Management of castrate resistant disease: after first line hormone therapy fails Rob Jones Consultant in Medical Oncology Beatson Cancer Centre Glasgow
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 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
Metastatic prostate cancer
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
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
Hormone treatment for prostate cancer 1941 surgical castration results in remission of metastatic prostate cancer Androgens (testosterone) Castration therapy still first treatment for APC
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. 18 24 months) Heavy burden of symptoms
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)
Four disease states Cancer in Prostate Alone Metastatic Disease Castration CRPC in Prostate Alone Metastatic CRPC
mcrpc in early 2011 Prognosis median survival 18 24 months High burden of symptoms Declining quality of life
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 16.3 1. Berthold DR et al. J Clin Oncol 2008;28:242-245.
Treatment number 2: Watchful waiting
Treatment option 2: hormones Anti-androgens Bicalutamide Low dose steroids (dexamethasone) Estrogens (diethlystilboestrol)
Treatment option 3: supportive care External beam radiotherapy Radioisotopes (eg. Strontium) Analgesia Bisphosphonates (eg. zoledronate) Supportive care
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
So much for early 2011 Later that year
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
New treatment 1: more chemotherapy Proportion of OS (%) 100 80 Cabazitaxel Median OS (months) MP CBZP 12.7 15.1 Hazard ratio 0.70 60 95% CI 0.59-0.83 P-value <.0001 40 Cabazitaxel Mitoxantrone 20 Number at risk 0 0 months 6 months 12 months 18 months 24 months 30 months MP 377 300 188 67 11 1 CBZP 378 321 231 90 28 4 1. de Bono et al. Lancet 2010; 376:1147-1154.
New treatment 2: hormone therapy Abiraterone Blocks androgen manufacture
New treatment 2: hormone therapy Abiraterone Steroids 1200 men mcrpc Previous docetaxel Abiraterone Steroids Placebo Very mild side effects Once daily tablet
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 2012. 2. Zytiga. Summary of Product Characteristics. Janssen-Cilag Ltd, 2011.
COU-AA-302 - Phase 3 Trial in Asymptomatic or Mildly Symptomatic Patients With Metastatic CRPC. 1000 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
Survival (%) Strong trend in OS primary endpoint 100 80 60 40 20 0 0 AA + P PL + P 3 6 9 12 15 18 21 24 27 30 Time to death (months) AA + P (median, mos): NR PL + P (median, mos): 27.2 HR (95% CI): 0.75 (0.61-0.93) P value: 0.0097 33 AA PL 546 542 538 534 524 509 503 493 482 465 452 437 412 387 258 237 120 106 27 25 0 2 0 0 Ryan et al. J Clin Oncol 2012;30 (suppl ):Abstract LBA4518 (Oral Presentation)
New treatment 3: Enzalutamide (MDV3100) Testes Cancer growth
AFFIRM trial Scher et al. 2012
Scher et al. 2012
Will this work in patients who ve had abiraterone? Probably not very much
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
Alpha Particles Have Very Short Range Range of α particle Range of β particle
Survival 922 men mcrpc Painful bone mets Radium-223 X 6 cycles Placebo X 6 cycles 14.0 mo 11.2 mo
ALSYMPCA Overall Survival 100 90 80 HR = 0.695; 95% CI, 0.552-0.875 P = 0.00185 % 70 60 50 40 30 20 10 Placebo, n = 268 Median OS: 11.2 months Radium-223, n = 541 Median OS: 14.0 months 0 Month 0 3 6 9 12 15 18 21 24 27 OS = overall survival.
% Without Skeletal-Related Event ALSYMPCA Time to First Skeletal-Related Event 100 90 80 70 60 50 40 30 20 10 HR = 0.610; 95% CI, 0.461-0.807 P = 0.00046 Placebo, n = 268 Median: 8.4 months Radium-223, n = 541 Median: 13.6 months 0 Month 0 3 6 9 12 15 18 21
New treatment 5: vaccination Sipuleucel T (aka Provenge ) Sipuleucel-T
Impact trial
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
Near future pathways Abiraterone/ Bicalutamide SipT WW WW Docetaxel PFS Cab Rad223 Enzalutamide BSC
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
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
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