log-rank P=0.06 Adeno NR Not-adeno (SCNC+IAC) Median=8.9 mo Small EJ. J Clin Oncol 2015:33(15S):269s(abs.5003)

37 Prediction of Abi / Enza efficacy AR-V7 status I Enzalutamide Abiraterone HR 8.5 ( ) p<0.001 HR 16.5 ( ) p<0.01 N = 31 Antonarakis, N Engl J med 2014 N = 31

38 Prediction of Abi / Enza efficacy AR-V7 status AR-V7 negative Median OS >16.0 mo (CI 95%: 16.0-NR) I Overallsurvival AR-V7 Positive Median OS 9.9 mo (CI 95%: ) HR 5.5 (CI 95%, ) P< Time (months) 62 US patients prospectively enrolled to receive enzalutamide (n=31) or abiraterone (n=31) Antonarakis, ESMO 2014 (# 7980)

39 cfdna - A promising tool to predict resistance to enzalutamide I Parameter (present vs. absent) PSA50 response rate RB1 loss 8% vs. 45% 0.01 MET gain/amp 0% vs. 43% 0.02 AR gain/amp 16% vs. 47% 0.02 AR mutation 27% vs. 44% 0.33 AR gene aberration (any) 19% vs. 54% MYC gain/amp 22% vs.43% 0.11 P Median PFS (mo) HR 1.4 vs < vs < vs < vs vs < vs P Plasma collected from 62 mcrpc patients progressing with various therapies (ABI, ENZA, other agents) Azad AA et al. J Clin Oncol 2015;33(suppl): abstract 5015 (poster presentation) cfdna: cell-free DNA; PFS: progression-free survival

40 Tumor heterogeneity also includes DNA repair defects I Phase II trial with olaparib (PARP inhibitor) N=50 mcrpc pts following chemotherapy (taxane) P < by log-rank test rpfs Biomarker-negative Median: 2.7 mo Biomarker-positive Median: 9.8 mo Biomarker: DNA repair defects Biopsy: 33% patients OS Biomarker-negative Median: 7.5 mo P = 0.05 by log-rank test Biomarker-positive Median: 13.8 mo Deletion / mutations in BRCA2, ATM, BRCA1, PALB2, CHEK2, FANCA, HDAC2 Months since trial entry Mateo J et al. N Engl J Med 2015;373: OS: overall survival; PARP: poly(adenosine diphosphate [ADP]- ribose) polymerase; rpfs: radiographic progression-free survival

41 How to target heterogeneity? C = Use therapies earlier and together Our current strategy is sequential: after failing to respond optimally to one drug, the patient is switched to another Increases the risk of multidrug resistance Clinical data support this hypothesis: cross resistance between AR-targeted agents

42 ARV7 expression and AA /Enza AA / Enza: ARV7 inducer Antonarakis, N Engl J med 2014

43 How to target heterogeneity? C = Use therapies earlier and together Extrapolating from the experience with HIV/AIDS, a combination of 2 therapies with non-overlapping mechanisms of resistance may prevent the emergence of drug resistance More intensive upfront therapy, with the goal of killing all PCa cells, may be more effective, as in CHAARTED and STAMPEDE Laskey SB & Siliciano RF. Nat Rev Microbiol 2014;12:772-8