First line cytotoxic treatment in castration resistant prostate cancer: What have we learned in the last twenty years?

1. First line cytotoxic treatment in castration resistant prostate cancer: What have we learned in the last twenty years? Ian F Tannock MD, PhD, DSc Princess Margaret Hospital and University of Toronto SOGUG, Madrid

2. Learning Goals of Presentation To become familiar with: • The historical development of first line chemotherapy for Castrate-Resistant Prostate Cancer (CRPC) • Effects of chemotherapy on survival, symptom control and quality of life • Toxicities associated with chemotherapy • Current trials evaluating the addition of molecular targeted agents with docetaxel and prednisone • Causes of drug resistance and prospects for the future SOGUG, Madrid

3. Potential conflicts of interest I have advised multiple companies about design of trials for prostate cancer for which I have received contributions to my research fund. I have chaired international company-sponsored trials for hormone-refractory prostate cancer (TAX-327, VENICE) I do not accept personal remuneration from companies SOGUG, Madrid

4. Mr Santos.... .... is a 68 year old man diagnosed with metastatic prostate cancer in bone 4 years ago He has hypertension and is “old for his age” He has been treated with: - goserelin (initial good response) - bicalutamide (added later for PSA: further response) - stopping bicalutamide (for PSA: no response) His PSA is increasing with a doubling time of 3 months He has aching pain (rated 3/10) largely controlled with codeine + acetaminophen How should he be treated? SOGUG, Madrid

5. Mr Santos does NOT need immediate chemotherapy He may respond to: • Other anti-androgens (e.g. nilutamide, flutamide) • Inhibitors of steroid synthesis (e.g. ketoconazole) • Estrogens such as DES • Glucocorticoids such as dexamethasone or prednisone New agents such as abiraterone acetate and MDV-3100 are likely to extend the period of hormone sensitivity • Because some men continue to respond to hormonal therapy the term “Castration-resistance” is more appropriate than “Hormone-refractory” SOGUG, Madrid

6. Principles of Management for castrate-resistant prostate cancer • For those with slowly rising PSA and minimal symptoms: • Consider further hormonal manipulations (e.g. DES, ketoconazole) or clinical trials of targeted agents • For those with symptoms or rapidly-rising PSA • Optimize pain control with regular dosing of narcotic medication, such as morphine • Give regular laxatives to control the constipation that will be caused by morphine • Consider local radiotherapy if there is a dominant site of pain • Consider chemotherapy or bone-seeking radioisotopes SOGUG, Madrid

7. Chemotherapy for castration-resistant prostate cancer Sporadic small trials were done in the 1980s, and the following reviews were published in 1985..... The answer remained: NO – until 1996 SOGUG, Madrid

8. The trial showed improved pain control with chemotherapy – but no difference in survival (it was not powered to show a survival difference) The FDA approved mitoxantrone and prednisone as palliative treatment for men with symptomatic HRPC – the first time a chemo drug had been approved based on a symptom control endpoint SOGUG, Madrid

9. Phase 3 Trials of Mitoxantrone + Corticosteroid M= mitoxantrone, P=prednisone, H=hydrocortisone SOGUG, Madrid

10. Main results of the Canadian trial of mitoxantrone + prednisone vs prednisone alone There was no improvement in survival but the trial was too small to detect such differences Mitoxantrone was approved by FDA – the first chemo agent to be approved for prostate cancer Mitoxantrone is well tolerated and remains an option for treatment SOGUG, Madrid

11. Mitoxantrone and prednisone became the comparator for later trials of chemotherapy SOGUG, Madrid

12. et al The TAX-327 study Docetaxel 75 mg/m2 q3wks x 10 cycles 1006 patients with CRPC Docetaxel 30 mg/m2 weekly for 5 of 6 weeks x 5 cycles Mitoxantrone 12 mg/m2 q3 wks x 10 cycles All patients received prednisone 10mg/day SOGUG, Madrid

13. Docetaxel 3wkly Docetaxel wkly Mitox 3 wkly Survival in TAX-327 Study 1.0 D 3 wkly Mitoxantrone Median = 18.9 months (p=0.009) Median = 16.5 months 0.5 Probability of Surviving 0.0 0 6 12 18 24 30 Months

14. More toxicity with docetaxel/estramustine compared to mitoxantrone (and with docetaxel/prednisone in TAX-327) SOGUG, Madrid

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16. ...with the following caution • 26 patients aged 74-87 treated at Cleveland Clinic (median age 76) • PSA response in 11/22 assessable men • 9 men (34%) hospitalized for toxicity (neutropenic fever, diarrhea, dehydration) We are examining the TAX-327 database to evaluate outcomes in very old men SOGUG, Madrid

17. TAX 327: Secondary Endpoints SOGUG, Madrid

18. Landmark analysis showed that both PSA response and pain response were independent predictors of longer survival SOGUG, Madrid

19. QL Response of pts with minimal symptoms Deterioration in QL Effect of docetaxel on minimally symptomatic patients • Many patients with minimal pain still had substantial impairment of quality of life (QL)

20. TAX-327 and SWOG 9916 • Chemotherapy can relieve symptoms and improve Quality of Life • No evidence to support early treatment of asymptomatic patients • Mitoxantrone + prednisone provides palliative benefit and is appropriate for some patients • Estramustine adds only toxicity and should not be used • On the basis of its survival advantage, docetaxel + prednisone is preferred treatment for most patients with cRPC SOGUG, Madrid

21. Mr Santos is treated with docetaxel every three weeks and prednisone • He has relief of pain and by the 3rd course of treatment he is able to stop taking morphine • His PSA declines steadily from 150 to 25 with the first 6 courses of treatment, but then begins to rise again to 70 after 8 courses • He develops numbness in his hands and feet. His docetaxel is stopped because of this progression and to avoid further side effects Should Mr Santos also receive a bisphosphonate? SOGUG, Madrid

22. Zoledronate8mg q3wks 643 pts with HRPC Zoledronate4mg q3wks Placebo q3wks • 8mg dose caused renal insufficiency and dropped • Less bone events with 4mg dose (44%) compared to placebo (33%, p=0.02) but no difference in QL • More low-grade toxicity with zoledronate SOGUG, Madrid

23. Use of Zoledronate with Chemotherapy • Zoledronate is a useful drug to decrease bone events in selected patients. • Some cases of osteonecrosis of the jaw • Annualzoledronate is sufficient to prevent osteopenia in patients on long-term anti-androgen therapy • I know of no evidence to support use of this expensive drug at 3-weekly intervals with chemotherapy • We are conducting a trial to evaluate duration of suppression of bone turnover after zoledronate SOGUG, Madrid

24. Might Mr Santos have greater benefit if treated with a molecular targeted agent in combination with docetaxel? SOGUG, Madrid

25. Increased emphasis on “time to event” endpoints as compared to “response” endpoints Early changes in PSA or pain to be ignored (unless overwhelming evidence of clinical progression) and treatment to be continued for at least 12 weeks No need to wait for anti-androgen withdrawal if there was no response to adding the anti-androgen Decreased emphasis on bone scans and rigorous requirements for defining progression by bone scan SOGUG, Madrid

26. R A N D O M I Z E Men with metastatic CRPC without prior chemotherapy (N=953) The ASCENT2 study: Docetaxel plus high-dose calcitriol versus docetaxel (plus prednisone) for patients with progressive CRPC (Scher et al, ASCO 2010) Docetaxel 36 mg/m² weekly 3/4+ 45 μg DN-101 + prednisone (ASCENT, n=477) Docetaxel 75 mg/m² q 3 wk+ prednisone (Control, n=476) • Study based on: • evidence that high dose calcitriol inhibits proliferation and stimulates apoptosis • a placebo-controlled phase II study suggesting that docetaxel with DN-101 increases survival compared to docetaxel alone SOGUG, Madrid

27. Results of ASCENT 2 Control Arm, N = 476 (137 died) ASCENT Arm N = 477 (174 died) Log-Rank Test P-value 0.002 Trial was stopped early after an interim analysis showed more deaths in the DN-101 arm SOGUG, Madrid

28. Docetaxel + prednisone +/- bevacizumab for CRPC (Kelly et al, ASCO, 2010) Primary endpoint = Survival (OS) Increase in OS and PFS are virtually identical to overview of 3 breast cancer trials – considered positive because primary endpoint was PFS SOGUG, Madrid

29. What can we learn from this negative experience? • Docetaxel is a difficult partner – as yet, no drug has augmented its benefit for men with CRPC • Even large randomized phase 2 trials may be poor predictors of results in phase III • The role of dexamethasone Some authors have suggested that the superior results of docetaxel compared to mitoxantrone in TAX327 and SWOG 99-16 might be due partly to dexamethasone In ASCENT2 the experimental arm received greater exposure to dexamethasone (24mg weekly 3/4) compared to the control arm (24mg q 3 weeks) but had poorer survival SOGUG, Madrid

30. Other trials are evaluating various molecular targeted agents with docetaxel Ongoing or completed phase III trials are evaluating: Aflibercept (VEGF-Trap) VENICE Lenolidamide (Thalidomide analogue) MAINSAIL Dasatanib (src/SFK inhibitor) Custirsen (OGX-011, anti-clusterin, pro-apoptotic) Endothelin A antagonists (atrasentan, zibotentan) Alpharadin (bone-seeking radioisotope) A trial of docetaxel + GVAX vaccine was negative SOGUG, Madrid

31. But to succeed we may need a more mechanistic approach to understanding causes of drug resistance in prostate cancer SOGUG, Madrid

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34. TUMOUR MICROENVIRONMENT Infiltrating cells (macrophages) Tumour cells Blood vessel - endothelial cells - fibroblasts Growth factors Chemokines High IFP ECM Modified from Minchinton and Tannock, Nat Rev Cancer 2006;6:583-92

35. TUMOUR MICROENVIRONMENT Decreasing nutritients and O2 Tumour cells Blood vessel Decreasing pH Modified from Minchinton and Tannock, Nat Rev Cancer. 2006;6:583-92 SOGUG, Madrid

36. TUMOUR MICROENVIRONMENT Decreasing nutritients and O2 Tumour cells Blood vessel Decreasing pH Decreasing cell proliferation Modified from Minchinton and Tannock, Nat Rev Cancer. 2006;6:583-92 SOGUG, Madrid

37. DRUG DISTRIBUTION Drug diffusion: molecular size, shape and solubility • Drug consumption: • drugs that bind avidly to DNA • basic drugs sequestered in acidic organelles • antibodies that bind to target antigens Drug delivery: concentration and time in blood high cell proliferation ECM ↑IFP Slide courtesy of Olivier Trédan DRUG low cell proliferation hypoxic cells SOGUG, Madrid

38. Liver metastases (arrows) from a xenograft in a nude mouse following injection of (fluorescent) mitoxantrone SOGUG, Madrid

39. We know that drug distribution is limiting for doxorubicin – probably also for docetaxel SOGUG, Madrid

40. Pantoprazole (PTP) improves the distribution of doxorubicin in tumours and augments activity of both doxorubicin and docetaxel Treated on days 0,7,14

41. On his next visit to clinic, Mr Scott is clearly failing, but his wife brings a newspaper clipping about a new type of immunotherapy for prostate cancerCouldn’t this treatment be used to save my husband’s life, she asks? Unfortunately, none of this is yet at a stage where it can help Mr Santos SOGUG, Madrid

42. Sipuleucel-T Estimated cost = $93,000

43. But no improvement in first line cytotoxic therapy! SOGUG, Madrid

44. Thanks to our international fellows who stimulate my ideas (but are not responsible for them).....and have done much of the work Especially: Dominik Berthold & BostjanSeruga