Metastatic prostate cancer

Metastatic prostate cancer Dr Alison Tree Consultant Clinical Oncologist Royal Marsden Hospital

2 Outline of the talk Metastatic prostate cancer scope Castration sensitive disease Castration resistant disease incl. novel therapies Symptom control cord compression, bone mets

3 Prostate cancer how big is the problem in the UK? CRUK cancer stats: http://www.cancerresearchuk.org/cancerinfo/cancerstats/

4 UK incidence and mortality of prostate cancer

5 We cure most prostate cancer

6 Improvements in survival? 1970s: 70% prostate cancer patients were dead by 5 years 2011: More than 80% survive 5 years Prostate cancer remains the second commonest cause of male cancer death in the UK Many patients with metastatic disease now live 5 years or more

7 Androgen dependance Image: Cancer.gov

8 But, in the absence of gonadal androgens Ang et al, Br J Cancer 2009

9 Metastatic prostate cancer - PSA Grist et al, J Steroid Biochem Mol biol 2014

10 Prostate specific antigen Helps sperm to swim Produced in the prostate Not ideal for diagnosing localised prostate cancer Reliable for monitoring metastatic disease

11 Common sites of metastases Bone metastases spinal cord compression common Lymph node metastases (esp pelvic and abdomen) End-stage can spread to liver, lungs Very rarely causes brain mets

12 Bone scan Multiple bone lesions consistent with metastases Bone only disease relatively common

Management algorithms

14 Castration

15 Androgen dependance Image: Cancer.gov

16 All men with metastatic disease (*) Should be on lifelong Androgen deprivation therapy* Dramatic symptom improvement Side effects: hot flushes, fatigue, muscle weakness, emotional lability, erectile dysfunction. Longer term bone mass loss and risk of CVD. Caveats end of life

17 How to start ADT Short course anti-androgen tablets (eg Bicalutamide 150mg od) for 3-4 weeks First LHRH analogue injection after 7-14 days of anti-androgen Thereafter LHRHa monthly, 3 monthly or 6 monthly for life Other option: Degarelix LHRH antagonist. No anti-androgen cover required, faster drop in testosterone

18 But earlier this year Everything changed

19 STAMPEDE MAMS trial design

20 Results of STAMPEDE arm C ADT alone (1000) vs ADT+ 6 cycles of docetaxel chemotherapy (around 600 pts) Randomised phase III Trial included locally advanced patients, but next slide is patients presenting with metastatic disease only

22 months 22 months prolongation of survival James N et al. J Clin Oncol 33, 2015 (suppl; abstr 5001), ASCO Annual meeting 2015.

22 ADT+Docetaxel now standard of care for fit men at first presentation of metastatic disease Often men up to 75 and beyond can manage chemo well Docetaxel 75 mg/m2 once every 3 weeks Febrile neutropenia 12% Fit men = performance status 2 or better

23 What are the active agents in CRPC?

24 NCCN guidelines for metastatic disease

25 Active agents in metastatic castrateresistant prostate cancer part 1 Docetaxel 2.5 months survival advantage over mitoxantrone (Tannock et al 2004) Taxane chemotherapy drug which is given intravenously and works by interfering with cell division. Risks nausea, fatigue, hair loss, neuropathy, VTE, febrile neutropenia

26 Active agents in metastatic castrateresistant prostate cancer part 1 Abiraterone post docetaxel 4 months improvement in survival 15.8 vs 11.2 mo (Fizzazi et al 2012) Abiraterone pre chemo 35.3 vs 30.1 mo (Ryan et al 2013, Rathkopft et al, 2014) Abiraterone (Zytiga) is an oral hormonal agent, stops extra gonadal androgen synthesis. Taken with bd Prednisolone. Side effects hypokalaemia, hypertension, liver enzyme derangement.

27 Active agents in metastatic castrateresistant prostate cancer- part 2 Enzalutamide pre chemo 32.4 vs 30.2 months (Beer et al, 2014) Enzalutamide post docetaxel: AFFIRM study 5 mo survival advantage 18.4 mo vs 13.6 months (Sher et al 2012 Enzalutamide (Xtandi) is an oral hormonal agent which reduces the action of androgens at the cell surface and within the cell. It is taken one a day without steroids. Side effects fatigue and small risk of seizures

28 Active agents in metastatic castrateresistant prostate cancer- part 2 Cabazitaxel post docetaxel TROPIC study de Bono et al 2010 15.1 vs 12.7 months Cabazitaxel is an intravenous chemotherapy agent. Side effects nausea, fatigue, hair loss, VTE, neutropaenia (+)

29 Active agents in metastatic castrateresistant prostate cancer- part 2 Radium 223 (Xofigo) ALSYMPCA study (Parker et al 2013) 14.9 vs 11.3 mo Radium is an intravenous bone targeting agent (Calcium mimic) carrying a localised radioactive isotope (alpha emitter). It is given in 6 injections monthly. Side effects very few.

30 Metastatic disease - 2013 LHRH analogues Consider Casodex withdrawal, stilboestrol, steroids Add antiandrogens Abiraterone Docetaxel Cabazitaxel

31 Metastatic disease LHRH analogues Add antiandrogens Consider Casodex withdrawal, stilboestrol, steroids Radium 223 Docetaxel Abiraterone Enzalutamide Cabazitaxel

32 Metastatic disease LHRH analogues Add antiandrogens Consider Casodex withdrawal, stilboestrol, steroids Radium 223 Docetaxel Abiraterone Enzalutamide Cabazitaxel

33 Optimal sequencing of agents Unknown

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35 Biomarkers which might help us in the future Androgen receptor mutations (eg AR-V7) Circulating tumour DNA

36 A sensible sequence of treatments might be Castration sensitive LHRHa plus docetaxel if fit (LHRH alone if not) Castration resistance When PSA fails, add bicalutamide 50mg od When PSA fails, withdraw bicalutamide (? Response) Bicalutamide withdrawal response?

37 A sensible sequence of treatments might be (part 2) When PSA fails, add dexamethasone 0.5mg od (nongonadal androgens) if frail or abiraterone/enzalutamide if fit, or Radium for boneonly disease For fit patients, consider Cabazitaxel or rechallenge with Docetaxel.

38 Common symptoms and palliation

39 Zoledronic acid Randomised trials vs placebo: Zoledronic acid delayed time to SRE (039 trial, Saad et al, JNCI 2002, 2004) No survival advantage,? Detriment in QOL Not recommended for SRE prophylaxis except in osteoporosis (ADT) or with (rare) lytic metastases.

40 Denosumab vs Zoledronic acid Human monoclonal antibody vs RANKL (inhibits osteoclasts) No OS advantage Fizazi et al Lancet 2011

41 Spinal cord compression Majority of radiotherapy emergencies Common complication of metastatic cancer 2.5 5% of all terminal cancer patients in last 2 years of life May also be presenting symptom (0.23% of cancer patients)

Pathophysiology

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Pathophysiology

Pathophysiology Extrinsic Compression Bone metastases enlarge and press on thecal sac Para-spinal tumour growth through neural foramina Destruction of cortical bone causing collapse and retropulsion of bony fragments Cord damage from oedema, axonal swelling and ischaemia necrosis

Site of compression Thoracic 60-80% Lumbosacral 15-30% Cervical <10% Up to 50% have multiple levels of involvement

Symptoms and Signs Pain Gait ataxia early sign Motor deficits Sensory deficits Autonomic dysfunction Can be difficult to distinguish from signs of general deterioration

48 Urgent MRI of WHOLE SPINE Delay in diagnosis and appropriate treatment leads to worsen neurological prognosis (and survival)

Cauda Equina Lesions below conus / at nerve roots Tend to be associated with lumbo sacral pain Radicular pain and lateralising signs and distal weakness commoner Urinary retention, constipation or impotence suspicious if new onset Reflexes lost in nerve root group

Grading Power (MRC) Grade 0 no muscle action Grade 1 muscles seen to contract but no movement Grade 2 movement occurs if gravity eliminated Grade 3 movement against gravity Grade 4 movement against up to 75% resistance Grade 5 movement against gravity and maximal resistance

51 Mandatory cord compression pathway Referral form to neurosurgical centre Dex 8mg bd with PPI cover Cases then discussed with a neurosurgeon (better functional outcome) If not for neurosurgery needs urgent radiotherapy Usually 20 Gy in 5 fractions daily over one week Wean off steroids once RT complete

52 Bone metastases Most metastatic prostate patients Can cause pain Palliative radiotherapy very effective 60-70% response of pain Around a third have a pain flare 1-3 days after RT

53 What dose for bone mets? 20 Gy in 5 fractions = 8 Gray in one fraction Yarnold et al, Radiother Oncol, 1999

54 Higher rate of pain recurrence with 8 Gy can repeat

55 Lymph node metastases Role of palliative radiotherapy Not often painful Lymphoedema of limbs due to lymphatic obstruction

56 Summary Lots of new therapies over the last 5 years All prolong survival metastatic prostate cancer survival now >5 years Optimal sequencing unknown Symptomatic complications common

57 Any questions?