Prostate Cancer: Vision of the Future By: H.R.Jalalian

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Alvin Hoover
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2 H. R. Jalalian Hematologist&Oncologist Baqiyatallah University of Medical Sciences 2

3 State of the art: vision on the future Diagnosis Surgery Radiotherapy Medical Oncology 3

4 Early Detection PSA sensitivity is low when the levels are only slightly raised Research is ongoing looking for more accurate ways of predicting the presence of cancer 4

5 Sate of the art: Early Detection Urine PCA 3 test (Progensa) New urine test looking at the amount of a prostate cancer gene product in the urine The greater the amount, the higher the chance of prostate cancer being present May become a useful additional test when deciding on initial or repeat biopsies 5

6 Sate of the art: Early Detection TMPRSS2:ERG test looks for an abnormal gene change called in prostate cells in urine collected after a DRE. This gene change is found in about half of all localized prostate cancers. It is rarely found in the cells of men without prostate cancer. Studies are under way to see if this test can be used for early detection of prostate cancer. 6

7 Diagnosis Diagnosis of prostate cancer is made by carrying out a prostate biopsy Doctors doing prostate biopsies often rely on transrectal ultrasound (TRUS) But standard ultrasound may not detect some areas containing cancer. 7

8 State of the art: Diagnosis A newer approach: color Doppler ultrasound More accurate sampling An even newer technique: the patient is first injected with a contrast agent containing microbubbles Promising results, but more studies will be needed MRI guided biopsy Negative TRUS guided biopsies, high suspicion 8

9 State of the art: Surgery Open and minimally invasive nerve sparing operations: standard of care Robot assisted minimally invasive systems (DaVinci) deliver 3D vision to the surgeon and level out even minimal shaking of his hands. To date, no study has shown superiority robotassisted surgery compared to open surgery performed by a highly experienced surgical team. 9

10 Radiotherapy Conformal radiation therapy (CRT) Intensity modulated radiation therapy (IMRT) Proton beam radiation help doctors avoid giving radiation to normal tissues as much as possible. to increase the effectiveness of radiation therapy while reducing the side effects. 10

11 State of the art: Radiotherapy Aims of research in radiotherapy: Improve effectiveness Reduce side effects 11

12 Improving Effectiveness: Increasing dose Changing daily dose/ length of treatment Addition of other treatment modalities New hormone treatments Chemotherapy Targeted agents 12

13 Reducing side effects Reducing dose to nearby organs: Intensity modulated radiotherapy (IMRT) Increasing accuracy of patient positioning 13

14 Sate of the art: Radiotherapy Intraoperative radiation Planning for brachytherapy can now even be done during the procedure. 14

15 Newer treatments early stage cancers These new treatments could be used either as the first type of treatment or after radiation therapy in cases where it was not successful. high intensity focused ultrasound (HIFU) destroys cancer cells by heating them with highly focused ultrasonic beams used more in Europe Not confirmed in USA 15

16 New treatments for advanced prostate cancer The majority of prostate cancers are stimulated by the male hormone testosterone Mainstay of treatment for advanced prostate cancer is removing this stimulus usually by suppressing the production of testosterone 16

17 New treatments for advanced prostate cancer In time the prostate cancer can start to progress without the stimulation of male hormones Chemotherapy is effective in improving quality and length of life Urgent need for effective treaments at this stage 17

18 Process of New Drug Development Laboratory development drug companies Small trials primarily to look for side effects Studies to look for activity against the cancer Much larger randomised studies to confirm expected effectiveness and side effects 18

19 Novel Agents in the Treatment Androgen Biosynthesis Inhibitors (ABI s)/novel antiandrogens Abiraterone, Enzalutamide (MDV-3100) Cytotoxics Cabazitaxel Immunotherapies Sipuleucel-T Bone\micro-environment directed therapies Alpharadin 19

20 State of the art: Hormone therapy Androgen Biosynthesis Inhibitors *Abiraterone Acetate TAK 700 VN/124 1 (TOK 001) Novel Anti Androgens * Enzalutamide (MDV3100) RD 162 EPI 001 (AR N Terminal) SNARE 1 (selective nuclear receptor exporter 1) * FDA approved 20

21 Novel Agents Targeting the Androgen Pathway Agent Function Phase Abiraterone Acetate CYP 17 α hydroxylase\12,20 lyase FDA approved inhibitor TAK 700 CYP 17,20 lyase inhibitor Phase III Enzalutamide (MDV3100) Anti androgen\androgen receptor signaling inhibitor ARN 509 Anti androgen Phase III AZD3514 AR down regulator\anti androgen Phase I Completed Phase III Ongoing Phase III in non castrate disease TOK 001 Anti androgen\cyp 17 inhibitor Phase I II EPI 001 Anti androgen\n terminal Domain pending clinical trials 21

22 Hormone therapy: Abiraterone (Zytiga) New drug that prevents the synthesis of male hormones Current studies have looked at patients who have already had chemotherapy and the results are encouraging Larger trials have now completed recruiting patients and the results are awaited Studies are also looking to see if this drug can improve the effectiveness of radiotherapy 22

23 State of the art: Chemotherapy Cabazitaxel New chemotherapy drug Recent large trial has shown activity in patients who have already had standard chemotherapy with improved response rates and survival 23

24 Immunotherapy Active immunotherapy tumor associated antigen is directly targeted by loading in that antigen in APC or into vaccine vector at protein or DNA level Antigen specific immunotherapy Sipuleucel T (Provenge) : FDA approved Poxvirus based vectors DNA based vaccines PROSTVAC: a virus that has been genetically modified to contain prostatespecific antigen (PSA) Early results with this vaccine have been promising 24

25 Immunotherapy Passive immunotherapy Antibodies to specific receptors/antigens Prostate Specific Membrane Antigen (PSMA) 25

26 Immunotherapy Immune Checkpoint Inhibitors Strategies to maintain activated tumor specific T cells by neutralizing co inhibitory receptors Anti cytotoxic T lymphocyte protein 4 (CTLA 4) Ipilumimab (Yervoy) already used to treat advanced melanoma Early syudies in PC have shown some benefit, but a recent larger study didn t find it helped men live longer. tremelimumab Anti program death 1 (PD 1) MDX

27 Targeted Therapy Drugs Newer drugs target specific parts of cancer cells or their surrounding environments. angiogenesis inhibitors Thalidomide (Thalomid ) FDA approved for Multuple Myeoloma Used combined with chemotherapy in an early study of men with advanced prostate cancer. While promising, this drug can cause major side effects 27

28 Bone Directed Therapies Radiofrequency ablation (RFA) control pain in men whose prostate cancer has spread to one or more areas in the bone early results are promising. Radioisotopes Naturally targets new bone growth in and around bone metastases Most acts as a calcium mimic Strontium 89 Samrarium 153 Radium 223 (Alpharadin ) 28

29 OS Benefit in Recent CRPC Trials Trial/ Agent/ Date Approved AFFIRM Enzalutamide 2012 Mechanism Androgen Receptor Signaling Inhibitor Comparator Survival (months) Hazard Ratio P-value Placebo 18.4 vs < COU-AA-301 Abiraterone + prednisone 2011 CYP17 Inhibitor Placebo + prednisone 14.8 vs < TROPIC Cabazitaxel + prednisone 2010 Cytotoxic Mitoxantrone + prednisone 15.1 vs < Alpharadin* 2012 Alpha-particle emitting radionuclide * Only 60% of these patients were post docetaxel patients Placebo 14.9 vs

30 1. Who is the right patient for which novel therapy? 2. What is the optimal sequencing of these agents? Does it matter? 3. How long do I give these agents? 4. Why are patients still relapsing? Picking the right treatment for the right patients at the right time 30

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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