Strategic decisions for systemic treatment. metastatic castration resistant prostate cancer (mcrpc)

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1 Strategic decisions for systemic treatment metastatic castration resistant prostate cancer (mcrpc) SAMO Luzern Richard Cathomas Onkologie Kantonsspital Graubünden

2 mcrpc and strategy? Basics of mcrpc New treatments since 2010 What drug when for which patient?

3 Basis of treatment until 2010 androgen deprivation therapy (ADT) Zoledronate in case of bone mets and castration-resistance docetaxel: only treatment with OS

4 Basis of treatment until 2010 androgen deprivation therapy (ADT) Zoledronate in case of bone mets and castration-resistance docetaxel: only treatment with OS Five new substances with improvement of overall survival since 2010 Sipuleucel T Cabazitaxel Abiraterone Radium 223 Enzalutamide (MDV3100)

5 Goserelin etc. CYP17 Inhib. -Abiraterone -Orteronel Enzalutamid Cabazitaxel Attard G et al. Clin Cancer Res 2011;17:

6 Substanz 1 point Indikation Median OS HR; p-value Publikation 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 ASCO 2012 (Zytiga ) rpfs pre-doc rpfs:0.43 Enzalutamid Survival mcrpc Post-Doc Mte 0.63;< NEJM 2012 Radium 223 Survival mcrpc Mte ASCO 2012 (Alpharadin ) Post Doc 0.69;

7 Cabazitaxel tubuline-binding taxane activity in docetaxel and paclitaxel refractory cell lines penetrates blood-brain barrier Intravenous every 3 weeks (6-10 cycles) Current dose 25mg/m2 Ongoing phase III trial 20mg vs 25mg/m2 Toxicity: More: neutropenia and diarrhea Less: alopecia, skin tox, neuropathy

8 Cabazitaxel post Docetaxel Efficacy Mitoxantron Cabazitaxel p-value Median OS 12.7mts 15.1 mts < PSA > 50% 17.8% 39.2% RR RECIST 4.4% 14.4% RR Pain 7.7% 9.2% 0.63 Toxicity Mitoxantron Cabazitaxel Neutro G3 58% 82% Febrile Nx G3 1% 8% Diarrhoe all G 11% 47% Diarrhoe G3 <1% 6% De Bono et al. Lancet 2010;376:

9 CYP 17 Inhibitors: Abiraterone Abiraterone Orteronel Abiraterone Oral 1000mg/d cont. + 10mg prednisone Attard G et al. JCO 2008

10 Abiraterone post Docetaxel Efficacy P (398 pat) Abi (797 p) p-value Median OS 11.2 mts 15.8 mts < PSA > 50% 5.5% 29.1% < RR RECIST 3% 14% <0.001 RR Pain 27% 44% Toxizität Placebo Abiraterone Fluid retention all 22.3% 30.5% Fluid ret G3 1.0% 2.3% Hypokaliämie all 8.4% 17.1% Hypo-K G3 0.8% 3.8% De Bono et al, N Engl J Med 2011

11 Abiraterone in chemo-naive Efficacy Plcb/Pred Abi/Pred HR Median OS 27.2 mts NR 0.75 rpfs 8.3mts NR 0.43 Time to PSA progr 5.6 mts 11.1 mts 0.49 Time to PS 10.9 mts 12.3 mts 0.58 Time to chemo 16.8 mts 25.2 mts 0.82 Toxicity G3/4 Plcb/Pred Abi/Pred Hypokalemia 1.9% 2.4% Hypertension 3.0% 3.9% ALT 0.7% 5.4% Further treatment at PD 60% vs 44% Ryan et al. #LBA4518 ASCO 2012

12 oral Oral 160mg/d cont De Bono et al. #4519 ASCO 2012

13 Enzalutamide post Docetaxel Efficacy Placebo MDV3100 HR/p-value Median OS 13.6 mts 18.4 mts 0.63 rpfs 2.9 mts 8.3 mts 0.40 PSA > 50% 1.5% 54% < RR RECIST 3.9% 28.9% < QoL response 17.8% 43.3% Placebo MDV3100 Fatigue 29% 34% - Diarrhea 18% 21% - Hot flushes 10 % 20% - 0% 0.6% Toxicity (all G) Seizure Scher et al. N Engl J Med 2012

14 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)

15 Radium 223 post Docetaxel Efficacy Placebo Radium HR/p-val Median OS 11.3 mts 14.9 mts /<0.001 Time to SRE 6.7 mts 12.2 mts 0.64 ALP > 30% 43% 3% <0.001 Placebo Radium Anemia 27% 27% ns Leucopenia 1% 4% ns Tc-penia 6% 8% ns Diarrhea 13% 22% Time to PSA Toxicity (all G) Parker et al. #LBA4512 ASCO 2012

16 Negative Phase III trials DN Docetaxel: high concentration oral calcitriol Bevacizumab + Docetaxel: anti VEGF antibody Lenalidomide + Docetaxel Angiogenesis, immune mechanism Atrasentan + Docetaxel Endothelin A antagonist Sunitinib/Prednisone vs Placebo/Prednisone Tyrosinekinase inhibitor (VEGFR, PDGFR) Zibotentan/BSC vs BSC Endothelin A antagonist Aflibercept + Docetaxel: VEGF trap: humanized fusion protein

17 Ongoing phase III trials Angiogenesis: Tasquinimod vs Placebo Angiogenesis, immune modulation Invasion and metastasis Dasatinib + Docetaxel vs Docetaxel TKI: Src, Kit, PDGFR Cabozantinib third line vs Mitoxantrone (1 pain RR) vs prednisone (1 OS) Androgen pathway TAK700 pre- and post-docetaxel Enzalutamide pre-docetaxel

18 Ongoing phase III trials: continued Immune mechanisms: Ipilimumab (Anti CTLA-4) vs Placebo ProstVAC (PSA vaccine) vs Placebo Survival pathways Custirsen + Docetaxel (first and second line) Cabazitaxel 25mg vs 20mg/m2 vs Docetaxel

19 Androgen deprivation therapy (ADT) First line treatment for ALL patients with advanced prostate cancer Response rate: 80-90% of patients Median progression free survival: 18 months Start of ADT? Intermittent ADT?

20 Castration-resistant PCa: CRPC Definition: progression of disease on castrate levels of testosterone (measure testosterone!) continue castration (lifelong) Re-Staging: CT and bone scan Lab: Hb, Lc, Tc, Creat, LDH, AP, PSA Need for antiresorptive treatment? Subsitution of calcium/vitamine D3

21 Overview mcrpc 2012 mcrpc Cabazitaxel Abiraterone Alpharadin Abiraterone Enzalutamid (Enzalutamid) ADT (androgen deprivation)? 2 ADT Docetaxel Cabozantinib Tasquinimod Ipilimumab Dasatinib Custirsen

22 Defining a strategy in mcrpc 2012 Help from trials? Help from biomarkers? Help from experts?

23 Strategy: Help from trials? Cabzitaxel (+ prednisone) 75% of patients with PD within 3 months after last doc Performance status 0-1; good bone marrow reserve Abiraterone (+ prednisone) 71% > 3 mts since docetaxel Pre-doc: asymptomatic/minimally symptomatic Exclusion criteria: Liver and cardiac function Enzalutamide 0.6% seizures: not with CNS disease (?) Radium 223 Symptomatic bone metastases Application by nuclear medicine (special requirements)

24 Strategy: Help from biomarkers? Prognostic markers Clinical factors: prior chemo, visceral mets, pain, radiographic progression Circulating tumor cells predictive markers? TMPRSS2-ETS fusion: predict response to abiraterone? EGFR and PTEN? - SAKK 08/07 negative predictive markers Elevated LDH: response Rapid PSA progression, pain, ECOG PS

25 SAKK 08/07: EGFR and PTEN as predictive markers? Cathomas et al. Clin Cancer Res 2012, epub 13 september

26 Strategy: Help from experts? Which drug for which patient? we have no clue really. What is the optimal sequence? I am tired of the question no data! patients should have exposure to as many drugs as possible Keep going if well tolerated and no rapid progression Don t let patient deteriorate too much monitor closely Oliver Sartor ASCO 2012

27 The evolution of CRPC Problem of cross-resistance of new agents Peter Nelson ASCO 2011

28 Decision aids for treatment choice Symptoms? Prior docetaxel? Metastatic burden: bone, visceral? Age and co-morbidities; PS 0-2? Neuroendocrine change? Prior tolerance of treatments? Laboratory: bone marrow, liver? Focal pain? Patient preference

29 What to do in Switzerland in 2012? Abiraterone pre-chemo not (yet) registered post-docetaxel: include in SAKK 08/11 phase III maintenance trial with orteronel (TAK 700)

30 Conclusions Define the patient situation in mcrpc Share decision process with patient Monitor patient with mcrpc closely keep on drug as long as possible but change early enough Need for interdisciplinary management! urology - radiation oncology medical oncology

ASCO 2012 Genitourinary tumors

ASCO 2012 Genitourinary tumors Post ASCO Bern 14-06-2012 Dr. med. Richard Cathomas leitender Arzt Onkologie, KSGR, Chur Renal cell cancer Changes in first line treatment? Prostate cancer 3 positive phase