Management of castrate resistant disease: after first line hormone therapy fails

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1 Management of castrate resistant disease: after first line hormone therapy fails Rob Jones Consultant in Medical Oncology Beatson Cancer Centre Glasgow

2 Relevant Disclosure I have received research support and honoraria from: Sanofi Aventis Janssen Bayer Novartis Dendreon AstraZeneca

Key messages Prostate cancer death is due to metastatic castration resistant disease Life prolonging treatments are available now More such treatments are coming very soon

3 Key messages Prostate cancer death is due to metastatic castration resistant disease Life prolonging treatments are available now More such treatments are coming very soon CRPC is becoming a managed disease As options improve, early initiation of treatment becomes important Ensuring access to the best possible treatment will be a challenge in NHS

4 Metastatic prostate cancer

5 Metastatic prostate cancer 30-40% of cases will have metastatic disease in the end Typical pattern of metastasis Bones 80% Other 40% The main cause of symptoms Pain Immobility Paralysis The ultimate cause of death from prostate cancer

6 How do we find it? Castration First rise PSA M1 at diagnosis Castration control CRPC Metastatic M0 at diagnosis WW LA Radiation relapsed Post RPR Non castrate Castration Castration control First rise PSA CRPC Metastatic As there is more screening, the relative proportions may change

7 Hormone treatment for prostate cancer 1941 surgical castration results in remission of metastatic prostate cancer Androgens (testosterone) Castration therapy still first treatment for APC

8 Castration resistant prostate cancer Castration therapy works in 95% of cases.. But it doesn t last for ever Average 18 months Metastastic, castration resistant prostate cancer (mcrpc) Relentless, inevitably fatal (average c months) Heavy burden of symptoms

9 How do we find it? Definition: Rising PSA OR new metastases in a patient with suppressed testosterone (<1.7nmol/l) In practice: Rising PSA despite on-going LHRHa (Pitfalls: poor compliance with LHRH)

10 Four disease states Cancer in Prostate Alone Metastatic Disease Castration CRPC in Prostate Alone Metastatic CRPC

11 mcrpc in early 2011 Prognosis median survival months High burden of symptoms Declining quality of life

12 Treatment option 1: Docetaxel Arm 1: docetaxel 75 mg/m 2 d1, pred 5 mg bd d1 21, q21 Arm 2: mitoxantrone 12mg/m 2 d1, pred 5 mg bd d1 21, q21 Median overall survival (OS) 19.2 (p=0.004) Docetaxel Mitoxantrone Berthold DR et al. J Clin Oncol 2008;28:

13 Treatment number 2: Watchful waiting

14 Treatment option 2: hormones Anti-androgens Bicalutamide Low dose steroids (dexamethasone) Estrogens (diethlystilboestrol)

15 Treatment option 3: supportive care External beam radiotherapy Radioisotopes (eg. Strontium) Analgesia Bisphosphonates (eg. zoledronate) Supportive care

16 Treatment objectives Improve current symptoms Especially pain Delay symptomatic deterioration Prevent disastrous symptoms Spinal cord compression Prolong survival Of these, only docetaxel has shown this.. Whilst minimising side effects of therapy

17 So much for early 2011 Later that year

18 New treatment 1: more chemotherapy Cabazitaxel Similar to docetaxel Designed to kill cancer cells which are resistant to docetaxel Given by drip once every 3 weeks with steroids Side effects similar to docetaxel

19 New treatment 1: more chemotherapy Proportion of OS (%) Cabazitaxel Median OS (months) MP CBZP Hazard ratio % CI P-value < Cabazitaxel Mitoxantrone 20 Number at risk 0 0 months 6 months 12 months 18 months 24 months 30 months MP CBZP de Bono et al. Lancet 2010; 376:

20 New treatment 2: hormone therapy Abiraterone Blocks androgen manufacture

21 New treatment 2: hormone therapy Abiraterone Steroids 1200 men mcrpc Previous docetaxel Abiraterone Steroids Placebo Very mild side effects Once daily tablet

22 New treatment 2: hormone therapy Abiraterone Androgen biosynthesis inhibitor Licensed in mcrpc following docetaxel failure Median OS: 15.8 months 11.2 months 1. Fizazi et al. Lancet Oncology Zytiga. Summary of Product Characteristics. Janssen-Cilag Ltd, 2011.

COU-AA-302 - Phase 3 Trial in Asymptomatic or

1000 patients with asymptomatic or mildly

Randomised 1:1 Stratified by: ECOG performance

1) Abiraterone acetate 1000 mg daily Prednisone

daily T R E A T U N T I L P R O G R E S S I O N

23 COU-AA Phase 3 Trial in Asymptomatic or Mildly Symptomatic Patients With Metastatic CRPC patients with asymptomatic or mildly symptomatic metastatic CRPC Chemotherapy naive Randomised 1:1 Stratified by: ECOG performance status (0 vs. 1) Abiraterone acetate 1000 mg daily Prednisone 5mg twice daily Placebo daily Prednisone 5mg twice daily T R E A T U N T I L P R O G R E S S I O N Primary endpoint: 50% improvement in radiologic progression-free survival and 25% improvement in overall survival

24 Survival (%) Strong trend in OS primary endpoint AA + P PL + P Time to death (months) AA + P (median, mos): NR PL + P (median, mos): 27.2 HR (95% CI): 0.75 ( ) P value: AA PL Ryan et al. J Clin Oncol 2012;30 (suppl ):Abstract LBA4518 (Oral Presentation)

25 New treatment 3: Enzalutamide (MDV3100) Testes Cancer growth

26 AFFIRM trial Scher et al. 2012

27 Scher et al. 2012

28 Will this work in patients who ve had abiraterone? Probably not very much

29 New treatment 4: Radium-223 is a Bone-targeted Alpha Emitter Radium acts as a calcium mimic Naturally targets new bone growth in and around metastases Ca Ra

30 Alpha Particles Have Very Short Range Range of α particle Range of β particle

31 Survival 922 men mcrpc Painful bone mets Radium-223 X 6 cycles Placebo X 6 cycles 14.0 mo 11.2 mo

32 ALSYMPCA Overall Survival HR = 0.695; 95% CI, P = % Placebo, n = 268 Median OS: 11.2 months Radium-223, n = 541 Median OS: 14.0 months 0 Month OS = overall survival.

33 % Without Skeletal-Related Event ALSYMPCA Time to First Skeletal-Related Event HR = 0.610; 95% CI, P = Placebo, n = 268 Median: 8.4 months Radium-223, n = 541 Median: 13.6 months 0 Month

34 New treatment 5: vaccination Sipuleucel T (aka Provenge ) Sipuleucel-T

35 Impact trial

36 Current pathways per NICE et al Aka what we re supposed to do Bicalutamide Watchful waiting Docetaxel PFS Abiraterone BSC Bicalutamide BSC XRT Corticosteroids DES Bone modifiers Current pathways per license Aka what s legal or sometimes in England Bicalutamide Watchful waiting Docetaxel PFS Abiraterone Cabazitaxel BSC Bicalutamide Watchful waiting Docetaxel PFS Cabazitaxel Abiraterone BSC

37 Near future pathways Abiraterone/ Bicalutamide SipT WW WW Docetaxel PFS Cab Rad223 Enzalutamide BSC

38 What does this mean? Survival gains are potentially signicant Side effects, for most, will be minimal Patients will need to receive chronic therapy Quality of life on treatment important focus To get maximum benefit, treatment will have to start early

39 Key questions today Bicalutamide Watchful waiting Docetaxel PFS Abiraterone BSC When to start treatment? How to treat men who are not for docetaxel What role for DES / Dex

40 Key questions for tomorrow(and beyond) What order to use these treatments? - optimise QoL - Ensure all patients get all treatments How will we afford these treatments? - cost effectiveness - NICE / SMC Abiraterone/ Bicalutamide SipT WW WW Docetaxel PFS Cab Rad223 Enzalutamide??K BSC

Management of castrate resistant disease: after first line hormone therapy fails

Management of castrate resistant disease: after first line hormone therapy fails Rob Jones Consultant in Medical Oncology Beatson Cancer Centre Glasgow Rhona McMenemin Consultant in Clinical Oncology The