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 Rhona McMenemin Consultant in Clinical Oncology The Newcastle upon Tyne Hospitals NHS Foundation Trust

2 Disclosure RJJ has received research support and honoraria from: Sanofi Aventis Johnson and Johnson Bayer Novartis AstraZeneca

4 Advanced Prostate Cancer Cancer in Prostate Alone Metastatic Disease Castration CRPC in Prostate Alone Metastatic CRPC

5 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 mcrpc is becoming a managed disease As options improve, early initiation of treatment becomes important

6 TREATMENT OPTIONS IN 2010

2 (p=0.004) 16.3 Docetaxel Mitoxantrone 1.

7 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) 16.3 Docetaxel Mitoxantrone 1. Berthold DR et al. J Clin Oncol 2008;28:

8 2: hormones Anti-androgens Bicalutamide ( Maximum Androgen Blockade ) Low dose steroids (dexamethasone) Estrogens (diethlystilboestrol)

9 3: supportive care External beam radiotherapy Radioisotopes (eg. Strontium) Analgesia Bisphosphonates (eg. zoledronate) Supportive care

10 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

11 Uncertainties Who should have chemotherapy? General fitness Other diseases Patient perceptions and choices (Age ) When should it be given? After all simpler therapies have failed? Early to prevent deterioration? Before symptoms have occurred? Once there are symptoms to treat?

12 So much for early 2011 TREATMENT OPTIONS 2012

13 Similar to docetaxel 4: more chemotherapy Cabazitaxel Designed to kill cancer cells which are resistant to docetaxel Given by drip once every 3 weeks with steroids Side effects similar to docetaxel

14 Proportion of OS (%) : more chemotherapy 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:

15 Blocks androgen manufacture 5: more hormone therapy Abiraterone

16 5: more hormone therapy Abiraterone Steroids 1200 men mcrpc Previous docetaxel Abiraterone Steroids Placebo Manageable side effects Once daily tablet

17 5: more hormone therapy Abiraterone Androgen biosynthesis inhibitor Licensed in mcrpc following docetaxel failure Median OS: 14.8 months 10.9 months 1. de Bono JS et al. Ann Oncol 2010; Abstract LBA5 (Presentation). 2. Zytiga. Summary of Product Characteristics. Janssen-Cilag Ltd, 2011.

18 COMING SOON.

19 6: more radiotherapy Radium-223 Injection every 4 weeks x 6 Side effects well tolerated Radioactive Mimics calcium Taken up by the tumours in the bones Targets radiotherapy to all bone secondaries 2.8 months survival gain Only for patients with painful bones

20 7: more hormone therapy (again) MDV3100 Androgen receptor binding drug Once daily tablet Side effects well tolerated 4.8 months survival gain Only post chemotherapy

21 Summary of options docetaxel 2. Second line hormone therapy 3. Supportive care cabazitaxel abiraterone Radium MDV3100

22 Case presentation 65 year old man Presenting with nocturia, PSA 287 Clinically malignant prostate on DRE, repeat PSA 353 TRUS guided biopsies capsular breach throughout, extensive infiltration of Gleason 4+5 disease Staging bone scan clear

23 Clinical progress goserelin Nadir PSA months later, by 10 months 9.2 bicalutamide added for six months with little effect Baseline PSA at first oncology visit 74 CT enlarged prostate with locoregional nodes and several small sclerotic foci

24 Clinical progress chemotherapy Commenced systemic chemotherapy with docetaxel in the Enthuse study Baseline PSA 261, completed 10 cycles, nadir PSA 29 but transient Palliative radiotherapy to bladder, very reluctant for further chemotherapy

25 Clinical progress hormones Very reluctant for further chemotherapy Enrolled in AFFIRM, PSA 967 and progressing radiological disease Nadir PSA 360, rising after 3 months with slow radiological progression

26 Investigations

27 Investigations

28 Clinical progress hormones Next step? Abiraterone access program

30 Proportion of OS (%) Clinical progress hormones and Response? chemotherapy now enrolled in PROSELICA TROPIC trial Cabazitaxel Mitoxantrone months 6 months 12 months 18 months 24 months 30 months 1. de Bono et al. Lancet 2010; 376:

31 Summary The role of clinical trials in this patient suited his personality facilitated access to new treatments pre licensing The chronicity of advanced and metastatic prostate cancer now five years following a diagnosis with at least locally advanced (and probably metastatic) cancer Treatment options while clinically driven always informed by patient choice

32 A future paradigm of treatment in mcrpc improving OS AR antagonists (eg. bicalutamide) Docetaxel Cabazitaxel New hormone therapies (abiraterone, MDV3100, TAK700) Immunotherapies (eg. Sipuleucel-T ( Provenge )

33 Treatment opportunities in mcrpc Asymptomatic, rising PSA Wide window of opportunity (highly variable) Controlled symptoms, rising PSA Poorly controlled symptoms Missed opportunity Life-threatening disease complications (bone marrow, SCC) Death

34 Deferred effective therapy Asymptomatic, rising PSA Controlled symptoms, rising PSA Poorly controlled symptoms Narrower window of opportunity for subsequent therapy Life-threatening disease complications (bone marrow, SCC) Death

35 Metastatic Prostate Cancer MINIMAL / NO SYMPTOMS SYMPTOMS Metastatic CRPC Metastatic CRPC

36 Metastatic Prostate Cancer MINIMAL / NO SYMPTOMS SYMPTOMS Metastatic CRPC Metastatic CRPC

37 Conclusions Treatment options for mcrpc are growing The challenge is to ensure that all patients get the best treatment available Most patients want to live without symptoms or side effects If you wait until it s too late, it s too late

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