High-risk prostate cancer: Integrating systemic treatment Karim Fizazi, MD, PhD Department of Medicine Institut Gustave Ro...
What to do? You should have a prostatectomy ! No  ! Radiation therapy ! Yes, but they also talk about hormones A patient w...
Systemic treatments  for prostate cancer <ul><li>Endocrine therapy </li></ul><ul><ul><li>Androgen Deprivation Therapy (=ca...
Androgen deprivation (ADT)  in high risk prostate cancer? <ul><li>Trials testing prolonged ADT: </li></ul><ul><ul><li>EORT...
Bolla M, Lancet 2002, 360: 103-108 EORTC trial 22863 PFS OS <ul><li>415 patients, mostly T3 (82%) </li></ul><ul><li>RT= 70...
RTOG 85-31 trial <ul><li>T3 or N+ </li></ul><ul><li>n=977 </li></ul><ul><li>10-y OS: 47% vs 38% (p= 0.004) </li></ul>Pilep...
Pilepitch, Int J Radiat Oncol Biol Phys 2005, 61: 1285-90
OS p= 0.02 Prostate cancer  specific OS p= 0.001 PFS p< 0.001 Messing et al.; N Engl J Med 1999, 341: 1781-1788 ADT in pN+...
Immediate ADT Improves OS  in pN+ patients Messing EM, et al.  New Engl J Med . 1999;341(24):1781-1788. Patients (n)   Imm...
Incidence of metastases RTOG 85-31: pN+ patients Overall survival (p= 0.03) All pN+ pN+, no RP n = 173 R Immediate LHRHa S...
Short-term or Long-term ADT combined with radiotherapy?
RTOG 8610: Phase III trial of  short term ADT + RT Overall survival (p=0.12) Disease-specific mortality (<0.01) N= 456 (me...
Trans-Taman ROG 96-01:  S hort term ADT + RT vs RT n= 818 T2b-T4 (all Gleason, all PSA)  85% high risk, RT: 66 Gy Median F...
D’Amico Phase III trial of  short term ADT + RT vs RT Overall survival (88% vs 78% at 5 y) D'Amico, A. V. et al. JAMA 2004...
RTOG 94-08 Schema S T R A T I F Y <ul><li>PSA </li></ul><ul><li><4 </li></ul><ul><li>4-20 </li></ul><ul><li>Grade  (Differ...
RTOG 94-08: Overall Survival 62% 57%
Duration of ADT  in high risk prostate cancer? <ul><li>Most positive trials with a benefit in OS used prolonged ADT (   2...
RTOG 92-02 trial  Hanks et al., J Clin Oncol 2003, 21: 3972-78 OS for Gleason 8-10 <ul><li>T2-T4, PSA < 150 </li></ul><ul>...
RTOG 92-02: 10 year update Cancer-specific survival (p=0.004) Distant metastases failure (p<0.0001) Biochemichal PFS (p<0....
Which duration for  endocrine therapy? <ul><li>Phase III EORTC 22961 (n=1117 T3): </li></ul><ul><ul><li>RT + H  6 months <...
Randomized EORTC Phase III Trial 22961  Locally Advanced Prostate Cancer N = 970  No further ADT ADT for 2.5 years RT, ext...
Long-Term ADT  prolongs clinical PFS Long-term ADT (n = 487) Short-term ADT (n = 483) Time, years 0 1 2 3 4 5 6 7 8 9 0 10...
Long-Term ADT  prolongs OS Time, years 0 1 2 3 4 5 6 7 8 9 0 10 20 30 40 50 60 70 80 90 100 Long-term ADT (n = 487) Short-...
Endocrine therapy:  Is there an alternative to ADT?
Bicalutamide instead of ADT? Trial 24 Europe / RoW (N=3603) Trial 25 Scandinavia (N=1218) Trial 23 N. America (N=3292) Sta...
Bicalutamide instead of ADT in association with radiotherapy?   0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1 2 3 4 5 6 7 ...
Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node  dissection? High risk localized prostate ca...
Tannock IF:  NEJM 351:1502-12, 2004 Fizazi K: Lancet Oncol 2007; 8: 994-1000 <ul><li>Docetaxel: established standard </li>...
ADJUVANT Docetaxel après prostatectomie
Sanofi-Aventis XRP6976J/3501 Study P.I. Mario Eisenberger - Primary endpoint:   PFS   - N=  228/ 1696   (high-risk localiz...
Phase III trials of Docetaxel  in Localized prostate cancer Study name PI Local treatment # patients ( enrolled / planned)...
High risk prostate cancer GETUG 12 trial ADT (3 years) + RXT Docetaxel  +  Estramustine (4 cycles) RANDOMI ZE Primary endp...
Docetaxel Phase III trial in localized CaP PSA response (GETUG 12 trial) PSA 3 months ≤ 0.2 ng/mL: 34% vs 15% p< 0.0001 Fi...
Cooperative   VA Study # 553  (D.Lin)   Docetaxel 75 q3w +  prednisone x 6 cycles Observation RANDOMI ZE PROGRESSION <ul><...
SPCG-12   AdPro PI:  G. Algren  (Sweden) N =  361  / 396 Primary Endpoint: PSA Progression RANDOMI ZE Docetaxel  x 6 cycle...
ADJUVANT Docetaxel après Radiothérapie
RTOG 0521 study  (H.M.Sandler) <ul><li>-  Primary endpoint:   OS </li></ul><ul><li>N=  536/ 600 planned  pts </li></ul><ul...
SPCG-13  AdRad  PI: PL. Kellokumpu-Lehtinen (Finland) N =  108  / 924 Endpoint: PSA progression rate RANDOMI ZE Docetaxel ...
NEO-ADJUVANT Docetaxel avant Prostatectomie
High risk:  Predicted bPFS<60 (Kattan nomogram) PSA<100 RANDOMI ZE Docetaxel 75  x 6 cycles  + AS (6 months) No medical tr...
NEO-ADJUVANT Docetaxel avant Radiothérapie
High risk: any of: - Gleason > 8 - T3-T4 - PSA>20 - pN+ LN dissection: all pts RANDOMI ZE Docetaxel 70  q3w  + Estramustin...
GETUG 12 trial: Population <ul><li>Gleason score    8  42% </li></ul><ul><li>T3  63% </li></ul><ul><li>PSA > 20 ng/mL  61...
<ul><li>Inclusion  </li></ul><ul><li>Intermediate-high risks: </li></ul><ul><li>T1b, T1c, T2a   </li></ul><ul><li>- Gleaso...
Inclusion  high risk: - Gleason ≥ 8 - T ≥ 3a - PSA>20 ng/mL RANDOMI ZE Docetaxel   x 4 cycles  + AS (3 years) AS (3 years)...
D’Amico Study Dana-Farber <ul><li>- Primary endpoint:   OS </li></ul><ul><li>- N=   350  planned  pts   </li></ul><ul><li>...
Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Bone targeting agents? High risk localized prostate cancer
Zoledronic Acid- Preventing Bone Metastasis in the Adjuvant Setting
Zoledronic Acid Can Inhibit this Process at Several Key Steps Adapted from Mundy GR, et al.  Nature Reviews Cancer . 2002;...
Overview of Other Antitumor / Prevention Trials with Zoledronic Acid <ul><li>Targeted total accrual > 20,000 MM, breast, p...
Prostate Cancer:  ZEUS   Zoledronic acid 4 mg q 3 months No Zoledronic acid*  <ul><li>1,433   patients </li></ul><ul><li>P...
Prostate Cancer:  RADAR   Key endpoints: Primary :  PSA Progression-free survival (at 5 years) Secondary : Overall surviva...
A multi-arm trial: STAMPEDE
Prostate Cancer:  STAMPEDE   Key endpoints: Primary : Failure free survival  Secondary : QOL, cost effectiveness, toxicity...
STAMPEDE Study Systemic Therapy in Advancing or Metastatic   Prostate cancer: Evaluation of Drug Efficacy (PI: N James) R ...
Conclusion: Systemic treatment  in high-risk localized prostate cancer <ul><li>Endocrine therapy: </li></ul><ul><ul><li>St...
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ECCLU 2011 - K. Fizazi - Prostate cancer: Locally advanced disease and patient advocacy - Integrating systemic therapy into high-risk disease

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  • RTOG 9408 was a randomized Phase III trial designed to evaluate if the addition of 4 months of Androgen Deprivation Therapy to standard external beam radiation would result in an improvement in overall survival. Patients studied had localized (T1b-T2b) adenocarcinoma of the prostate and a PSA of &lt; 20. Patients were stratified by PSA, by Grade and by whether the nodes were negative by clinical or surgical evaluation. The study asked for re-biopsies of the prostate at two years after treatment. (45 seconds)
  • Here is the overall survival curve demonstrating the superiority of the hormone + RT arm. (10 seconds)
  • The veterans affairs study is designed to prospectively evaluate the efficacy of early adjuvant chemotherapy using docetaxel and prednisone added to the standard of care for patients who are potentially cured by radical prostatectomy but who are at high risk of relapse. Patients are stratified for PSA, GS, tumour stage and the presence of positive margins. Almost 700 patients are planned to be enrolled. Chemotherapy will be given for 4 months. Patients will be followed for a minimum of 1 and a maximum of 5 years. JUST LAUNCHED. INVESTIGATORS’MEETING APRIL. FIRST PATIENT EXPECTED Q3 2006.
  • TAB, AA will be discontinued at the end of RT. LHRHA will continue for 24 months from initiation. RT will begin 8 weeks after the initiation of HT. STUDY OPENED WITH 8 PATIENTS ENROLLED.
  • 7 38 Radiation + 6 months of HT is one standard way of treating high risk prostate cancer. In the trial we want to see wether or not adding TXT will make the treatment more effective.
  • Metastasis to bone occurs via a multi-step process, and inhibition of any of these steps could prevent metastasis to bone 1 The primary malignant neoplasm promotes new blood vessel formation (angiogenesis) Cancer cells must then invade the blood vessels, wherein they form multi-celled aggregates Aggregates of tumor cells form emboli that lodge in capillary beds in bone Cancer cells can adhere to vascular epithelial cells to escape the blood vessels and must extravasate through the extracellular matrices to enter the bone microenvironment As cancer cells enter the bone, they are exposed to factors in the bone microenvironment, such as growth factors released from the bone matrix during osteolysis, which may promote tumor growth Zoledronic acid can inhibit multiple steps in the metastatic process and has demonstrated direct and indirect antitumor activities in preclinical assays 2 Reference Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer . 2002;2(8):584-593. Lipton A. Emerging role of bisphosphonates in the clinic-Antitumor activity and prevention of metastasis to bone. Cancer Treat Rev . 2008. May 15. [Epub ahead of print]
  • Overview of Zoledronic acid in other antitumor and prevention trials ABCSG-12 Stage I, II breast cancer patients in a randomized, open-label, multi-center, active-control, parallel-assignment, 4-arm, efficacy study of DFS and RFS at 5 years and OS at 3 years (N = 1,803) AZURE Stage II, III breast cancer patients in a randomized, open-label, multi-center, active-control, parallel-group trial of DFS, time to bone metastases, OS and SREs (N = 3,360) SUCCESS Stage I, II, III breast cancer patients in a randomized, open-label, multi-center, 2x2 factorial design, controlled study of DFS, OS, metastases-free survival, and safety (N = 3754) SWOG 0307 Stage I, II, III breast cancer patients in a randomized, active-control, multi-center study of DFS, OS, time to progression, safety, and compliance (N = 4,500). Bone markers and dental substudies NATAN Stage II, III refractory breast cancer patients in a randomized, open-label, multi-center, active-control, parallel-assignment, safety/efficacy study of EFS, OS, bone metastases-free survival, safety, compliance and breast tumor response (N = 654) ZEUS Prostate cancer patients with no distant metastases in a randomized, open-label, multi-center study of proportion of patients with bone metastases at 2 years, time to bone metastases, OS, PSA doubling time, bone markers, and BMD (N = 1,434) RADAR Stage T2b-4 prostate adenocarcinoma patients in a randomized, open-label, multi-center, active-control, factorial-assignment, safety/efficacy study of PSA-RRFS and OS (N = 1,071) 2419 Study Stage III NSCLC patients in a randomized, open-label, active control, parallel assignment, safety/efficacy study of time to occurrence of bone metastases, rate of bone metastases at 6, 12, 18, and 24 months, TTP, rate and risk of SREs, time to first SRE, OS at 12 and 24 months, BSP expression in primary tumor (substudy) of ZOL vs no ZOL (N = 446) STAMPEDE A multi-arm cooperative trial in patients undergoing androgen-deprivation therapy for high-risk prostate cancer; multiple endpoints throughout the study; trial design is subject to change
  • ECCLU 2011 - K. Fizazi - Prostate cancer: Locally advanced disease and patient advocacy - Integrating systemic therapy into high-risk disease

    1. 1. High-risk prostate cancer: Integrating systemic treatment Karim Fizazi, MD, PhD Department of Medicine Institut Gustave Roussy Villejuif, France
    2. 2. What to do? You should have a prostatectomy ! No ! Radiation therapy ! Yes, but they also talk about hormones A patient with high-risk prostate cancer
    3. 3. Systemic treatments for prostate cancer <ul><li>Endocrine therapy </li></ul><ul><ul><li>Androgen Deprivation Therapy (=castration) </li></ul></ul><ul><ul><li>Androgen Receptor inhibitors </li></ul></ul><ul><li>Chemotherapy </li></ul><ul><ul><li>Docetaxel </li></ul></ul><ul><ul><li>Others </li></ul></ul><ul><li>Bone-targeting agents </li></ul><ul><ul><li>Zoledronic acid </li></ul></ul><ul><ul><li>Denosumab </li></ul></ul><ul><li>Others? </li></ul>
    4. 4. Androgen deprivation (ADT) in high risk prostate cancer? <ul><li>Trials testing prolonged ADT: </li></ul><ul><ul><li>EORTC (Bolla 2002) </li></ul></ul><ul><ul><li>RTOG 85-31 (Pilepitch 2005) </li></ul></ul><ul><ul><li>Messing trial in pN+ (Messing 1999) </li></ul></ul><ul><li>Trials testing short-term ADT </li></ul><ul><ul><li>RTOG 86-10 (Mack Roach 2008) </li></ul></ul><ul><ul><li>D’Amico 2004 </li></ul></ul><ul><ul><li>Denham 2005 </li></ul></ul><ul><li>Trials testing ADT duration: </li></ul><ul><ul><li>EORTC (Bolla) </li></ul></ul><ul><ul><li>RTOG 92-2 (Hanks 2003) </li></ul></ul>
    5. 5. Bolla M, Lancet 2002, 360: 103-108 EORTC trial 22863 PFS OS <ul><li>415 patients, mostly T3 (82%) </li></ul><ul><li>RT= 70 Gy </li></ul><ul><li>5-year OS: 78% vs 62% </li></ul>RT + ADT 3 years RT R
    6. 6. RTOG 85-31 trial <ul><li>T3 or N+ </li></ul><ul><li>n=977 </li></ul><ul><li>10-y OS: 47% vs 38% (p= 0.004) </li></ul>Pilepich, Int J Radiat Oncol Biol Phys 2005, 61: 1285-90 RT + ADT life-long RT R
    7. 7. Pilepitch, Int J Radiat Oncol Biol Phys 2005, 61: 1285-90
    8. 8. OS p= 0.02 Prostate cancer specific OS p= 0.001 PFS p< 0.001 Messing et al.; N Engl J Med 1999, 341: 1781-1788 ADT in pN+ Prostate cancer? <ul><li>n= 98 (Prostatectomy pN+) </li></ul><ul><ul><ul><li>LHRHa (life-long) </li></ul></ul></ul><ul><li>R </li></ul><ul><ul><ul><li>LHRHa if occurrence of metastases </li></ul></ul></ul><ul><li>OS: 72% vs 49% (p= 0.025) </li></ul>
    9. 9. Immediate ADT Improves OS in pN+ patients Messing EM, et al. New Engl J Med . 1999;341(24):1781-1788. Patients (n) Immediate therapy 47 47 40 8 Observation 51 49 37 5 P = .02 0 0.2 0.4 0.6 0.8 1.0 0 20 40 60 80 100 120 Months Observation Immediate therapy
    10. 10. Incidence of metastases RTOG 85-31: pN+ patients Overall survival (p= 0.03) All pN+ pN+, no RP n = 173 R Immediate LHRHa Surveillance Lawton CA, J Clin Oncol 2005, 23: 800-807
    11. 11. Short-term or Long-term ADT combined with radiotherapy?
    12. 12. RTOG 8610: Phase III trial of short term ADT + RT Overall survival (p=0.12) Disease-specific mortality (<0.01) N= 456 (median age: 70 y) 1987-1992 Bulky (5 x 5 cm) tumors Mack Roach III et al., J Clin Oncol 2008; 26: 585-91 4 month ADT + RT RT R
    13. 13. Trans-Taman ROG 96-01: S hort term ADT + RT vs RT n= 818 T2b-T4 (all Gleason, all PSA) 85% high risk, RT: 66 Gy Median FU: 5.9 y 6 month ADT better Distant failure (p=0.047) Cancer-specific survival (p=0.04) Denham JW, Lancet Oncol 2005; 6: 841-50 RT RT + 3 months CAB RT + 6 months CAB R
    14. 14. D’Amico Phase III trial of short term ADT + RT vs RT Overall survival (88% vs 78% at 5 y) D'Amico, A. V. et al. JAMA 2004;292:821-827. N= 206 (1995-2001) PSA>10 (<40) or Gleason ≥ 7 or T3 (MRI) Conformal RT (70 Gy) RT RT + 6 month ADT R
    15. 15. RTOG 94-08 Schema S T R A T I F Y <ul><li>PSA </li></ul><ul><li><4 </li></ul><ul><li>4-20 </li></ul><ul><li>Grade (Differentiation) </li></ul><ul><li>Well </li></ul><ul><li>Moderate </li></ul><ul><li>Poor </li></ul><ul><li>Nodal Status </li></ul><ul><li>N0 (surgical) </li></ul><ul><li>NX </li></ul>4-month ADT + RT (ADT 2 months before and during RT 66.6 Gy) RT (66.6 Gy) R n= 2028 patients with T1-T2 CaP
    16. 16. RTOG 94-08: Overall Survival 62% 57%
    17. 17. Duration of ADT in high risk prostate cancer? <ul><li>Most positive trials with a benefit in OS used prolonged ADT (  2 years) </li></ul><ul><li>2 positive trials on OS with short ADT (D’Amico 2004, RTOG 94-08) </li></ul><ul><li>Phase III trials comparing ADT duration: </li></ul><ul><ul><li>RTOG 92-02 ( 4 vs 24 months) </li></ul></ul><ul><ul><li>Canadian trial: 3 vs 8 m (Crook J, 2004), n=378 </li></ul></ul><ul><ul><li>EORTC trial ( 6 vs 36 months) </li></ul></ul>
    18. 18. RTOG 92-02 trial Hanks et al., J Clin Oncol 2003, 21: 3972-78 OS for Gleason 8-10 <ul><li>T2-T4, PSA < 150 </li></ul><ul><li>n = 1554 </li></ul><ul><li>Goserelin started before RT </li></ul><ul><li>RT 65-70 Gy </li></ul><ul><li>Randomisation: </li></ul><ul><ul><li>Goserelin 4 versus 24 months </li></ul></ul><ul><ul><li>RT field (prostate vs pelvis) </li></ul></ul>
    19. 19. RTOG 92-02: 10 year update Cancer-specific survival (p=0.004) Distant metastases failure (p<0.0001) Biochemichal PFS (p<0.0001) OS (p=NS) (p=0.006 if Gleason ≥8) Horwitz EM, J Clin Oncol 2008; 26: 2497-2504
    20. 20. Which duration for endocrine therapy? <ul><li>Phase III EORTC 22961 (n=1117 T3): </li></ul><ul><ul><li>RT + H 6 months </li></ul></ul><ul><ul><li>RT + H 3 years </li></ul></ul><ul><li>Results: </li></ul><ul><ul><li>bPFS: 59% vs 78%; HR: 2.29; p< 0.0001 </li></ul></ul><ul><ul><li>cPFS: 69% vs 82%; HR: 1.93; p< 0.0001 </li></ul></ul><ul><ul><li>OS: 80% vs 85%; HR: 1.43; p= 0.02 </li></ul></ul>Bolla, ASCO 2007, Abstr 5014 Standard = 3 years
    21. 21. Randomized EORTC Phase III Trial 22961 Locally Advanced Prostate Cancer N = 970 No further ADT ADT for 2.5 years RT, external beam radiation therapy; ADT, androgen deprivation therapy; PFS, progression-free survival; OS, overall survival. Bolla M et al. JCO , 2007. 25(18S):5014; www.clinicaltrials.gov RT + 6 mo ADT Patients assessed for PFS and OS No disease progression “ Short-term ADT” “ Long-term ADT ”
    22. 22. Long-Term ADT prolongs clinical PFS Long-term ADT (n = 487) Short-term ADT (n = 483) Time, years 0 1 2 3 4 5 6 7 8 9 0 10 20 30 40 50 60 70 80 90 100 HR= 1.93, P <.0001 Patients alive, % Bolla, ASCO 2007, Abstr 5014
    23. 23. Long-Term ADT prolongs OS Time, years 0 1 2 3 4 5 6 7 8 9 0 10 20 30 40 50 60 70 80 90 100 Long-term ADT (n = 487) Short-term ADT (n = 483) P = .019 (H0: Long ADT superior) HR: 1.43 P = .6543 (H0: Short ADT non-inferior) Patients alive, % Bolla, ASCO 2007, Abstr 5014
    24. 24. Endocrine therapy: Is there an alternative to ADT?
    25. 25. Bicalutamide instead of ADT? Trial 24 Europe / RoW (N=3603) Trial 25 Scandinavia (N=1218) Trial 23 N. America (N=3292) Standard care (radiotherapy, radical prostatectomy or watchful waiting) initiated by investigator as per local practice Bicalutamide EPC Programme (N=8113) 1:1 randomisation to bicalutamide 150 mg or standard care alone Follow-up for overall survival and time to objective disease progression
    26. 26. Bicalutamide instead of ADT in association with radiotherapy? 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1 2 3 4 5 6 7 8 9 10 HR=0.65 (0.44, 0.95) p=0.028 placebo Bicalutamide 0 Time to death (years) Proportion surviving EPC program 2006 Overall survival
    27. 27. Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
    28. 28. Tannock IF: NEJM 351:1502-12, 2004 Fizazi K: Lancet Oncol 2007; 8: 994-1000 <ul><li>Docetaxel: established standard </li></ul><ul><li>in metastatic prostate cancer </li></ul>Rationale for chemotherapy in localized CaP <ul><li>In Oncology, minor OS benefit in the metastatic setting </li></ul><ul><li>usually transfers in higher benefit in localized disease </li></ul><ul><li>(breast, colon, etc) </li></ul>HR= 0.81, p= 0.02
    29. 29. ADJUVANT Docetaxel après prostatectomie
    30. 30. Sanofi-Aventis XRP6976J/3501 Study P.I. Mario Eisenberger - Primary endpoint: PFS - N= 228/ 1696 (high-risk localized disease, ) - Stratification: Age (> 65 vs < 65) / Predicted prob. of 5-y FFP / Country Observation Leuprolide 18 months Leuprolide 18 months + Docetaxel 75 q3w x 6 cycles Deferred arm PROGRESSION P R O G R E S S I O N P R O G R E S S I O N Leuprolide 18 months Leuprolide 18 months + Docetaxel 75 q3w x 6 cycles Immediate arm R A N D O M I Z E RP ACCRUAL STOPPED
    31. 31. Phase III trials of Docetaxel in Localized prostate cancer Study name PI Local treatment # patients ( enrolled / planned) Status GETUG 12 K. Fizazi (France) XRT 413 / 400 Accrual completed RTOG 0521 H. Sandler (USA) XRT 600 /600 Accrual completed TAX 3501 M. Eisenberger (USA) RP 228 /1700 Early accrual termination AdPro Ahlgren (Sweden) RP 361 /396 Ongoing DANA FARBER A. D’Amico (USA) XRT 191 /350 Ongoing VA # 553 CAP Montgomery (USA) RP 152 /636 Ongoing CALGB 90203 Eastham (USA) RP 126 /750 Ongoing AdRad Kellokumpu-Lehtinen (Fin) XRT 108 /924 Ongoing NCIC Mc Kenzie (Can) XRT 24 / 530 Ongoing
    32. 32. High risk prostate cancer GETUG 12 trial ADT (3 years) + RXT Docetaxel + Estramustine (4 cycles) RANDOMI ZE Primary endpoint: Progression-free survival n = 413/400 pts Stratification - Gleason  8 - PSA>20 - T3 - pN+ / pN- ADT (3 years) + RXT PI: K. Fizazi
    33. 33. Docetaxel Phase III trial in localized CaP PSA response (GETUG 12 trial) PSA 3 months ≤ 0.2 ng/mL: 34% vs 15% p< 0.0001 Fizazi et al., ASCO GU Symposium 2010, Abstr 7 n= 413
    34. 34. Cooperative VA Study # 553 (D.Lin) Docetaxel 75 q3w + prednisone x 6 cycles Observation RANDOMI ZE PROGRESSION <ul><li>pT3b or T4; </li></ul><ul><li>pT3a + GS ≥ 7; </li></ul><ul><li>Pre-op PSA > 20 ng/ml; </li></ul><ul><li>Kattan nomogram PSA prog > 50% at 5 yrs </li></ul><ul><li>Primary endpoint: PFS </li></ul><ul><li>Secondary endpoints: Metastasis free survival, Cancer-specific survival, QOL and toxicity and Time to initiation of androgen deprivation </li></ul><ul><li>N= 152/ 636 planned pts </li></ul>RP
    35. 35. SPCG-12 AdPro PI: G. Algren (Sweden) N = 361 / 396 Primary Endpoint: PSA Progression RANDOMI ZE Docetaxel x 6 cycles Observation <ul><li>Prostatectomy </li></ul><ul><li>and post-op PSA<0.5 </li></ul><ul><li>High risk: </li></ul><ul><li>pT2 GS 4+3 </li></ul><ul><li>G 8-10 & SM + </li></ul><ul><li>pT3 and GS ≥ 7 </li></ul><ul><li>if pre op PSA ≥ 10, </li></ul><ul><li>LN Dissection </li></ul>
    36. 36. ADJUVANT Docetaxel après Radiothérapie
    37. 37. RTOG 0521 study (H.M.Sandler) <ul><li>- Primary endpoint: OS </li></ul><ul><li>N= 536/ 600 planned pts </li></ul><ul><li>Stratification: </li></ul>Androgen Suppression (2 y) + Radiotherapy * (72 -75.6 Gy) RANDOMI ZE Docetaxel 75 q3w x 6 + Prednisone Androgen Suppression (2 y) + Radiotherapy * * (72 -75.6 Gy) <ul><ul><li>1: Gleason > 9, PSA < 150, and any T-stage </li></ul></ul><ul><ul><li>2: Gleason 8, PSA < 20, and any > T2 </li></ul></ul><ul><ul><li>3: Gleason 8, PSA > 20-150, and any T-stage </li></ul></ul><ul><ul><li>4: Gleason 7, PSA > 20-150, and any T-stage </li></ul></ul>* LHRH A + AA * * 3DCRT/IMRT
    38. 38. SPCG-13 AdRad PI: PL. Kellokumpu-Lehtinen (Finland) N = 108 / 924 Endpoint: PSA progression rate RANDOMI ZE Docetaxel x 6 cycles + AS AS <ul><li>Neo-adj ADT + RT </li></ul><ul><li>Any of: </li></ul><ul><li>- T2 GS 7 & PSA > 10 </li></ul><ul><li>T2 GS 8-10, any PSA </li></ul><ul><li>T3 </li></ul>
    39. 39. NEO-ADJUVANT Docetaxel avant Prostatectomie
    40. 40. High risk: Predicted bPFS<60 (Kattan nomogram) PSA<100 RANDOMI ZE Docetaxel 75 x 6 cycles + AS (6 months) No medical treatment CALGB 90203 PI: J. Eastham (US) Prostatectomy N = 126 / 750 Endpoint: 3 year bPFS
    41. 41. NEO-ADJUVANT Docetaxel avant Radiothérapie
    42. 42. High risk: any of: - Gleason > 8 - T3-T4 - PSA>20 - pN+ LN dissection: all pts RANDOMI ZE Docetaxel 70 q3w + Estramustine x 4 cycles + AS (3 years) AS (3 years) GETUG 12 PI: K. Fizazi (FRA) Local treatment at 3 months (RT) N = 413 / 400 Started 11/02, Accrual completed 11/06 Endpoint: PFS
    43. 43. GETUG 12 trial: Population <ul><li>Gleason score  8 42% </li></ul><ul><li>T3 63% </li></ul><ul><li>PSA > 20 ng/mL 61% </li></ul><ul><li>pN+ 28% </li></ul><ul><li># Adverse factors </li></ul><ul><li>1 36% </li></ul><ul><li>2 39% </li></ul><ul><li>3 18% </li></ul><ul><li>4 6% </li></ul>
    44. 44. <ul><li>Inclusion </li></ul><ul><li>Intermediate-high risks: </li></ul><ul><li>T1b, T1c, T2a </li></ul><ul><li>- Gleason > 7 </li></ul><ul><li>- PSA>10 </li></ul><ul><li>PSA velocity>2 ng/mL/year </li></ul><ul><li>T2c, T3a, T3b, or T4 </li></ul>RANDOMI ZE Docetaxel x 3 cycles + AS (6 months) AS (6 months) Dana Farber 05-043 PI: A. D’Amico (US) Radiotherapy N = 191 / 350 Endpoint: OS
    45. 45. Inclusion high risk: - Gleason ≥ 8 - T ≥ 3a - PSA>20 ng/mL RANDOMI ZE Docetaxel x 4 cycles + AS (3 years) AS (3 years) NCIC CTG (DART) Study Chair: M. McKenzie (CAN) Radiotherapy N = 24 / 530 Endpoint: DFS
    46. 46. D’Amico Study Dana-Farber <ul><li>- Primary endpoint: OS </li></ul><ul><li>- N= 350 planned pts </li></ul><ul><li>- Stratification: -Clinical category T1b to T2b and a PSA > 10 ng/ml Or </li></ul><ul><ul><ul><ul><ul><li>Clinical category T1b to T2b and a biopsy Gleason score > 7 Or </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Clinical category T2c or T3a, T3b, or T4 disease Or </li></ul></ul></ul></ul></ul><ul><li> - Clinical category T1b – T2b and PSA velocity >2.0ng/ml per year </li></ul>6-month T A S Docetaxel 60 q3w x 3 cycles then Docetaxel 20 wkly x 7 + Radiotherapy 70 Gy 6-month T A S and Radiotherapy 70 Gy RANDOMI ZE High-risk localized/LA disease
    47. 47. Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Bone targeting agents? High risk localized prostate cancer
    48. 48. Zoledronic Acid- Preventing Bone Metastasis in the Adjuvant Setting
    49. 49. Zoledronic Acid Can Inhibit this Process at Several Key Steps Adapted from Mundy GR, et al. Nature Reviews Cancer . 2002;2:584-593. Invasion Angiogenesis Primary tumor Metastases Adhesion & extravasation Arrest in distant capillary Micrometastases Inhibits angiogenesis Decreases adhesion to bone Synergy with anticancer drugs Induces tumor cell apoptosis Stimulates immune surveillance Decreases matrix invasion Direct antitumor effect Indirect antitumor effect
    50. 50. Overview of Other Antitumor / Prevention Trials with Zoledronic Acid <ul><li>Targeted total accrual > 20,000 MM, breast, prostate and lung cancer patients </li></ul>Name Patients Treatment arms Primary endpoint ABCSG-12 1,803 BC pts (Stage I, II ) TAM; ANA; TAM + ZOL (4mg q 6 mo); ANA + ZOL (4mg q 6 mo) DFS at 5 years AZURE 3,360 BC pts (Stage II, III ) Standard therapy  ZOL (4mg q 1mo; q 3 mo; q 6 mo) DFS at 5 years SUCCESS 3,754 BC pts (Stage I, II, III) FEC + DOC then endocrine therapy + ZOL 3 or 5 y; FEC + DOC + GEM then endocrine therapy + ZOL 3 or 5 y DFS at 5 years SWOG 0307 4,500 BC pts (Stage I, II, III) ZOL (4mg q 1mo; q 3 mo); CLO (1600mg q d); IBAN (50mg q d) DFS at 3 years NATAN 654 BC pts (Stage II, III) Standard therapy  ZOL (4mg q 1mo; q 3 mo; q 6 mo) EFS at 5 years ZEUS 1,434 PC pts (No distant mets) ZOL (4mg q 3mo); No ZOL Proportion of pts with bone mets at 4 years RADAR 1,071 PC pts (Stage T2b-4) Short-term AD  ZOL (4mg q 3 mo) Intermediate-term AD  ZOL (4mg q 3 mo) PSA-RFS at 5 years 2419 study 446 NSCLC pts (Stage III) ZOL (4mg q 1 mo); No ZOL Time to occurrence of bone mets at 2 years STAMPEDE 3,300 PC pts (high-risk) ADT and 1. No additional therapy; 2. Taxotere; 3. ZOL; 4. Celecoxib; 5. Celecoxib + ZOL; 6. Taxotere + ZOL + Celecoxib Failure-free survival, OS (multiple phases)
    51. 51. Prostate Cancer: ZEUS Zoledronic acid 4 mg q 3 months No Zoledronic acid* <ul><li>1,433 patients </li></ul><ul><li>Prostate cancer, M0 </li></ul><ul><li>+/- previous local curative treatment, +/- ADT </li></ul><ul><li>High risk PCa with at least one of the following criteria: </li></ul><ul><li>Gleason Score 8-10 </li></ul><ul><li>pN+ </li></ul><ul><li>PSA  20 at diagnosis </li></ul>Treatment duration 4 years <ul><li>Key endpoints </li></ul><ul><ul><li>Primary : Time to bone metastases (at 4 years) </li></ul></ul><ul><ul><li>Others : Overall survival, PSA doubling time, substudies on bone markers </li></ul></ul>R
    52. 52. Prostate Cancer: RADAR Key endpoints: Primary : PSA Progression-free survival (at 5 years) Secondary : Overall survival QOL, bone metastases free survival, BMD <ul><li>1,000 patients </li></ul><ul><li>Prostate Cancer </li></ul><ul><li>T2a (Gleason score >/= 7 and </li></ul><ul><li>PSA >/= 10), T2b-4, N0, M0 </li></ul><ul><li>Stratification: </li></ul><ul><li>T2a/T2b/T3,4 </li></ul><ul><li><60 y/60-70 y/>70 y </li></ul><ul><li>Gleason primary pattern 1-3/4,5 </li></ul><ul><li>PSA <10/10-20/>20 </li></ul><ul><li>Treatment center </li></ul>Short term AD (STAD) – LHRH analogue for 5 mo prior to and during first mo of radiation treatment (total 6 mo) + Zoledronic Acid 4 mg q 3 mo / 18 mo Intermediate term AD – LHRH analogue as for STAD arm, but continued for further 12 mo (total 18 mo) Short term AD (STAD) – LHRH analogue for 5 mo prior to and during first mo of radiation treatment (total 6 mo) Treatment 18 mo / follow-up > 5 years Intermediate term AD – LHRH analogue as for STAD arm, but continued for 12 mo (total 18 mo) + Zoledronic Acid 4 mg q 3 mo / 18 mo R
    53. 53. A multi-arm trial: STAMPEDE
    54. 54. Prostate Cancer: STAMPEDE Key endpoints: Primary : Failure free survival Secondary : QOL, cost effectiveness, toxicity, SREs, overall survival AD + zoledronic acid (Z) AD + celecoxib + Z n = 3300 Prostate Cancer - High risk newly diagnosed - or PSA relapse after RP/RXT - or metastases Androgen suppression (AD) AD + T + Z AD + celecoxib AD + Taxotere (T) R Pilot Confirm Safety in 210 patients on trial for min 18 weeks Efficacy stages I - IV Reject arms not improving Failure Free Survival at each stage <ul><li>Follow-up until death </li></ul>
    55. 55. STAMPEDE Study Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (PI: N James) R A N D O M I S E Hormones (H) H + D + Z H + Docetaxel (D) H + Zoledronate (Z) H + Celecoxib H + Celecoxib + Z Endpoints: FFS Stages 1-3 Reject arms not improving FFS >50% Confirm safety Pilot Safety N= 1085/ 3300-6000
    56. 56. Conclusion: Systemic treatment in high-risk localized prostate cancer <ul><li>Endocrine therapy: </li></ul><ul><ul><li>Standard= ADT x 3 years (+ XRT) </li></ul></ul><ul><ul><li>No data with prostatectomy </li></ul></ul><ul><ul><li>Bicalutamide 150: 1 trial, no comparison with ADT </li></ul></ul><ul><li>Docetaxel: </li></ul><ul><ul><li>10 phase III trials ongoing </li></ul></ul><ul><ul><li>First results of GETUG 12 at ASCO 2011 </li></ul></ul><ul><li>Zoledronic acid: </li></ul><ul><ul><li>3 phase III trials </li></ul></ul><ul><ul><li>First results ~ 2012? </li></ul></ul>

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