Alessandra Felici, Oncologia Medica A Istituto Regina Elena Rome The near future: molecular targeted therapies for metastatic prostate cancer NEW PERSPECTIVES.

Alessandra Felici, Oncologia Medica A

Istituto Regina Elena

Rome

The near future: molecular targeted therapies for

metastatic prostate cancer

NEW PERSPECTIVES IN METASTATICPROSTATE CANCER

Rome, June 15, 2012CINBO

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The Two-Compartment Model

• Epitheliel compartment: prostate cancer ephitelial cells

• Stromal compartment: bone microenvironment (hematopoietic cells, fibroblasts, endothelial cells, adipocytes, macrophages, osteoblasts, osteoclasts and mesenchymal stem cells + soluble extracellular matrix rich in growth factors and cytokines)

• Epithelial targeting therapies

• Stromal targeting therapies

• Epithelial-stromal targeting therapies

Epithelial Targeting Therapies

• Chemotherapy (intrinsic defect in epithelial cell apoptosis due to BCL2 overexpression and PTEN loss)

• Oligonucleotides antisense that target clusterin (a chaperone protein involved in cell proliferation and survival)

Epithelial Targeting Therapies

• Chemotherapy (intrinsic defect in epithelial cell apoptosis due to BCL2 overexpression and PTEN loss)

• Oligonucleotides antisense that target clusterin (a chaperone protein involved in cell proliferation and survival)

Androgen-dependent prostate cancer

Schalken, BJU, 2007

Androgen-independent prostate cancer

Stavridi, Cancer Treatment Reviews, 2010

Changes in gene expression with progression of prostate cancer

Epithelial Targeting Therapies

• Chemotherapy (intrinsic defect in epithelial cell apoptosis due to BCL2 overexpression and PTEN loss)

• Oligonucleotides antisense that target clusterin (a chaperone protein involved in cell proliferation and survival)

Chaperone protein

Clusterin Hsp27

OGX-011(custirsen)

OGX-427

Clusterin structure

Zoubeidi A et al. Clin Cancer Res 2010;16:1088-1093

Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with

metastatic castration-resistant prostate cancer

• D/P ± OGX-011 640 mg iv weekly (82 pts)

• PSA decline ≥ 50%: 58% arm A v 54% arm B• PFS: 7.3 v 6.1 mos (95% CI 5.3-8.8; 95% CI 3.7-8.6)

• OS: 23.8 v 16.9 mos (95% CI 16.2-not reached; 95% CI 12.8-25.8)

• Main side effects: fever, rigors, diarrhea, rash

Chi KN, J Clin Oncol, 2010

Randomized phase II trial of Custirsen (OGX-011) in combination with docetaxel or mitoxantrone as second-line

therapy in patients with metastatic castrate-resistant prostate cancer progressing after first-line docetaxel: CUOG trial P-06c

20 DPC

77% pain responses

PSA declines ≥50%: 60%

OS: 15.8 mos

Time to pain progression (TTPP): 10.0 mos

22 MPC

46% pain responses

PSA declines ≥50%: 27%

OS: 11.5 mos

Time to pain progression (TTPP): 5.2 mos

Saad, Clin Cancer Res, 2011

Rocci, Cancer Res, 2005Zoubeidi, Cancer Res, 2007

Chi KN, et al. ASCO 2012.

Patients with progressive mCRPC who received no prior

chemotherapy for metastatic disease

(N = 33)

Primary endpoint: PD at 12 wks

Secondary endpoints: PSA decline, measurable disease response, PFS, TTP, CTC count, serum/plasma HSP27

OGX-427 600 mg IV x 3. loading doses within 10 days, then 1000 mg IV weekly +

Prednisone 5 mg PO BID

Prednisone 5 mg PO BID*

*Crossover allowed upon disease progression

OGX-427: synthetic oligonucleotide inhibitor of Hsp27 gene expression

First-Line OGX-427 + Prednisone vs Prednisone in mCRPC

Chi KN, et al. ASCO 2012.

Outcome, n (%) OGX-427/Prednisone Prednisone

Disease progression at 12 wks (n = 17) (n = 15)

•No disease progression 12 (71; 95% CI: 0.440,0.897)

6 (40;95% CI:0.163,0.677)

•Disease progression 5 (29) 9 (60)

Best PSA decline from baseline (n = 22) (n = 20)

•≥ 80% 2 (9) 1 (5)

•≥ 60% 11 (50) 4 (20)

•≥ 30% 13 (59) 6 (30)

•Any 17 (77) 11 (55)

Measurable disease response (n = 9) (n = 12)

•CR 1 (11) 0

•PR 3 (33) 0

•SD 1 (11) 7 (58)

•PD 0 2 (17)

OGX-427/Prednisone in mCRPC: Results

Chi KN, et al. ASCO 2012.

Incidence of All Laboratory Treatment-Emergent Events

OGX-427 + Prednisone

(n = 22)

Prednisone (n = 20)

Grade 3/4 Grade 3/4

Lymphopenia, n 4 (11%) 2 (10%)

Chills, n 1 (5%) 0

Hyperglycemia, n 3 (14%) 1 (5%)

Elevated creatinine, n 1* (5%) 0

Fatigue, n 1 (5%) 0

Hypertension, n 1 (5%) 0

Hyponatremia, n 1 (5%) 0

*1 case of grade 4 hemolytic uremic syndrome reported at Wk 7.

OGX-427/Prednisone for mCRPC: Toxicity

Stromal Targeting Therapies

• Endothelin type A (ETA) receptor antagonist (Atrasentan)

• Monoclonal antibodies against RANKL (Denosumab)

• Antiangiogenic Agents

Stromal Targeting Therapies

• Endothelin type A (ETA) receptor antagonist (Atrasentan)

• Monoclonal antibodies against RANKL (Denosumab)

• Antiangiogenic Agents

Antiangiogenesis Agents

– Bevacizumab (VEGFmAb)– Lenalidomide (thalidomide analog)– Aflibercept (VEGF Trap)– Sunitinib (multitargeted small molecule VEGFR TKI)– Sorafenib (multitargeted small molecule VEGFR TKI)– Tasquinimod

RESULTS (79 pts)• 75% had a ≥ 50% PSA decline• 59% had a partial response• Median PFS 8 months (1st end point)• Overall median survival: 24 months

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A Phase 2 Study of Estramustine, Docetaxel, and Bevacizumab in Men With Castrate-Resistant Prostate Cancer

Results From Cancer and Leukemia Group B Study 90006

TOXICITY

• 69% neutropenia without fever

• 25% fatigue

• 9% thrombosis/emboli

Picus, Cancer, 2011

1050 pts with chemotherapy-naive progressive mCRPC

Docetaxel 75 mg/m2, PDN 5 mg bid ± beva 15 mg/kg, q21

OS: 22.6 v 21.5 mos H(R: 0.91; 95% CI 0.78 to 1.05; p=.181) (primary end-point)

PFS: 9.9 v 7.5 mos (p<.002)

OR: 49.4% v 35.5% (p=.0013)

Grade 3/4 toxicities: 75.4% v 56.2% (p≤.001)

Randomized, Double-Blind, Placebo-Controlled Phase III Trial Comparing Docetaxel and Prednisone With or Without Bevacizumab in Men With

Metastatic Castration-Resistant Prostate Cancer: CALGB 90401

Kelly, J Clin Oncol, 2012

Phase II docetaxel, bevacizumab, thalidomide and prednisone (60 pts)

•89,6% had <50 % PSA response•Overall response 64%•PFS: 18,3 mos•OS: 28,2 mos

Bamidele Adesunloye, ASCO 2012

54 pts

30 pts had measurable disease: 1 CR and 25 PR by RECIST

PFS: 22 mos

90% alive at 12 mos

25 of study: 17 for radiographic progression, 8 for other reasons

46 (85.2%) has maximal PSA decline of >50%

Dual antiangiogenic therapy + docetaxel and prednisone resulted in high PSA and tumor response. Toxicities were manageable.

Multitargeted Tirosin Kinase Inhibitors

Fizazi, BJU, 2010

Tasquinimod

• Oral quinoline-3-carboxamide derivative that bind S100A9 protein

• Growth inhibition: up-regulation of TSP-1; down-regulation of HIF-1 α protein, androgen receptor protein, glucose transporter-1 protein

• Anti-angiogenic response: decrease tumor tissue level of VEGF

201 asymptomatic or mildly symptomatic pts with bone-metastases (134 T, 67 placebo)

PFS at 6 mos: 69% vs 37% (median PFS: 7.6 mos vs 3.3 mos) p<.001

Time to symptomatic progression was longer in T treated pts (p=0.039; HR:0.42)

Side effects: GI disorders, fatigue, musculoskeletal pains, elevations of pancreatic and inflammatory biomarkers

Phase II Randomized, Double-Blind, Placebo-Controlled Study of Tasquinimod in Men With Minimally Symptomatic

Metastatic Castrate-Resistant Prostate Cancer

Pili, J Clin Oncol 29:4022-4028, 2011

All pts

Visceral mets

Bone mets

°_+

Epithelial-Stromal Targeting Therapies

• Novel Agents that Interfere with Androgen Signaling (Abiraterone, TAK-700, MDV3100)

• Targeted Agents (Dasatinib, Cabozantinib)

• Immunotherapy (Sipuleucel-T, Ipilimumab, PROSTVAC-VF)

• Is a potent targeted therapy that inhibits MET and VEGFR2• MET pathway activation promotes tumor growth, invasion and

metastasis.• Overexpression of MET and/or its ligand HGF are associated with

prostate cancer metastasis. • In preclinical studies, androgen ablation upregulates MET signaling.

Hussain, ASCO 2011

Cabozantinib (XL184)

Cabozantinib (XL184) in Chemotherapy-Pretreated mCRPC: Results from a Phase 2 Non-Randomized

Expansion Cohort (Abstract n. 4513)

Smith, ASCO 2012

Key Eligibility Criteria:Prior Docetaxel (>225 mg/m2) and bone metastases documented on bone scanRadiographic progression within 6 months of last taxane dose

Bone Scan Response by Independent Radiology Review

Two dose level explored sequentially: 100 mg po QD (N=93); 40 mg po QD (N=51)

Results and Toxicity

Phase II Cabozantinib Summary

• Cabozantinib 100 mg QD demonstrates robust clinical activity in docetaxel-pretreated mCRPC patints:– 67% complete or partial bone scan responses– 80% regression of measurable disease– 46% madian pain improvment in patients with pain score

<4• 56% decrease or discontinued narcotics• Activity regardless of prior abiraterone and/or cabazitaxel therapy• Preliminary evidence supports clinical activity at 40 mg QD• Manageable AEs

Phase III trials in mCRCP with survival advantages

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FDA regulatory approvals in mCRCP in US

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Conclusions

• Despite the significant advances in treatment options for patients with CRPC, their prognosis remains poor.

• Targeting multiple signaling pathways may yield better results

• A big challenge is the inability to tailor therapy individually based on the unique characteristics of a particular cancer

• Every patient with CRPC should be encouraged to participate in clinical trial