Prostate cancer. SAMO Masterclass Richard Cathomas Onkologie Kantosspital Graubünden

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1 Prostate cancer SAMO Masterclass Richard Cathomas Onkologie Kantosspital Graubünden

2 Setting the stage 1. Metastatic vs non-metastatic 2. Hormone-naive prostate cancer CRPC: castration-resistant prostate cancer Silberstein JL et al. Transl Androl Urol 2013

3 What will not be discussed Pathology Localized prostate cancer PSA relapse after localized treatment Non-metastatic castration resistant prostate cancer

4 Metastatic prostate cancer Hormone-naive Castration resistant Supportive treatments

5 Metastatic Prostate Ca until 2010 mcrpc ADT (androgen deprivation) 2 ADT Docetaxel

6 Metas. Hormone-naive PCa: Androgen deprivation therapy (ADT) Standard first line treatment for all patients with advanced prostate cancer Response rate: 80-90% of patients Median progression free survival: months Important questions: Start of ADT? at time of diagnosis of mets Antiandrogen monotherapy? less effective Complete androgen blockade? generally no Intermittent ADT? less effective NEW 2014: early docetaxel?

7 Docetaxel in hormone-naive PCa CHAARTED study, ASCO pts, randomized phase III; ECOG-SWOG 60% with high volume extent 4 bone mets ( 1 outside spine/pelvis), visceral mets ADT vs ADT + docetaxel 75mg/m2 6 cycles Start within 120 days; no prednisone OS high volume : 49 vs 32 Monate (HR 0.60) ADT + Docetaxel new standard if: Fit for docetaxel High volume according to definition Start within 3 months of diagnosis Sweeny et al. Abstract LBA2 ASCO 2014

8 Met.Castration-resistant PCa: mcrpc Definition: progression of disease on castrate levels of testosterone (measure testosterone!) continue castration (lifelong) Evaluation: Disease burden: extent, visceral mets Disease dynamic: PSA DT, LDH, Pathology Symptomatic Time on prior ADT

9 Metastatic castration-resistant prostate cancer (mcrpc) Treatments: overview Resistance mechanisms Sequence vs Combinations

10 Docetaxel - TAX 327 Docetaxel q3w 19.2 Monate Docetaxel q1w 17.8 Monate Mitoxantron 16.3 Monat 1006 pts; Cross-Over 30 % Tannock et al. NEJM 2004; Berthold et al JCO 2008 Armstrong et al, JCO 2007;25:

11 Five substances with prolongation of overall survival in phase III trials since 2010 Sipuleucel T Cabazitaxel Abiraterone Radium 223 Enzalutamide

12 Substance 1 EP Indication Median OS HR; p-value Publication Sipuleucel-T Survival mcrpc Mte NEJM 2010 (Provenge ) 80% pre-d 0.78; 0.03 Cabazitaxel Survival mcrpc Mte Lancet 2010 (Jevtana ) Post-Doc 0.7; < Abiraterone Survival mcrpc Mte NEJM 2011 (Zytiga ) Post-Doc 0.65;< Abiraterone Survival mcrpc OS: 0.75 NEJM 2013 (Zytiga ) rpfs pre-doc rpfs:0.43 Enzalutamide Survival mcrpc Mte NEJM 2012 (Xtandi ) Post-Doc 0.63;< Enzalutamide Survival mcrpc Mte NEJM 2014 (Xtandi ) rpfs Pre-Doc 0.7;< Radium 223 Survival mcrpc Mte NEJM 2013 (Xofigo ) Post Doc 0.69;

13 Increased survival in the era of modern treatment for mcrpc Omlin AG et al. Eur Urol 2013

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15 Sipuleucel-T - Active cellular immunotherapy: vaccine - Very complex logisitics - Not available in Europe More convenient immune therapies in the future? Drake CG. Nat Rev Immunol 2010 Kantoff et al N Engl J Med 2010;363:

16 Cabazitaxel tubuline-binding taxane activity in docetaxel and paclitaxel refractory cell lines penetrates blood-brain barrier Intravenous every 3 weeks (6-10 cycles) Post Docetaxel setting: 75% Taxane refractory Current dose 25mg/m2 Ongoing phase III trial 20mg vs 25mg/m2 Toxicity: More: neutropenia Less: alopecia, nail changes, dysgeusia, neuropathy De Bono et al. Lancet 2010;376:

17 CYP17 Inhibition - Abiraterone Abirateron Abirateron Oral daily continuous, + 10mg prednisone De Bono et al NEJM 2011 Ryan et al NEJM 2013 Pre/Post Docetaxel Side effects: Hypokalemia, Hypertension, Edema

18 Enzalutamide AR-pathway: Triple blockade Oral daily continous No need for prednisone Pre/post docetaxel Side effects: -Fatigue -Seizures (rare) Scher et al. NEJM 2012; Beer TM et al. NEJM 2014

19 Radium 223 Radium 223 acts as calcimemtic naturally targets bone growth in and around bone metastases excreted by small intestine Alpha emitter: short penetration, only a few celldiameters (2-10) Intravenous 1x/month by nuclear medicine (x6)

20 Negative phase III trials! Substance Mechanism Phase III Publication DN-101 High dose Vitamine D Doc vs Doc + DN-101 J Clin Oncol 2011 NEG Bevacizumab Angiogenesis Doc vs Doc + Bevacizumab J Clin Oncol 2012 NEG Lenalidomide Immunomodulation Doc vs Doc + Lenalidomide ESMO 2012 NEG Aflibercept Angiogenesis Doc vs Doc + Aflibercept ASCO GU 2013 NEG Dasatinib Src-Inhibitor Doc vs Doc + Dasatinib ASCO GU 2013 NEG Atrasentan Endothelin A Rec Antago. Doc vs Doc + Atrasentan ASCO 2012 NEG GVAX Vaccine Doc vs Doc + GVAX ASCO GU 2009 NEG Zibotentan Endothelin A Rec Antago. Doc vs Doc + Zibotentan J Clin Oncol 2013 NEG

21 Overview mcrpc 2014 mcrpc Abiraterone Enzalutamid Radium 223 (Sipuleucel-T) Cabazitaxel Abiraterone Radium 223 Enzalutamid Docetaxel ADT (androgen deprivation)? 2 ADT Docetaxel Tasquinimod Ipilimumab PARP Inhib.

22 Resistance mechanisms Castration resistance Cross-resistance Abi-Enz Cross-resistance Taxane Abi/Enza

23 Mechanisms for castration resistance Possible cause for Abi-Enza cross resistance Abiraterone Enzalutamide Seruga B et al. Nat Rev Clin Oncol 2011

24 Abi Enza Cross Resistance cave: small retrospective analyses; post-docetaxel Enza Abi PSA RR 3-8% PFS 3-4mts OS 7-11 mts Noonan Ann Oncol 2013;24: Loriot Annals of Onc 2013;24: Abi Enza PSA RR 25 30% PFS 4mts OS 7 mts Schrader Eur Urol 2013

25 Cross resistance: Taxane Abi/Enza? Thadani-Mulero M et al. Cancer Res 2012;72:

26 Possible treatment choices First line options Abiraterone Enzalutamide Docetaxel Radium (bone mets only) Trial Second line options Docetaxel-naive Docetaxel All other options not tested/registered Prior docetaxel Cabazitaxel Abiraterone Enzalutamide Radium 223 (bone mets) Trial

27 Decision aids for first line treatment No predictive (bio-)markers Possible clinical factors Duration of response to primary ADT Tumour load: Visceral metastases, Symptoms Possible patient factors: Age, PS, co-morbidities, co-medication Account for possible cross resistance (?)

28 Response to primary ADT: an important prognostic marker SWOG 9346 Hussain M et al. J Clin Oncol 2006;24: Angelergues A et al. ASCO GU 2014?Also a predictive marker: novel hormone agents less effective?

29 Importance of monitoring Best benefit for patient: use all available options Change of treatment: not too early not too late PSA Measurements: Monthly, BUT : Cautious interpretation in first 12 weeks PSA only no reason for change CT und Szintigraphy: Generally every 12 weeks, consider prolongation of interval in asymptomatic pts and excellent PSA responders MRI Long-Spine At baseline in case of extensive bone disease and very early in case of symptoms

30 What about combinations? No proven benefit over sequential treatment Good candidates + ongoing trials: Enzalutamide plus abiraterone Radium plus abiraterone or enzalutamide Enzalutamide + taxane Abiraterone + taxane Beware: Radium + docetaxel: need to dose reduce docetaxel

31 Proportion of Subjects Without SRE Bone health: Denosumab vs Zoledronat in mcrpc HR 0.82 (95% CI: 0.71, 0.95) P = (Non-inferiority) P = (Superiority) 1.00 Denosumab Zoledronic acid 0.75 No change: -Overall survival -Progression free survival 0.50 Inclusion criteria mcrpc Bone metastases Study Month Don t forget Calcium + Vit D! Fizazi K et al. Lancet 2011;377:

32 Prolongation of time to SRE with new treatments Radium 223 Parker et al ASCO Monate MDV3100 DeBono et al ASCO Monate

33 Take home messages Define disease setting before taking decisions Met. Hormon-naive PCa: ADT Consider Docetaxel for extensive disease Met. Castration-resistant PCa: Sequential treatment: but sequence not defined Cross resistance: not complete but be aware Treat as long as possible: but switch early enough Interdisciplinary management and TRIALS