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Joaquim Bellmunt

Metastatic Prostate Cancer. Role of Chemotherapy. EORTC-GU Group. Joaquim Bellmunt. Hradec Králové, Czech Republic 9 October 2008. J.Bellmunt 09/2008. Hormone-refractory disease. Clinical Decision pathway (suspected AI).

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Joaquim Bellmunt

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  1. Metastatic Prostate Cancer. Role of Chemotherapy EORTC-GU Group Joaquim Bellmunt Hradec Králové, Czech Republic 9 October 2008 J.Bellmunt 09/2008

  2. Hormone-refractory disease.Clinical Decision pathway (suspected AI) • Measurable disease progression/PSA progression: 50% Increase confirmed in two serial determinations. Castrate levels of testosterone. CAB • Antiandrogen withdrawal*: sometimes PSA decrease with clinical benefit (FWS).Response after 4-6 weeks after AAW in 25% (10-30%). • Second hormonal manipulation: steroids,progestágens...Response < 6 months in 20%. • Start non-hormonal therapy**. *Scher HI JCOl 93;11:8:1566-72 **Raghavan D Semin Oncol88;15:371-89 J.Bellmunt 09/2008

  3. Options after AAW.Androgen-independent prostate cancer may respond to • Ketoconazole • Corticosteroids • Aminoglutethimide • Other anti-androgens • Withdrawal of anti-androgens • Oestrogens • Progestational agents • Chemotherapy • Novel agents J.Bellmunt 09/2008

  4. HRPC til June 2004: mitoxantrone/pred chemotherapy • Using QoL endpoints, two randomized studies showed an advantage for the combination of mitoxantrone + corticosteroid vs corticosteroids alone (FDA approved), -palliating pain w/o extending S- Tannock I, et al. J Clin Oncol 1996;14:1756–1764 Kantoff P, et al. J Clin Oncol 1999;17:2506–2513 J.Bellmunt 09/2008

  5. Taxane-based chemotherapy - ASCO, June 2004 - Two landmark phase III trials showed benefit with docetaxel-based chemotherapy in M1 HRPC Petrylak & Tannock, 7 Oct NEJM 351;1502-1520, 2004 J.Bellmunt 09/2008

  6. J.Bellmunt 09/2008

  7. Conclusion. SWOG trial (I) • Docetaxel–estramustine demonstrated over mitoxantrone–prednisone: • a 20% (95% CI, 3%–33%; p<0.01) decrease in the risk of death as estimated by the proportional hazard survival model • a 27% (95% CI, 14%–37%; p<0.0001) increase in progression-free survival • an increase in PSA response (50% vs 27%; p<0.0001) • an increase in objective response rate (17% vs 11%; p=0.15) Higher rates of toxicity were seen with docetaxel–estramustine yet there was no difference in toxic death rates or rate of study discontinuation J.Bellmunt 09/2008

  8. TAX327A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer HRPC Stratification: Pain level PPI ≥2 or AS ≥10 vs PPI <2 or AS <10 Karnofsky PS ≤70 vs ≥80 Taxotere 75mg/m2 Q3 + Prednisone 10mg orally given daily (up to 10 cyc) RANDOMIZE Taxotere 30mg/m2 Wkly (x5,t5)+ Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily Treatment duration in all 3 arms = 30 wks 804 Patients To Be Entered (Dec 2001 700 pts entered) Expanded to 1100 pts J.Bellmunt 09/2008

  9. Overall Survival 1.0 Docetaxel 3 wkly 0.9 Docetaxel wkly 0.8 Mitoxantrone 0.7 0.6 Probability of Surviving 0.5 Median survival Hazard (mos) ratio P-value D 3 wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4– – 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 Months J.Bellmunt 09/2008

  10. TAX 327:docetaxel 3 weekly: Conclusions • Safe and well tolerated • Significantly improves: • survival (18.9 vs 16.5 months) 24% reduction in the risk of death (95% CI, 0.62–0.94; p=0.009) • PSA decline: 45% vs 32%, p=0.0005 • pain response: 35% vs 22%, p=0.01 • quality of life J.Bellmunt 09/2008

  11. Tax 327 vs SWOG 9916How these results match and mean? Both trials are confirmatory, of a new standard of care.This 20–24% reduction in the risk of death may be even diluted by crossover. * Do we continue to use estramustine?->NO Petrylak DP, et al. Nejm 2004; Eisenberger MA, et al. Nejm 2004 J.Bellmunt 09/2008

  12. Global conclusions coming from the two trials. • Three-weekly docetaxel with or without estramustine demonstrated over mitoxantrone + prednisone: • a 20–24% reduction in the risk of death • An increase in progression-free survival • an increase in PSA response rate • an increase in objective response rate • Overall, therapy was well tolerated (Δ QoL) J.Bellmunt 09/2008

  13. ASCO Prostate 2007Berthold et al [Abstract 5005] • At the time of the initial report 557 of 1006 participants in the trial had died. • Report an updated survival analysis of the TAX 327 study. • Survival of all patients and subgroups according to age, PSA baseline, Karnofsky PS and QoL will be shown • By January 2007, 276 additional deaths were recorded resulting in a total of 883 deaths J.Bellmunt 09/2008

  14. J.Bellmunt 09/2008

  15. Comparison of initial and updated analysis * 95% confidence interval indicated Berthold et al. JCO in press J.Bellmunt 09/2008

  16. Phase III study Docetaxel produced a more favourable survival hazard ratio than mitoxantrone: Symptomatic Asymptomatic TAX 327: improved survival in asymptomatic and symptomatic patients with mHRPC Hazard ratio in favour of: Docetaxel 3qw Mitoxantrone ITT Age <65 Age ≥65 Age ≥75 Pain no Pain yes KPS ≥80 KPS ≤70 1.4 0.2 0.4 0.6 0.8 1 1.2 J.Bellmunt 09/2008

  17. What is the optimal management for metastatic HRPC patients? • If both derive benefit…: Do I treat asymptomatic patients or wait for symptomatic progression? • Symptomatic response is less common than PSA response. Higher percent of pain-free patients tolerate 10 cycles than those with pain J.Bellmunt 09/2008

  18. Survival by Pain J.Bellmunt 09/2008

  19. Survival by PSA baseline J.Bellmunt 09/2008

  20. In TAX 327 patients aged >75 years experienced the same benefit with docetaxel as younger patients (Tannock et al, 2004) There is an increased risk of neutropenia in elderly patients receiving docetaxel Greater cautioncloser monitoring of blood counts, and, when appropriate, growth factor support Age alone should not discount a patient with metastatic AIPC from receiving chemotherapy Hazard ratio in favour of: 3qw Docetaxel Mitox ITT Age <65 Age ≥65 Age ≥75 Pain no Pain yes KPS ≥80 KPS ≤70 1.4 0.2 0.4 0.6 0.8 1 1.2 Elderly - Conclusions J.Bellmunt 09/2008

  21. Survival by Age J.Bellmunt 09/2008

  22. TAX 327: A multivariate prognostic model incorporating PSA kinetics • 1006 men with HRPC • 686 men 3 or more baseline PSA measurements each separated by at least 1 week (univariate analysis) • 635 men PSA kinetics + all other data available (multivariate analysis) • Median PSA 114 mg/ml (n=1006) • Median PSA-DT 55 days (n= 686) Amstrong et al, Clin Canc Res, in press J.Bellmunt 09/2008

  23. TAX 327: A multivariate prognostic model incorporating PSA kineticsin HRPCAJ Armstrong 222 2x2 table showing HR for death according to baseline PSA and PSADT J.Bellmunt 09/2008

  24. TAX 327: A multivariate prognostic model incorporating PSA kinetics in HRPCAJ Armstrong 222 J.Bellmunt 09/2008

  25. HRPC: 2007 paradigm HRPC • Chemotherapy for Hormone Refractory Prostate Cancer • Robust data on “Why” • New data on “When” Further hormonal manipulations - Some cases of asymptomatic PSA progression • all symptomatic cases • all cases with bone scan progression • by PSA and PSA-DT considerations docetaxel J.Bellmunt 09/2008

  26. What does the future hold?How to build on these results ? 1.- Move to earlier stages: • (AIPC) asymptomatic PSA rise without metastases or symptoms • Second-line therapy: unmet medical need • (ADPC) Neoadjuvant, Adjuvant,PSA progresion/high risk 2.- Build on docetaxel (+/-) targeting other mechanisms of HR with novel agents J.Bellmunt 09/2008

  27. Xrt,RP Currently used Trials ongoing Move to earlier stages: Expanding the role of chemotherapy in the treatment of prostate cancer Adjuvant HRPC, non-metastatic (E1899 D vs 2nd KH) HRPC, metastatic, first-line PSA relapse, RTOG0014 (CtHT vs HT), MSKCC Neoadjuvant Second-line options Prostate cancer treatment continuum Hormonsensitive Hormonrefractory Endpoint selection: survival, time to progression vs palliation J.Bellmunt 09/2008

  28. Xrt,RP Currently used Trials ongoing Move to earlier stages: Expanding the role of chemotherapy in the treatment of prostate cancer Adjuvant HRPC, non-metastatic (E1899 D vs 2nd KH) HRPC, metastatic, first-line PSA relapse, RTOG0014 (CtHT vs HT), MSKCC Neoadjuvant Second-line options Prostate cancer treatment continuum Hormonsensitive Hormonrefractory Endpoint selection: survival, time to progression vs palliation J.Bellmunt 09/2008

  29. cT1-T2b  RRP pGS 8 or pT3b,pT4 N1or pG7+EPE + Margin(+ve) + Undetectable PSA Primary Endpoint: 90% power to detect 30%  OS (10y 13y) n=1360, closed due to 3 cases of leukaemia SWOG-9921/CALGB: Post-prostatectomy adjuvant therapy CAD x 2y Mitoxantrone–prednisone x 6 + CAD x 2 years J.Bellmunt 09/2008

  30. RTOG 9902: Adjuvant Hormonal Therapy/RT vs Hormonal Therapy/RT + Chemo R A N D O M I Z E Hormonal therapy x 2 yrs + Rt High risk Primary endpoint: Overall survival (n=1440) Hormonal therapy x 2 yrs + Rt Chemotherapy (TEE) • Accual held • Excess thromboembolism • 397 of planned 1440 patients were accrued between 1/2000 to 10/2004 • Toxicity likely due to estramustine led to early closure of RTOG 9902 J.Bellmunt 09/2008

  31. RTOG 0014-androgen-dependent prostate cancer: PSA relapse after local therapy Chemo-hormonal therapy x 4 cycles then hormonal therapy alone • T/E q 3 • T/E q w • P/E q w • KAVE • New active regimens R A N D O M I S E PSA relapse (n=1050) Primary endpoint: Overall survival Hormonal therapy until failure Closed Feb 2005 due to tox J.Bellmunt 09/2008

  32. ECOG 1899: AIPC without metastases Docetaxel + estramustine R A N D O M I S E AIPC no mets Primary endpoint: Objective PFS (n=590) Ketoconazole+ hydrocortisone Closed Dec 2004 (no longer recruitment. Lack of accrual) J.Bellmunt 09/2008

  33. Sanofi-Aventis XRP6976J/3501 Study GlobalP.I. Mario Eisenberger P R O G R E S S I O N PROGRESSION R A N D O M I Z E Leuprolide 18 months Deferred arm Observation Leuprolide 18 months + Docetaxel 75 q3w x 6 cycles RP Immediate arm P R O G R E S S I O N Leuprolide 18 months Leuprolide 18 months + Docetaxel 75 q3w x 6 cycles - Primary endpoint:PFS - N=84/1696 (high-risk localized disease, ) - Stratification: Age (> 65 vs < 65) / Predicted prob. of 5-y FFP / Country J.Bellmunt 09/2008

  34. What does the future hold?How to build on these results ? 1.- Move to earlier stages: • (AIPC) asymptomatic PSA rise without metastases or symptoms • Second-line therapy: unmet medical need • (ADPC) Neoadjuvant, Adjuvant,PSA progresion/high risk 2.- Build on docetaxel (+/-) targeting other mechanisms of HR with novel agents J.Bellmunt 09/2008

  35. Growth Factors and Receptors Suramin Liarozole SU 101 Herceptin, 2C4 Anti-EGF receptor Mabs or TKIs (C225,Iressa) Differentiating agents Retinoids, Cox2 inh Vit D analogs (Calcitriol) Butyrates, PPARg Invasion and metasta (sis Marimastat AG3340 BAY 9566 Antiangiogenesis TNP-470 Thalidomide, Linomide Tecogalan Angiostatin, endostatin Sorafenib, Bevacizumab Apoptosis and the cell Cycle G3139 (antisense bcl2) mTor inhibitors Proteosome inhibitor Flavopiridol SAHA Thapsigargin Taxanes Monoterpenes (POH) Novel Targets for Prostate Cancer Therapy J.Bellmunt 09/2008

  36. Bcl-2 Antisense Enables Cell Death J.Bellmunt 09/2008

  37. Docetaxel and Oblimersen Sodiumvs Docetaxelalone in HRPC EORTC 30021 Randomized Trial RANDOMIZE Oblimersen 7 mg/kg/day D1-7 Docetaxel 75 mg/m2 D5 q 3 w vs Docetaxel 75mg/m2 D1 q 3 w Stratification: Institution, M0 vs M1 (measurable disease), prior estracyt, prior bisphosphonates 1st line J.Bellmunt 09/2008

  38. CALGB 9040: Phase III study of Docetaxel+/- Bevacizumab in HRPC (n=1,020 pts) RANDOMIZE Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg po daily Bevacizumab 15 mg/Kg Q3 wks Stratification Halabi nomogram COMPLETED Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg po daily Placebo CALGB, ECOG, NCIC Primary end point is PFS J.Bellmunt 09/2008

  39. EFC6546: VENICE Study Multicenter, double blind, randomized study R A N D O M I Z E Aflibercept 6mg/kg IV over 1hr, day 1 TXT 75mg/m² , day 1 Prednisone 10mg/day, continuously q 3 weeks m HRPC Stratification factor: ECOG PS (0,1 vs 2) 1190 pts/ 200 sites Placebo, day 1 TXT 75mg/m² , day 1 Prednisone 10mg/day, continuously q 3 weeks • 3 years accrual expected. • 1st: Overall Survival: 20% risk reduction of death. From 19 to 24 months. • Interim analysis at 647 death (862 events required overall) • 2nd: Pain, PSA, QoL, DPFS • Treatment until PD, consent withdrawn, or unacceptable toxicity. • Follow up until death J.Bellmunt 09/2008

  40. Phase III Study of Docetaxel + Placebo vs Docetaxel + Atrasentan in HRPC (SWOG 0421) • Eligibility: • Progressive mets HRPC • ECOG PS <2, selected 3 • Bone mets • Stratification: • Type of prog • Pain • Extra-skeletal disease • Bisphoshonates RANDOMIZE Docetaxel 75 mg/m2 Q3 wks Prednisone 10mg + Atrasentan 10 mg Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg + Placebo Primary endpoint is PFS J.Bellmunt 09/2008

  41. ASCENT study: Randomized study of Docetaxel +/-high-dose Calcitriol in HRPC (n=250 pts) RANDOMIZE Stratification Pain level PPI ≥ 2 or AS ≥ 10 vs. PPI < 2 or AS < 10 Karnofsky ≤ 70 vs. ≥ 80 Docetaxel 36 mg/m2 weekly 3 of 4 wks + DN-101 45 mg po daily Docetaxel 36 mg/m2 weekly 3 of 4 wks + Placebo Primary end point: PSA response ASCENT : Androgen-independent prostate cancer Study of Calcitriol Enhancing Taxotere J.Bellmunt 09/2008

  42. 1.00 DN-101 Placebo 0.75 Probability of Survival 0.50 0.25 0.00 0 12 24 36 48 60 72 84 Weeks ASCENT Study: Survival 23.5 mos Median Survival DN-101 23.5 mos (estimated) Placebo 16.4 mos (observed) 16.4 mos Hazard Ratio (95% CI) Unadjusted 0.70 (0.48 – 1.028), P = 0.070 Multivariate 0.67 (0.45 – 0.97), P = 0.035 Beer T, ASCO 2005 J.Bellmunt 09/2008

  43. Satraplatin and Prednisone Against Refractory Cancer SPARC Trial (n=912) R A N D O M I Z E Satraplatin 80 mg/m2/d x 5 po q5wks + Prednisone 5 mg x 2/daily Q 35 days Progressive HRPC 1 prior chemo Placebo + Prednisone 5 mg x 2/daily Q 35 days 2:1 1° Endpoint: 30% increase in TTP with  85% power 2° Endpoints: OS, time to pain progression J.Bellmunt 09/2008

  44. Progression Free Survival 100 90 S 80 P Median (wks) 11.1 9.7 70 60 Survival Probability (%) HR: 0.67 (95% CI: 0.57 - 0.77) Satraplatin + Prednisone 50 Log-Rank P = 0.0000003 40 30 Placebo + Prednisone 20 10 0 0 10 20 30 40 50 60 70 80 90 Weeks J.Bellmunt 09/2008

  45. Initial expectations Satraplatin is a valid option for second line therapy. New studies with other agents in combination can improve these results NON FDA APPROVAL J.Bellmunt 09/2008

  46. CHARACTERISTICS of CNTO 328 • Murine McAb • Chimeric • Strong Inhibitor of IL-6 • Half-life: 14-17 days Murine Human Ig1K J.Bellmunt 09/2008

  47. Part 1: Primary endpoint: Safety Study Design (Open-Label) 9 PtsHRPC, Prior docetaxel treatment Mitoxantrone + prednisone + CNTO 328 Part 2: Primary endpoint: PFS Arm A - Mitoxantrone + prednisone + CNTO 328 (n=67) 134 PtsHRPC, Prior docetaxel treatment CLOSED due to TOXICITY R 1:1 Arm B - Mitoxantrone + prednisone (n=67) • Mitoxantrone: 12 mg/m2 over a 30 minute infusion every 3 weeks • CNTO 328: 6 mg/kg over a 2 hour IV infusion every 2 weeks • Prednisone: 5 mg bid J.Bellmunt 09/2008

  48. Rediscovering the Androgen Receptor as a New Target • ABIRATERONE • MDV 3100 • Others J.Bellmunt 09/2008

  49. N MW = 391.55 RO RO = AcO 3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene Abiraterone Acetate (CB7630) • Oral irreversible inhibitor of CYP17 (P450c17) • 17α –hydroxylase • C17,20-lyase • Inhibits testosterone production in testis, adrenal glands and prostate J.Bellmunt 09/2008

  50. The androgen receptor is a critical target in castration-resistant prostate cancer Hypotheses: • Castration-resistant prostate cancer (CRPC) frequently remains driven by a ligand-activated androgen receptor (AR). • CRPC tissues exhibit substantial residual androgen levels despite GnRH therapy, suggesting intracrine or paracrine signaling • CYP17 inhibition leads to increased ACTH and C-21 steroid levels that might activate a promiscuous AR and drive CRPC growth. Attard et al, BJC 2006 J.Bellmunt 09/2008

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