Development and Complications of Bone Metastases in Men With Prostate Cancer

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1 Development and Complications 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 castration-resistant and metastasize to bone 1 Castration-Sensitive Castration-Resistant Increased Risk of Fracture and Other Skeletal Complications Death PSA/Tumor Burden Start of ADT Increased Risk for Developing Bone Metastases Bone Metastases ADT: Increased Risk for Bone Loss Time 2

3 Many Men With Castration-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 Bone metastases commonly cause debilitating bone pain and pathologic fractures 7-9 Once bone metastases develop, median survival is 21.7 months for men with CRPC (n=171) 10 Consider a bone scan to promptly detect bone metastases in men with rising PSA despite ADT 3

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: 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.

5 Bone Metastases Are Associated With Important Clinical Consequences Consequences of bone metastases in men with prostate cancer: Increased mortality Compared to men without bone metastases, the increased risk for death is: 15 HR=6.6 for men with bone metastases and no skeletal-related events (SREs) HR=10.2 for men with bone metastases plus SREs Debilitating bone pain Patients with bone metastases often experienced debilitating bone pain 16 2 of 3 patients required narcotic pain medication after receiving palliative radiation therapy to bone 17 Fracture and functional impairment Physical and functional impairment was seen in patients who experienced an SRE such as radiation to bone or pathologic fracture 18,19 The average length of stay among men hospitalized for a pathologic fracture was 6.6 days 20 Reduced quality of life A reduced quality of life was reported in men who experienced an SRE such as radiation to bone 19 Increased medical costs Healthcare costs were significantly higher for men with prostate cancer and bone metastases compared with those without bone metastases 21 5

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

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 22,23 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 24 Development of Bone Metastases 2 Circulating prostate cancer cells initially adhere to cells lining blood vessels in bone marrow 25 3 Tumor cells are actively recruited to the bone microenvironment by multiple factors and preferentially adhere to areas of increased bone turnover

ADT increases bone resorption and subsequently releases multiple factors in the bone

metastases 32 37 in Men With Prostate Cancer 6 Increased bone resorption releases

bone destruction leading to the further development of bone metastases 30,31 4 Tumor

overproduce growth factors 30,31 5 Increased levels of growth factors drive excessive

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 30,31 4 Tumor cells that have invaded bone secrete multiple factors that stimulate osteoblasts to overproduce growth factors 30,31 5 Increased levels of growth factors drive excessive osteoclast activity and bone resorption resulting in destruction of the bone matrix 30,31 7

$debilitating bone pain, fracture, physical and functional impairment, and increased mortality In men with prostate cancer and rising PSA despite ADT, the risk of bone metastases is increased with PSA$

8 Development and Complications of Bone Metastases in Men With Prostate Cancer Over 80% of men with CRPC will develop bone metastases which can lead to important clinical consequences, such as debilitating bone pain, fracture, 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 The development of bone metastases depends on complex interactions between prostate cancer cells and the bone microenvironment Consider a bone scan to promptly detect bone metastases in men with rising PSA despite ADT 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: Yau V, et al. J Pain Symptom Manage. 2004;27: Saad F, et al. Urol Oncol. 2006;24: Saad F, et al. J Natl Cancer Inst. 2004;96: Kantoff PW, et al. N Engl J Med. 2010;363: 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 Sathiakumar N, et al. Prostate Cancer Prostatic Dis. 2011;14: Gralow J, Tripathy D. J Pain Symptom Manage. 2007;33: Hartsell WF, et al. J Natl Cancer Inst. 2005;97: Coleman RE. Clin Cancer Res. 2006;12(20 suppl):6243s 6249s. 19. Weinfurt KP, Li Y, Castel LD, et al. Ann Oncol. 2005;16: Barlev A, et al. J Manag Care Pharm. 2010;16(9): 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 R1-V1 3/12

Castrate-resistant prostate cancer: Bone-targeted agents. Pr Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

Castrate-resistant prostate cancer: Bone-targeted agents Pr Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France Disclosure Participation in advisory boards or as a speaker for: Amgen, Astellas,