Prostate cancer update: Dr Robert Huddart Cancer Clinic London

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Basil Roy Ryan
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1 Prostate cancer update: 2013 Dr Robert Huddart Cancer Clinic London

2 Recent developments Improved imaging New radiotherapy technologies Radiotherapy for advanced disease Intermittent hormone therapy New drugs

3 Koh and Sohaib, Radiol Clinic N Am 2012

4 Potential applications Pre diagnostic MRI (to select patients for biopsy) Targeting biopsies Checking patients with negative biopsy for rebiopsy Surveillance follow up Detection of recurrence Targetted radiotherapy

5 NNT screen is 1410 to prevent 1 CaP death NNT is 48 to prevent 1 CaP

6 Traditional pathway New pathway Raised PSA Raised PSA Biopsy MRI assessment MRI for staging No tumour tumour Observed and Biopsy on progression Biopsy

7 18F-Choline PET/CT Conventional imaging (CT, MRI) suffers from inadequate specificity, particularly in the detection of LN metastases. Excellent for bony metastases (sensitivity 79%, specificity 97%) Has high specificity (96% 1 ), but limited sensitivity (66%) for nodal mets (nodes often small +limit of PET resolution =3-5mm) 1. Beheshti M, et al. Radiology Mar;254(3): Beheshti M, et al. Mol Imaging Biol Jun;12(3):360.

8 MRI CT

11 Applications of Choline PET Intra prostatic targeting Staging high risk patients Detection of recurrence in High PSA patients

12 Radiotherapy developments Intensity Modulated Radiotherapy Image guided radiotherapy Fiducial markers Online imaging Stereotactic radiotherapy

13 IMRT: More precise dose distributions

14 Developments in Radiotherapy: IGRT Fiducial markers

15 Cone beam CT

17 19

18 20

19 Why is this important? More accuracy allows smaller margins that can reduce toxicity More focused therapy allows dose escalation Fewer bigger treatments (convenience, More effective?)

20 Lancet Oncol PSA control 71% 60% 74 Gy 64 Gy Bowel dysfunction UCLA-PCI

21 Locally advanced prostate cancer Take home message: Effective treatment helps (cures) more patients than treating localised cancer

22 Hormones and RT better than RT alone in locally advanced CaP

23 Hormones and Radiotherapy for locally advanced prostate cancer PRO7 trial Warde et al Significant survival benefit with greater benefit than prostatectomy v watchful waiting

24 New treatments Initial therapy Castration treatments

25 LHRH Analogues Antiandrogens LHRH Analogue LHRH LHRH Brain Pituitary Brain Pituitary LH ACTH LH ACTH Testis Adrenal Gland Testis Adrenal Gland Prostate Cancer Antiandrogen Prostate Cancer

26 Degarelix: LHRH Antagonists Klotz et al

27 Tombal et al 2010: Secondary analysis of RCT Eur Urol

28 LHRH Antagonists (Degarelix) For Rapid testosterone suppression Drawbacks Skin reactions Larger injection than LHRHa Best For: Immediate primary treatment of symptomatic patients Precise place to be defined No good for: No specific ci

29 Issue with LHRH therapy Bone health Risk of cardiovascular disease

Intermittent Hormone therapy Crook et al 2012 NEJM 367 895-903 Qol : Global scores

30 Intermittent Hormone therapy Crook et al 2012 NEJM Qol : Global scores trend for IHT NS Less Hot flashes, urinary symptoms, fatigue and better sexual desire

31 New therapies

32 New drugs proven to improve survival in castrate resistant prostate cancer pre 2009 Docetaxel

33 Advanced Prostate Cancer Algorithm 2009 Dexamethasone 0.5mg LHRH Anti androgen Docetaxel Mitoxantrone Stilboesterol

34 New drugs proven to improve survival in Castrate resistant prostate cancer Abiraterone (Zytiga) [NICE approved] Enzalutamide Alpharadin Carbazitaxel [London CDF] Sipuleucil-T

35 Abiraterone inhibits CYP450c17: One enzyme, two functions A key enzyme in androgen synthesis

36 Abiraterone: antitumour activity 70% of patients PSA fall by 50% 50% of patients PSA fall by 90% Patients with measurable disease > 50% objective response rate HRPC is still hormone driven!

37 Abiraterone phase III trial COU-301 Increased Toxcities: Fluid retention (31% v 22%, Hypokalaemia (17% v 8%), cardiac events 10% v8% NS) De Bono et al N Engl J Med May 26; 364(21):

38 Ryan et al Abiraterone:Pre chemotherapy

39 Enzalutamide phase III Potent androgen receptor inhibitor Super casodex

40 TROPIC trial: Carbazitaxel v Mitozantrone in Post Docetaxel CRPC Carbazitaxel new generation taxane- active in docetaxel resistant tumours DeBono et al 2010 Lancet

41 Radionuclides Alpha emitters are big and have low penetration Alpha-emitter, Radium-223 is safe given in repeated doses and may alter natural history

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III

metastases No known visceral metastases Postdocetaxel or unfit for

Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R A N D O

(50 kbq/kg) + Best standard of care Placebo (saline) + Best

42 ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT PATIENTS Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Postdocetaxel or unfit for docetaxel STRATIFICATION Total ALP: < 220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R A N D O M I S E D 2:1 N = injections at 4-week intervals Radium-223 (50 kbq/kg) + Best standard of care Placebo (saline) + Best standard of care Planned follow-up is 3 years Clinicaltrials.gov identifier: NCT

44 IMPACT study Kantoff et al 201 NEJM Dendritic cell vaccine

45 Advanced Prostate Ca algorithm 2007 Dexamethasone 0.5mg LHRH Anti androgen Docetaxel Mitoxantrone Stilboesterol

46 LHRH Advanced Prostate Ca algorithm 2014? Anti androgen Abiraterone Docetaxel Denusumab? Enzalutamide Carbazitaxel Alpharadin Other treatments? Experimental therapies Stilboesterol

47 Bisphosphonates? Time to skeletal event Saad et al. JNCI 94(19) 2002

48 Figure 2 Kaplan-Meier curves of key efficacy endpoints () Time to symptomatic bone metastasis Matthew R Smith, Fred Saad, Robert Coleman, Neal Shore, Karim Fizazi, Bertrand Tombal, Kurt Miller, Paul... Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial The Lancet Volume 379, Issue

49 Conclusions Many new developments have occurred in prostate cancer in the last 5 years Treatment algorithms are changing Positive impact on prostate cancer patients Cost!

50 Quiz

51 After the bones which is the commonest sites of prostate cancer metastases a. Brain b. Liver c. Para aortic lymph nodes d. lung e. Pleura

52 Which of these statements about PSA are true? a. PSA is a serine threonine protease found in seminal fluid b. It is elevated in 80% of patients with metastatic prostate cancer d. Response in PSA acts as a good surrogate for improved survival e. Doubling in PSA in <6 months tends to indicate the presence of metastatic disease

53 Which of these side effects is more common after Bicalutamide rather than treatment with a LHRH agonist Impotence 2. Hot flushes 3. Muscle weakness 4. Gynaecomastia 5. Osteoporosis

54 Which of these treatments has been proven to improve survival after docetaxel? Denusomab Strontium Enzalutamide Dexamethasone Mitoxantrone

55 Which of these treatments has been approved by NICE for treatment of CRPC? Mitoxantrone Enzalutamide Abiraterone Carbazitaxel Sipuleucil T

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 Relevant Disclosure I have received research support