Neoadyuvancia y Adyuvancia con Hormonoterapia y Quimioterapia en la Enfermedad Localizada y Localmente

Avanzada

Albert FontServicio de Oncología Médica

Institut Català d´Oncologia Hospital Germans Trias i Pujol, Badalona

Guadalajara, 18 de junio del 2009

V Reunión Nacional de Avances en Cáncer de Próstata

Treatment of localized and locally-advanced prostate cancer according to risk groups

Pisansky et al. NEJM 2006

Relative Risk of Prostate Cancer-Specific Mortality according to Treatment and Risk Group

Risk Group Surgery RR 95% CI P

Radiotherapy RR 95% CI P

Low

Intermediate

High

1.0 4.9 1.7-8.1 .003 14.2 5.0-23.4 <.0001

1.0 5.6 2.0-9.3 .0012

14.3 5.2-24.0 <.0001

D´Amico et al. J Clin Oncol 2003;21:2163-2172

Two multi-institutional databases including 7316 patients

Weckermann D, et al. J Clin Oncol 2009;27:1549

Prostate cancer as a systemic disease (I)Prognostic impact of CK+ prostate cancer cells in bone

marrow before prostatectomy

Schwarzenbach H, et al. Clin Cancer Res 2009;15:1032

Prostate cancer as a systemic disease (II)Cell-free tumor DNA and circulating tumor cells in blood

plasma in prostate cancer

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

Gomella LG et al. Urology 2003;62(supp6B):46

Summary of neoadjuvant hormonal therapy trials with > 100 patients enrolled

Adjuvant chemotherapy in high-risk localized prostate cancer

Study No pts Regimen Surgery Results

Schmidt, 1996 184 Cyclophosphamide vs Yes No difference in OS

EMP vs Observation

Wang, 2000 96 ADT + Mitox ( 4 c) vs ADT Yes Improvement withMitox

Rosenbaum, 2005 77 Docetaxel wkly (6 months) Yes PFS: 15.7 m

Srinivas, 2006 20 Docetaxel wkly (6 months) Surgery/RT Well tolerated

EMP: Estramustine ADT: Androgen deprivation therapy Mitox: Mitoxantrone

Trials with Docetaxel

SWOG 9921: Hormonal therapy vs hormonal therapy plus chemotherapy after prostatectomy

High Risk Localized Prostate Cancer after

Radical Prostatectomy

RANDOMIZE

Hormonal Therapy ( 2 years)

Hormonal Therapy (2 years) plus + mitoxantrone/prednisone

(6 cycles)

(n=1360 p)

Primary Endpoint: Overall Survival

Status: Closed

Veteran Affairs CSP 553 study: Adjuvant chemotherapy in high-risk localized

prostate cancer

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

RANDOMIZE

Docetaxel (75 mg/m2 every 3 weeks) + prednisone

( 6 cycles)

Observation

(n= 636 p)

Primary Endpoint: Progression-free survival

Study start: June 2006

Hormonal and radiation therapy or hormonal and radiation therapy followed by docetaxel:

RTOG 0521 study

High Risk Prostate Cancer:

• Gleason 7-8/PSA 20-150

•Gleason 8/PSA < 20/T2-4

•Gleason>9/ PSA< 150

Primary Endpoint: Survival at 4 yearsStart Date: December 2005

N= 600 p

ADT ( 8 weeks) RT (72-75 Gy) + ADT (20 months)

ADT ( 8 weeks) RT (72-75 Gy) + Docetaxel ( 6 cycles)+ ADT (20 m)

RANDOMIZE

Rationale for neoadjuvant treatment of prostate cancer

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

Study No. Pts Regimen Pathological Results

pCR ECE LN SM+

Van Poppel, 1995

29

Estramustine

0 41% NR 52%

Pettaway, 2000

30

KAVE

0 67% 37% 17%

Clark, 2001

16

Estramustine/

VP-16

0 56% 13% 13%

Konety, 2004

35 Taxol/estramustine/

carboplatin

0 53% 5% 22%

Ko, 2006

12 Taxol/

estramustine 0 NR 8% 25%

Phase II trials of non-docetaxel-based chemotherapy (I)

ECE: extracapsular extension LN: Lymph nodes SM+: Surgical margins involved

Study No. Pts Regimen Pathological Results pCR ECE LN MR+

Dreicer, 2004

29

Docetaxel (wkly)

0 49% 14% 50%

Febbo, 2005

16

Docetaxel (wkly)

0 62% 0% NR

Garzotto, 2006

22

Docetaxel/

Mitoxantrone

0 34% 29% 34%

Friedman, 2008

15 Docetaxel/

capecitabine

0 56% 13% 40%

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

Study No. Pts Regimen Pathological Results pCR ECE LN MR+

Hussain, 2003

21

Docetaxel/

Estramustine

0 70% 10% 30%

Magi-Galluzzi,

2007

29

Docetaxel (wkly)

0 82% 14% 39%

Sella, 2008

22

Docetaxel/

Estramustine

0 36% 23% 27%

Chi, 2008

72 Docetaxel (wkly)

3% 44% 6% 27%

Mellado, 2009

57

Docetaxel (wkly)

6% 47% 4% 35%

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

Study No. Pts Regimen Pathological Results pCR ECE LN MR+

Hussain, 2003

21

Docetaxel/

Estramustine

0 70% 10% 30%

Magi-Galluzzi,

2007

29

Docetaxel (wkly)

0 82% 14% 39%

Sella, 2008

22

Docetaxel/

Estramustine

0 36% 23% 27%

Chi, 2008

72 Docetaxel (wkly)

3% 44% 6% 27%

Mellado, 2009

57

Docetaxel (wkly)

6% 47% 4% 35%

Phase II trials of docetaxel-based chemotherapy with hormonal therapy

Chi et al , 2008

Mellado et al, 2009

Regimen

Docetaxel (wkly) plus

ADT

Docetaxel (wkly) plus

ADT

Treatment Duration

6 months

3 months

No of patients

72

57

Risk Factors 1 2 3

41 (65%) 19 (30%)

3 (5%)

33 (58%) 21 (36%)

3 (5%)

Median follow-up

42 months

35 months

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

Chi et al , 2008

Mellado et al, 2009

Pathological Response Surgical Margins + Extracapsular extension Lymph nodes involved pCR Significant PR (*)

17 (27%)

28 (44%)

4 (6%)

2 (3%)

16 (25%)

18 (35%)

24 (47%)

2 (4%)

3 (6%)

10 (18%)

Outcome Biochemical relapse BFS in p with significant PR

19 (30%)

89%

18 (31%)

Docetaxel-based chemotherapy with hormonal therapy in high-risk localized prostate cancer (II)

(*) Significant PR: <5%-10% tumor or less by volume in prostatectomy

26%

Neoadjuvant hormonal and radiation therapy with/without docetaxel in high-risk prostate

cancer: Dana-Farber Institute study

High Risk Prostate Cancer:

• T1b-2a + PSA> 10 or Gleason >7

•T2c-T4

RANDOMIZE

Primary Endpoint: Overall survival

Start Date: June 2005

N= 350 p

ADT ( 6 months ) + Docetaxel x 3 cycles followed by RT (70 Gy) + Docetaxel (20 mg/m2/wkly)

ADT ( 6 months ) + RT (70 Gy)

Neoadjuvant docetaxel and hormonal therapy vs prostatectomy alone in high-risk localized prostate

cancer: CALGB 90203 study

High Risk Prostate Cancer:

• Biochemical PFS < 60% by Kattan nomogram

•PSA < 100 ng/ml

•Clinical stage: T1-3a

Primary Endpoint: Biochemical progression free survival at 3 years

Start Date: December 2006

N= 750 p

Prostatectomy

Docetaxel ( 6 cycles)

+ ADT (18-24 weeks) Prostatectomy

RANDOMIZE

Efstathiou et al. Clin Cancer Res 2007

Genetic markers involved in prostate cancer biology

Potential for new targeted therapies

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

High-risk localized Advanced hormone-refractory

Primary endpoint

Pathological

response

Biochemical-progresion free survival,

overall survival

No of patients required

Low

High

Follow-up

Short

Long

Tumor tissue

available

Yes

Not usually

Predictive genetic markers

Yes More difficult

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

Study Regimen Results

Vuky J, et al. Cancer 2009

Docetaxel (wkly)/gefitinib

(31p)

PSA responses: 21 p (68%) Extracapsular extension: 13 p (43%) Positive SM: 11 p (33%) No pT0 was observed

Mathew P, et al. J Urol 2009

Docetaxel (wkly)/imatinib

(36p)

Extracapsular extension: 22 p (65%) Positive SM: 6 p (18%) No pT0 was observed

Oh W.K, et al Proc ASCO 2009

Docetaxel/bevacizumab (41 p)

Partial responses by erMRI: 36% p No pathological results

•Median decline in tumor volume was 46%

•36% of patients had a partial response by erMRI

•9 p (22%) had a PSA declines > 50%

Institution Regimen No. pts Endpoint

U. British Columbia

OGX-011

45 p

Pathological complete

response Hoosier

Oncology Group

Dasatinib 39 p Pathological complete response

M.D Anderson Sunitinib

42 p

Tumor response

Ongoing trials with new targeted therapies as neoadjuvant treament in high-risk

localized prostate cancer (I)

Institution Regimen No. pts Endpoint

Fred Hutchinson

Cancer Research

Center

Sorafenib 20 p

Molecular studies (transcript profiles)

NCI

Everolimus 30 p Pathological complete

responses

Sidney Kimmel Comprehensive Cancer Center

Sirolimus 60 p Pharmacogenetic studies

MSKCC

Vorinostat 38 p Pathological complete

responses

Ongoing trials with new targeted therapies as neoadjuvant treament in high-risk

localized prostate cancer (II)

Genetic markers to predict eficacy of neoadjuvant therapies

Role of BRCA 1

Kennedy RD, et al. JNCI 2004;96:1659-68

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 –9MHCCEV1: IC50 = 6.21 x 10 –6M

HCCBR116: IC70 = 1.9 x 10 –9MHCCEV1: 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

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

Quinn JE, et al. Clin Cancer Res 2007;13:7413-20

BRCA1 mRNA expression predict survival in ovarian cancer patients treated with chemotherapy

Schayek H, et al. Clin Cancer Res 2009;15: 1558

BRCA1 expression in prostate cancer

BRCA1 – a predictive marker of response to docetaxel-based chemotherapy in prostate cancer

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.

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

What can we do to improve?