ASCO 2012 Genitourinary tumors

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1 ASCO 2012 Genitourinary tumors Post ASCO Bern Dr. med. Richard Cathomas leitender Arzt Onkologie, KSGR, Chur

2 Renal cell cancer Changes in first line treatment? Prostate cancer 3 positive phase III trials for mcrpc The end of Intermittent Androgen Deprivation? Bladder cancer Testis cancer No notable news

3 (Clear cell) Renal cell carcinoma FIRST LINE: # 4501: Tivozanib phase III trial #CRA 4502: patient preference Sunitinib vs Pazopanib (PISCES) Promising results in 2nd/3rd line: #4504 Cabozantinib (XL 184): 28% RR 72%DCR, 14.7 mts PFS #4505 Anti PD-1 Ab (BMS ) RR 31%, PFS at 24 weeks 67%

4 Differences of TKI: -Different potency/affinity -Different TK spectrum/selectivity -Different half life Barghava P, Robinson OM. Curr Oncol Rep 2011;13:

5 Renal cell carcinoma Tivozanib #4501 VEGFR 1-2-3; long half life > 3 days Oral 1.5mg/d 3 weeks on 1 week off randomized 1:1 vs sorafenib 517 pts, 70% treatment naive; 30% prior IFN 1 endpoint: PFS (independent radiol.review) PFS : 11.9 vs 9.1 mts (HR 0.756, p=0.037) PFS treatment naive: 12.7 mts vs 9.1 mts ORR 33% vs 23% (p=0.014) Toxicity: hypertension, HFS, diarrhea Motzer et al. #4501 ASCO 2012

RCC preference trial #4502 1 endpoint: patient preference at 22 weeks

6 RCC preference trial # endpoint: patient preference at 22 weeks Other endpoints: physician pref, QoL 126 pts Escudier et al. #4502 ASCO 2012

7 Main reasons for preference: better QoL, less fatigue, less taste change Discrepancy to CTC AE toxicity assessment: much smaller difference Escudier et al. #4502 ASCO 2012

8 28% off treatment in 22 weeks Treatment period 1 Treatment period 2 End of randomised phase Primary analysis Pazopanib, n=86 Sunitinib, n=68 n=62 n=54 Withdrawals 18 (21%): 9 (10%) Adverse event 4 (5%) Lack of efficacy 1 (1%) Investigator discretion 2 (2%) Withdrew consent 2 (2%) Death Withdrawals 6 (9%): 1 (1%) Adverse event 2 (3%) Lack of efficacy 3 (4%) Death 8 excluded due to progressive disease during treatment period 1 PD on 1 paz 12 (14%) 63% Sunitinib, n=82 Pazopanib, n=68 n=64 n=60 Withdrawals 14 (17%): 7 (9%) Adverse event 3 (4%) Lack of efficacy 1 (1%) Protocol deviation 2 (2%) Withdrew consent 1 (1%) Investigator discretion Withdrawals 4 (6%): 1 (1%) Adverse event 1 (1%) Lack of efficacy 1 (1%) Death 1 (1%) Protocol deviation 4 excluded due to progressive disease during treatment period 1 PD on 1 sun 7 (9%) 73% 168 randomised 136 dosed with both drugs (ITT population) Escudier et al. #4502 ASCO completed questionnaires 114 in primary analysis (mitt population) 22% off treatment in 22 weeks

9 Renal cell carcinoma conclusions Tivozanib: new option in first line Critical points: sorafenib is not standard 1st line TKI Efficacy less impressive than expected Comparison of toxicity difficult So far not available in Switzerland Sequence of treatments: Patient preference in favor of pazopanib: BUT Efficacy comparison pazopanib sunitinib awaited New drugs will change the landscape soon

10 Prostate cancer UPDATES #LBA4519: MDV3100 post Docetaxel #LBA4512: Radium 223 ESMO 2011 ASCO GU 2012 NEWS #LBA 4518: abiraterone in chemo-naive mcrcp # 4: Intermittent androgen deprivation IAD Clear results or not?

11 Prostate cancer MDV3100 #4519 ENZALUTAMIDE= MDV3100: novel antiandrogen 1199 pts; orally 160mg/d all post-docetaxel vs placebo 2:1 No mandatory prednisone 1 endpoint: overall survival De Bono et al. #4519 ASCO 2012

12 Prostate cancer MDV3100 #4519 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% Toxicity (all G) Placebo MDV3100 Fatigue 29% 34% - Diarrhea 18% 21% - Hot flushes 10 % 20% - Seizure 0% 0.6% De Bono et al. #4519 ASCO 2012

13 Conclusions MDV3100 #4519 New treatment option for mcrpc So far data only in post docetaxel pts Phase III pre-docetaxel ongoing Not yet available in Switzerland Many new questions When? Who? How long? Resistance mechanisms? De Bono et al. #4519 ASCO 2012

Prostate cancer Radium #LBA 4512 922 pts; randomized 2:1 vs placebo iv infusion 1x/month (50kBq/kg x6)

14 Prostate cancer Radium #LBA pts; randomized 2:1 vs placebo iv infusion 1x/month (50kBq/kg x6) Post-Docetaxel (60%)or unfit for docetaxel Symptomatic, > 2 bone mets Parker et al. #LBA4512 ASCO 2012

15 Prostate cancer Radium #LBA 4512 Efficacy Placebo Radium HR/p-val Median OS 11.3 mts 14.9 mts Time to PSA /<0.001 Time to SRE 6.7 mts 12.2 mts 0.64 ALP > 30% 43% 3% <0.001 Toxicity (all G) Placebo Radium Anemia 27% 27% ns Leucopenia 1% 4% ns Tc-penia 6% 8% ns Diarrhea 13% 22% Parker et al. #LBA4512 ASCO 2012

16 Conclusions Radium #LBA 4512 New option for mcrpc with bone mets Very good tolerance Soon available in Switzerland in extended access program However Lack of activity against non-bone mets Feasability of chemo post-radium? Ideal patient unknown

17 Abiraterone in chemo-naive: #LBA4518 Chemotherapy-naive mcrpc (no/mild symptoms) All remain on ADT (LHRH analogues) Co-1 endpoints: OS, radiographicpfs 1088 pts; randomized 1:1 Abi/Pred vs Plac/Pred IDMC (independent data monitoring committee) Unblinding of the study (43% of events) Median Follow up 22.2 months Ryan et al. #LBA4518 ASCO 2012

18 #LBA4518 subsequent therapy Ryan et al. #LBA4518 ASCO 2012

19 Abiraterone in chemo-naive: #LBA4518 Efficacy Plcb/Pred Abi/Pred HR Median OS 27.2 mts NR 0.75 rpfs 8.3mts NR 0.43 Time to opiate use 23.7 mts NR 0.69 Time to chemo 16.8 mts 25.2 mts 0.58 Time to PS 10.9 mts 12.3 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% Ryan et al. #LBA4518 ASCO 2012

20 Conclusions Abiraterone in chemo-naive: #LBA4518 Clear benefit from abiraterone Closed prematurely by IDMC: OS not significant according to prespecified criteria but other endpoints met However: Unclear when to start treatment in mcrpc Registration in Switzerland so far for post-docetaxel

21 Substanz Sipuleucel-T (Provenge ) Cabazitaxel (Jevtana ) Abiraterone (Zytiga ) Abiraterone (Zytiga ) MDV3100 Radium 223 (Alpharadin ) 1 point Indikation Median OS HR; p-value Survival mcrpc Mte 80% pre-d 0.78; 0.03 Survival mcrpc Mte Post-Doc 0.7; < Survival mcrpc Mte Post-Doc 0.65;< Survival mcrpc OS: HR 0.75 rpfs Pre-Doc rpfs:hr 0.43 Survival mcrpc Mte Post-Doc 0.63;< Survival mcrpc Mte Post-Doc 0.7; <0.005 Publikation NEJM 2010 Lancet 2010 NEJM 2011 ASCO 2012 ASCO 2012 ASCO 2012

22 #4 SWOG 9346: Intermit. ADT (IAD) N= /1995 9/2008 N= 1535 Hussain et al. #4 ASCO 2012 Restart: -PSA >20 -PSA > baseline

23 #4 SWOG 9346: Intermit. ADT (IAD) Statistical plan 1 endpoint: OS with IAD is non-inferior to CAD Upper bound hazard ratio = 1.20 Results Median OS CAD 5.8 yrs vs IAD 5.1 yrs HR 1.09 (CI ) Subgroups: minimal disease worse with IAD Hussain et al. #4 ASCO 2012

24 #4 SWOG 9346: Intermit. ADT (IAD) Quality of life (# 4571) sign. better libido/less impotence on IAD slightly better emotional/physical function Post-plenary discussion Hussain/Oh: CAD is standard, IAD is inferior All other major personalities: surprised by robustness of conclusions fell into trap not non-inferior inferior, HR crosses 1.0, QoL vs maximal survival Hussain et al. #4 ASCO 2012

25 #4 SWOG 9346: Intermit. ADT (IAD) Metastatic disease PSA failure; non-metastatic CAD YES YES IAD NO?? YES Informed discussion -Overall survival -Quality of life -Follow up

26 Evoting question #1 Man 74 yrs with metastatic prostate cancer very good general condition, no symptoms. Castration with LHRH agonist since 2009 (time of diagnosis of bone metastases, 4 bone mets) Currently rising PSA 21 ng/ml, doubling time 5 months, two new bone lesions in bone scan, no other metastases. How would you treat the patient? a) Start chemotherapy with docetaxel b) Start treatment with abiraterone c) Start bicalutamide, control every 6-12 weeks d) No treatment, watch and wait, control every 6-12 weeks

27 Evoting question #2 How will the results of the tivozanib trial and of the patient preference trial (sunitinib/pazopanib) influence your choice of first line treatment for patients with progressive metastatic clear cell renal cell carcinoma? a) No change of current practice, await further results b) Start using tivozanib when available c) Increase use of pazopanib

28 Evoting question #3 Man79 yrs, known cardiovascular disease. Prostate cancer with several bone mets diagnosed 6 months ago and started treatment with LHRH agonist. Complains of sweats, otherwise well. No bone pain. PSA has fallen under treatment from 534ng/ml to 2.5 ng/ml. How do you continue treatment? a) Continue LHRH, add calcium/vitamine D b) Continue LHRH, add calcium/vitamine D, start zoledronic acid (4mg/month) or denosumab (120mg/month) c) stop LHRH, start bicalutamide 150mg/d d) Stop LHRH, add calcium/vitamine D, check PSA 2-3 months

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

Strategic decisions for systemic treatment metastatic castration resistant prostate cancer (mcrpc) SAMO Luzern 14.09.2012 Richard Cathomas Onkologie Kantonsspital Graubünden richard.cathomas@ksgr.ch mcrpc