Prostate Cancer 2009 MDV Anti-Angiogenesis. Anti-androgen Radiotherapy Surgery Androgen Deprivation Therapy. Docetaxel/Epothilone

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1 Prostate Cancer 2009 Anti-Angiogenesis MDV 3100 Anti-androgen Radiotherapy Surgery Androgen Deprivation Therapy Docetaxel/Epothilone Abiraterone DC therapy Bisphosphonates Denosumab

4 Secondary Hormonal Therapy

7 What Determines Whether a Patient Is Castrate Resistant? Has an attempt been made to suppress the patient s testosterone production through orchiectomy or hormone suppression therapy with an LHRH agonist with or without an antiandrogen (ie, ADT)? Is the patient s testosterone level < 50 ng/ml? If the answer to both is yes, the patient is castrate resistant

8 BMI Predicts Survival in HRPC Pooled analysis of 8 CALGB studies in men with prostate cancer who progressed on both ADT and antiandrogen withdrawal (N = 1216) Elevated BMI significantly predictive of longer OS, contrary to original hypothesis HR: 0.97 (95% CI: ; P <.001) Parameter Normal (< 25) *P <.0001 vs normal. Halabi S, et al. J Clin Oncol. 2005;23: Overweight (25-29) BMI Category Mildly Obese (30-34) Moderately to Severely Obese ( 35) Median OS, mos HR (95% CI) * ( ) 0.69* ( ) 0.58* ( )

9 Bone Metastases and Bisphosphonates

Bone Metastasis in Prostate Cancer Bone: most frequent site of prostate cancer

in axial skeleton, then appendicular skeleton Main source of prostate cancer

growth in the bone marrow microenvironment [1] PTHrP IL-6 PGE 2 TNF M-CSF Osteoblast

10 Bone Metastasis in Prostate Cancer Bone: most frequent site of prostate cancer metastasis Favorable microenvironment for prostate tumor cells Lesions first appear in axial skeleton, then appendicular skeleton Main source of prostate cancer associated morbidity Tumor Cells The vicious cycle of bone metastases and tumor cell growth in the bone marrow microenvironment [1] PTHrP IL-6 PGE 2 TNF M-CSF Osteoblast RANKL Osteoclast BMP PDGF FGFs IGFs TGF-β Bone 1. Roodman GD, et al. N Engl J Med. 2004;15:

11 Prophylaxis of Bone Metastases in Prostate Cancer With Zoledronic Acid Bisphosphonates inhibit bone resorption by inhibiting osteoclast activity and proliferation Zoledronic acid approved in combination with standard therapy Zoledronic acid effective in randomized, double-blind, phase III study of prostate cancer patients with bone metastasis following ADT [1] Significant 25% decrease in number of patients experiencing SREs (P =.021) Significantly longer time to first SRE (P =.01) 1. Saad F, et al. J Natl Cancer Inst. 2002;94:

12 Chemotherapy

13 Clinical Trials If a clinical trial is available, it is the first choice of treatment

14 TAX-327: Docetaxel vs Mitoxantrone Median OS significantly longer (P =.004) with docetaxel plus prednisone vs mitoxantrone plus prednisone in patients with metastatic HRPC (N = 1006) Neither age nor baseline PSA level affected survival rates Proportion Alive Docetaxel 3-wkly Docetaxel wkly Mitoxantrone Yrs Berthold DR, et al. J Clin Oncol. 2008;26: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

16 Docetaxel Failure

18 Abiraterone Effects

19 Abiraterone Acetate in CRPC Abiraterone inhibits CYP17 Study Targets androgen receptor signaling by inhibiting androgen synthesis CTC decline associated with improved OS Phase I/II chemotherapy naive Patients with CTC Decline, % 5 CTCs at baseline 34 Decline from > 5 to < 5 CTCs 55 CTC decline by 30% 65 Phase II post-docetaxel 5 CTCs at baseline 76 Decline from > 5 to < 5 CTCs 50 CTCs decline by 30% 73 Reprinted with permission from de Bono JS, et al. ASCO Abstract Probability Time to PSA Progression Phase I/II study (chemo naive) Phase II study (post-docetaxel) Median TTP 399 days 0.25 Median TTP 231 days Days

MDV3100: Novel Androgen Receptor Antagonist Phase I/II dose-escalation study in patients with progressive CRPC (N = 87 to date) showed significant PSA reductions in most evaluable patients PSA Change

20 MDV3100: Novel Androgen Receptor Antagonist Phase I/II dose-escalation study in patients with progressive CRPC (N = 87 to date) showed significant PSA reductions in most evaluable patients PSA Change From Baseline at Week 12 for Chemotherapy-Naive Patients (60, 150, and 240 mg/day) Dose Level, mg/day 90% PSA Decline, n (%) 60 2/22 (9) 150 3/23 (13) 240 8/28 (29) Scher HI, et al. ASCO Abstract Reprinted with permission.

21 Docetaxel/Prednisone ± Dasatinib in CRPC: Phase III Study Patients with metastatic CRPC (Planned N = 1380) Docetaxel + Prednisone + Placebo daily Docetaxel + Prednisone + Dasatinib 100 mg PO daily Primary endpoint: OS Secondary endpoints: untx, time to first SRE, pain intensity, time to PSA progression, tumor response rate, SD, safety/tolerability Available at:

22 VENICE Study Design Multinational, multicenter, double blind, randomized study maipc Stratification factor : ECOG PS (0,1 vs 2) R A N D O M I Z E 1:1 Death Taxotere plus Pred q3w 600 pts + Placebo day 1, q 3 weeks Safety data monitored by and DMC (Q 6 months) Treatment planned until PD, consent withdrawn, or unacceptable toxicity Follow up until death 22

23 Immunotherapy

24 Immunotherapy for CRPC Tumors able to evade immune surveillance Evidence suggests mechanism related to ability to prevent autoimmune disease [1] Investigational immunotherapies for CRPC Sipuleucel-T vaccine: autologous dendritic cell based fusion of PAP and GM-CSF GVAX vaccine: GM-CSF transduced irradiated prostate cancer cells ProstVac: recombinant PSA-expressing vaccinia virus Ipilimumab (MDX-010): monoclonal antibody against CTLA-4 1. Mapara MY, et al. J Clin Oncol. 2004;22:

25 DC-based therapy DC developed from patient monocytes Pulsed with target antigens Stimulated to maturation and inoculated back into patient Currently in Phase II and Phase III trials for melanoma, prostatic carcinoma and lymphoma. Tumour-specific immune responses measured

New Treatment Modalities and Clinical Trials for HRPC 계명의대 김천일

New Treatment Modalities and Clinical Trials for HRPC 계명의대 김천일 Castrate-Resistant Prostate Cancer (CRPC) Current standard therapy Androgen receptor (AR) in CRPC New systemic therapies Hormonal therapy