1. Guadalajara, 18 de junio del 2009
V Reunión Nacional de Avances en Cáncer de Próstata
Neoadyuvancia y Adyuvancia con Hormonoterapia y Quimioterapia en la Enfermedad Localizada y Localmente Avanzada
Albert Font
Servicio de Oncología Médica
Institut Català d´Oncologia
Hospital Germans Trias i Pujol, Badalona
Guadalajara, 18 de junio del 2009

2. Treatment of localized and locally-advanced prostate cancer according to risk groups
Pisansky et al. NEJM 2006

3. Relative Risk of Prostate Cancer-Specific Mortality according to Treatment and Risk Group
Two multi-institutional databases including 7316 patients
D´Amico et al. J Clin Oncol 2003;21:

4. Prostate cancer as a systemic disease (I)
Prognostic impact of CK+ prostate cancer cells in bone marrow before prostatectomy
Weckermann D, et al. J Clin Oncol 2009;27:1549

5. Prostate cancer as a systemic disease (II)
Cell-free tumor DNA and circulating tumor cells in blood plasma in prostate cancer
Schwarzenbach H, et al. Clin Cancer Res 2009;15:1032

6. Is there a role for chemotherapy in high-risk localized prostate cancer ?
Prostate cancer is a systemic disease even in early stages
Pretreatment clinical factors such as Gleason score, PSA levels and clinical stage can select patients with high risk of PSA recurrence and prostate cancer-related death (D´Amico, 2003)
Treatment options for men with high-risk localized prostate cancer remain inadequate
Chemotherapy is effective in advanced hormone-refractory prostate cancer
Hormonal therapy followed by prostatectomy has not improved long-term outcomes in high-risk patients treated in the neoadjuvant setting

7. Summary of neoadjuvant hormonal therapy trials with > 100 patients enrolled
Gomella LG et al. Urology 2003;62(supp6B):46

8. Adjuvant chemotherapy in high-risk localized prostate cancer
Study No pts Regimen Surgery Results
Schmidt, Cyclophosphamide vs Yes No difference in OS
EMP vs Observation
Wang, ADT + Mitox ( 4 c) vs ADT Yes Improvement with
Mitox
Rosenbaum, Docetaxel wkly (6 months) Yes PFS: 15.7 m
Srinivas, Docetaxel wkly (6 months) Surgery/RT Well tolerated
EMP: Estramustine ADT: Androgen deprivation therapy Mitox: Mitoxantrone
Trials with Docetaxel

9. SWOG 9921: Hormonal therapy vs hormonal therapy plus chemotherapy after prostatectomy
Hormonal Therapy ( 2 years) R A N D O M I Z E
High Risk Localized Prostate Cancer after Radical Prostatectomy
Hormonal Therapy (2 years) plus
+ mitoxantrone/prednisone
(6 cycles)
(n=1360 p)
Primary Endpoint: Overall Survival
Status: Closed

10. Veteran Affairs CSP 553 study: Adjuvant chemotherapy in high-risk localized prostate cancer
Docetaxel (75 mg/m2 every 3 weeks) + prednisone
( 6 cycles) R A N D O M I Z E
High Risk Localized Prostate Cancer after Prostatectomy
(pT3b or T4, pT3a+Gleason > 7, PSA > 20 ng/ml or risk of PSA progression > 50% )
Post-RP: PSA < 0.1
Observation
(n= 636 p)
Primary Endpoint: Progression-free survival
Study start: June 2006

11. High Risk Prostate Cancer: Primary Endpoint: Survival at 4 years
Hormonal and radiation therapy or hormonal and radiation therapy followed by docetaxel: RTOG 0521 study R A N D O M I Z E
ADT ( 8 weeks) RT (72-75 Gy) + ADT (20 months)
High Risk Prostate Cancer:
Gleason 7-8/PSA
Gleason 8/PSA < 20/T2-4
Gleason>9/ PSA< 150
ADT ( 8 weeks) RT (72-75 Gy) + Docetaxel ( 6 cycles)+ ADT (20 m)
N= 600 p
Primary Endpoint: Survival at 4 years
Start Date: December 2005

12. Rationale for neoadjuvant treatment of prostate cancer

13. Neoadjuvant trials in high-risk localized prostate cancer
Non-docetaxel based chemotherapy with/without hormonal therapy
Docetaxel-based chemotherapy without hormonal therapy
Docetaxel-based chemotherapy with hormonal therapy
Ongoing phase III trials
Trials with new targeted therapies

14. Phase II trials of non-docetaxel-based chemotherapy (I)
ECE: extracapsular extension LN: Lymph nodes SM+: Surgical margins involved

15. Phase II trials of docetaxel-based chemotherapy without hormonal therapy (II)

16. Phase II trials of docetaxel-based chemotherapy
with hormonal therapy (III)

17. Phase II trials of docetaxel-based chemotherapy
with hormonal therapy

18. Docetaxel-based chemotherapy with hormonal
therapy in high-risk localized prostate cancer (I)

19. Docetaxel-based chemotherapy with hormonal therapy in high-risk localized prostate cancer (II)
26%
(*) Significant PR: <5%-10% tumor or less by volume in prostatectomy

20. High Risk Prostate Cancer: Primary Endpoint: Overall survival
Neoadjuvant hormonal and radiation therapy with/without docetaxel in high-risk prostate cancer: Dana-Farber Institute study R A N D O M I Z E
ADT ( 6 months ) + Docetaxel x 3 cycles followed by RT (70 Gy) + Docetaxel (20 mg/m2/wkly)
High Risk Prostate Cancer:
T1b-2a + PSA> 10 or Gleason >7
T2c-T4
ADT ( 6 months ) + RT (70 Gy)
N= 350 p
Primary Endpoint: Overall survival
Start Date: June 2005

21. Neoadjuvant docetaxel and hormonal therapy vs prostatectomy alone in high-risk localized prostate cancer: CALGB study R A N D O M I Z E
High Risk Prostate Cancer:
Biochemical PFS < 60% by Kattan nomogram
PSA < 100 ng/ml
Clinical stage: T1-3a
Prostatectomy
Docetaxel ( 6 cycles)
+ ADT (18-24 weeks)
Prostatectomy
N= 750 p
Primary Endpoint: Biochemical progression free survival at 3 years
Start Date: December 2006

22. Genetic markers involved in prostate cancer biology
Potential for new targeted therapies
Efstathiou et al. Clin Cancer Res 2007

23. Why may new therapies be explored in high-risk localized prostate cancer?

24. Impact of new targeted therapies as neoadjuvant therapy for high-risk prostate cancer

25. Median decline in tumor volume was 46%
36% of patients had a partial response by erMRI
9 p (22%) had a PSA declines > 50%

26. Ongoing trials with new targeted therapies as neoadjuvant treament in high-risk localized prostate cancer (I)

27. Ongoing trials with new targeted therapies as neoadjuvant treament in high-risk localized prostate cancer (II)

28. Genetic markers to predict eficacy of neoadjuvant therapies Role of BRCA 1
Kennedy RD, et al. JNCI 2004;96:

29. Reconstitution of wild-type BRCA1 results in sensitivity to antimicrotubule agents paclitaxel and vinorelbine in BRCA1 mutant HCC1937 cell line
HCCBR116: IC50 = 7.73 x 10 –9M
HCCEV1: IC50 = 6.21 x 10 –6M
HCCBR116: IC70 = 1.9 x 10 –9M
HCCEV1: IC70 = 1.7 x 10 –5M
PACLITAXEL (1000x)
VINORELBINE (10000x)
(A)
(B)
(A) Dose inhibition curves comparing the IC50-70 values of (A) Paclitaxel and (B) Vinorelbine in the BRCA1 mutant HCC1937 cells reconstituted with exogenous wild type BRCA1 (HCCBR116) compared to HCC1937 cells reconstituted with empty vector (HCCEV1). In each case the HCCBR116 cells display a marked increase in sensitivity to these antimicrotubule agents compared to the HCCEV1 cells.
Quinn et al. Cancer Res 2003

30. Estudios con small interfering RNA inducen resistencia a taxanos mientras que la reconstitución de BRCA-1 aumenta la sensibilidad a paclitaxel y vinorelbina
La supresión de BRCA-1 aumenta la sensibilidad a cisplatino y la resistencia a paclitaxel
siRNA of BRCA1 led to paclitaxel and docetaxel resistance, and reconstitution of BRCA1 enhanced sensitivity to paclitaxel and vinorelbine
Abrogation of BRCA1 increases sensitivity to cisplatin and resistance to paclitaxel
Quinn et al. Clin Cancer Res 2007

31. BRCA1 mRNA expression predict survival in ovarian cancer patients treated with chemotherapy
Quinn JE, et al. Clin Cancer Res 2007;13:

32. BRCA1 expression in prostate cancer
BRCA1 – a predictive marker of response to docetaxel-based chemotherapy in prostate cancer
Schayek H, et al. Clin Cancer Res 2009;15: 1558

33. Conclusions
Several phase II trials have confirmed the safety and feasibility of neoadjuvant chemotherapy followed by prostatectomy in high-risk localized prostate cancer
A significant percentage of patients can attain a significant pathological response after neoadjuvant chemotherapy – associated with better prognosis
High-risk patients may be optimal candidates for testing the activity of new therapies in the neoadjuvant setting
The analysis of predictive and prognostic genetics markers should be included in these studies.
Close collaboration between urologists, medical oncologists and radiotherapists is required to develop multimodal strategies.

34. What can we do to improve?
We need new strategies in translational research and clinical trials in prostate cancer. We can learn a lesson from investigation in NSCLC or breast cancer