Development of Bone Metastases in Men With Prostate Cancer

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Oliver Armstrong
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1 Development of Bone Metastases in Men With Prostate Cancer Explore the Causes Understand the Consequences

2 Natural History of Prostate Cancer Progression Many prostate tumors may become castrate-resistant and metastasize to bone 1 Hormone-Sensitive Castrate-Resistant Death PSA/Tumor Burden Initial Diagnosis and Therapy (Surgery/RT) Start of ADT Bone Metastases Increased Risk for Developing Bone Metastases ADT Time 2

Castrate-Resistant Death PSA/Tumor Burden Initial Diagnosis and Therapy

3 Many Men With Castrate-Resistant Prostate Cancer (CRPC) Develop Bone Metastases Over 80% of men with CRPC will develop bone metastases 2-5 Nearly half of men with CRPC developed at least one bone metastasis within 2 years 6 There are currently no FDA approved treatments to delay time to bone metastases in men with CRPC 7 The Prevention of Bone Metastases for Men With CRPC Represents an Area of Unmet Medical Need 3

metastasis within 2 years 6 There are currently no FDA approved treatments to delay time to bone

4 Identification of Men at Risk for Bone Metastases Is Important In men with prostate cancer and rising PSA despite ADT, the risk of bone metastases is increased with: 7 10 High absolute PSA levels (>10 ng/ml) Rapidly rising PSA levels or short PSA doubling time Shorter PSA Doubling Time Is Associated With Decreased Bone Metastasis-Free Survival Proportion of Patients With Bone Metastases or Died PSADT <6.3 months PSADT months PSADT >18.8 months PSADT = PSA doubling time Years Since Randomization Assignment 4 A retrospective analysis of 201 patients with nonmetastatic prostate cancer and PSA progression despite ADT showed a statistically significant correlation of baseline PSA levels and increasing PSA velocity with shorter time to bone metastases. Baseline PSA level greater than 10 ng/ml (relative risk, 3.18, 95% CI, ; P<0.001) and PSA velocity (relative risk, 4.34 for each 0.01 increase in PSA velocity; 95% CI, ; P<0.001) independently predicted shorter time to first bone metastasis in the reduced multivariate Cox regression model.

Died 1.0 0.8 0.6 0.4 0.2 0 PSADT <6.3 months PSADT 6.3 18.8 months PSADT >18.8 months 0 0.5 1.0 1.5 2.0 2.5 3.

5 Bone Metastases Are Associated With Important Clinical Consequences Consequences of bone metastases in men with prostate cancer: Increased mortality 11 In men with bone metastases from prostate cancer and no skeletal-related events, the one-year mortality rate was 4.7 times higher than in men with no bone metastases Debilitating bone pain 12 Patients with bone metastases often experienced debilitating bone pain Physical and functional impairment 13,14 Physical and functional impairment was seen in patients who experienced a skeletal-related event such as radiation to bone or pathologic fracture Reduced quality of life 14 A reduced quality of life was reported in men who experienced a skeletal-related event such as radiation to bone Increased medical costs 15 Healthcare costs were significantly higher for men with prostate cancer and bone metastases compared with those without bone metastases 5

$and functional impairment was seen in patients who experienced a skeletal-related event such as radiation to bone or pathologic fracture Reduced quality of life 14 A reduced quality of life was$

6 The Development of Bone Metastases Depends on Complex Interactions Between Prostate Cancer Cells and the Bone Microenvironment Multiple factors influence interactions between the tumor cells, the seed, and the bone microenvironment, the soil, to promote the development of bone metastases 16,17 1 Prostate cancer cells shed from the primary tumor enter the circulation, and release growth factors, cytokines, and other proteins which promote adhesion and proliferation to the bone 18 Development of Bone Metastases 2 Circulating prostate cancer cells initially adhere to cells lining blood vessels in bone marrow 19 3 Tumor cells are actively recruited to the bone microenvironment by multiple factors and preferentially adhere to areas of increased bone turnover

growth factors, cytokines, and other proteins which promote adhesion and proliferation to the bone 18 Development of Bone Metastases 2 Circulating prostate cancer cells initially adhere to

7 ADT increases bone resorption and subsequently releases multiple factors in the bone microenvironment which may create more fertile conditions for the development of bone metastases in Men With Prostate Cancer 6 Increased bone resorption releases growth factors from the bone matrix, which may further stimulate tumor growth and bone destruction leading to the further development of bone metastases 24,25 4 Tumor cells that have invaded bone secrete multiple factors that stimulate osteoblasts to overproduce growth factors 24,25 5 Increased levels of growth factors drive excessive osteoclast activity and bone resorption resulting in destruction of the bone matrix 24,25 7

destruction leading to the further development of bone metastases 24,25 4 Tumor cells that have invaded bone secrete multiple factors that stimulate osteoblasts to

8 Development of Bone Metastases in Men With Prostate Cancer The prevention of bone metastases for men with CRPC represents an area of unmet medical need Over 80% of men with CRPC will develop bone metastases which can lead to important clinical consequences, such as debilitating bone pain, physical and functional impairment, and increased mortality In men with prostate cancer and rising PSA despite ADT, the risk of bone metastases is increased with PSA levels >10 ng/ml, rapidly rising PSA levels or short PSA doubling time There are currently no FDA approved treatments to delay time to bone metastases in men with CRPC The development of bone metastases depends on complex interactions between prostate cancer cells and the bone microenvironment 1. Smith MR. Eur Urol Suppl. 2009;8: Scher HI, Morris MJ, Kelly WK, et al. Clin Cancer Res. 2005;11: Tannock IF, de Wit R, Berry WR, et al. N Engl J Med. 2004;351: Petrylak DP, Tangen CM, Hussain MHA, et al. N Engl J Med. 2004;351: Shah RB, Mehra R, Chinnaiyan AM, et al. Cancer Res. 2004;64: Smith MR, Cook R, Lee KA, Nelson JB. Cancer. 2011;117: National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Prostate Cancer. V Smith MR, Kabbinavar F, Saad F, et al. J Clin Oncol. 2005;23: Petrylak DP. Eur Urol Suppl. 2007;6: Moreira D, Aronson W, Terris M, et al. J Urol. 2010;183(suppl):e335-e Nørgaard M, Jensen AO, Jacobsen JB, et al. J Urol. 2010;184: Gralow J, Tripathy D. J Pain Symptom Manage. 2007;33: Coleman RE. Clin Cancer Res. 2006;12(20 suppl):6243s 6249s. 14. Weinfurt KP, Li Y, Castel LD, et al. Ann Oncol. 2005;16: Schulman KL, Kohles J. Cancer. 2007;109: Chiang AC, Massague J. N Engl J Med. 2008;359: Piris A, Mihm MC. Cancer Treat Res. 2007;135: Loberg RD, Logothetis CJ, Keller ET, Pienta KJ. J Clin Oncol. 2005;23: Fidler IJ. Nat Rev Cancer. 2003;3: Pienta KJ, Loberg R. Clinical Prostate Cancer. 2005;4: Chung LWK, Baseman A, Assikis V, Zhau HE. J Urol. 2005;173: Tantivejkul K, Kalikin LM, Pienta KJ. J Cell Biochem. 2004;91: Logothetis CJ, Lin SH. Nat Rev Cancer. 2005;5: Roodman GD. N Engl J Med. 2004;350: Mundy GR. Nat Rev Cancer. 2002;2: Padalecki SS, Carreon M, Grubbs B, Cui Y, Guise TA. Oncology. 2003;17: Jennbacken K, Tesan T, Wang W, et al. Endocrine-Related Cancer. 2010;17: Lee YC, Cheng CJ, Huang M, et al. J Pathol. 2010;221: Michaelson MD, Marujo RM, Smith MR. Clin Cancer Res. 2004;10: van der Pluijm G, Que I, Sijmons B, et al. Cancer Res. 2005;65: Thalmann GN, Anezinis PE, Chang SM, et al. Cancer Res. 1994;54: Amgen Inc. All rights reserved. MC53390-D 5M/6-11 P48108

despite ADT, the risk of bone metastases is increased with PSA levels >10 ng/ml, rapidly rising PSA levels or short PSA doubling time There are currently no FDA approved treatments to delay time to

Pathophysiology of bone metastasis : how does it apply to pain treatment in palliative care? JP Vuillez, Grenoble, France

Pathophysiology of bone metastasis : how does it apply to pain treatment in palliative care? JP Vuillez, Grenoble, France Bone metastases 70 % of prostate and breast cancers 30 % of lung, bladder and thyroid