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#902P Prevalence of Non-metastatic Castration-Resistant Prostate Cancer in Europe Alexander Liede, Oliver Günther, Brian Bennett, and Steven Wong 1 Model Assumptions and Source Data • The model estimated prevalent patients within each clinical state at a specific point in time using a dynamic patient flow model to accurately represent how tumors progress, go into remission, recur, and respond to multiple courses of therapy (Figures 1 & 2). – Patients could enter a specific state (“inflow”) as the result of either newly diagnosed cancer, recurrence, or progression (Figure 2). – The model also accounts for all-cause mortality (“outflow”) associated with each state over time. Recurrence or progression represent outflows from clinical states, including presence/absence of clinically detectable metastatic disease, prior treatment, and castration-sensitive and CRPC phases (during ADT treatment). – In this model, patients could only move forward from state to state, and could not move backward into a previous state. • The model uses a 19-year simulation initiating in 2008, using annual PC incidence and distribution across the stage at diagnosis. • The fundamentals of the model are described by Verdecchia et al (2002)10 for estimation and projections of cancer prevalence from cancer registry data. Prevalence is estimated from the modeled incidence and survival estimates and approximates the limited-duration prevalence that would be recorded in a cancer registry. – Relative survival estimates are derived directly from incidence and follow-up data and population life tables, using standard survival analysis methods. – All incident cases of PC recorded by country-level cancer registry (or GLOBOCAN1 if country-level data were not available or not current), are allocated to cells within a two-dimensional matrix defined by age at the index date and the number of years passed since diagnosis (duration). Limited-duration prevalence is the resulting sum of numbers from corresponding index date and duration combinations. Limited-duration prevalence is also segmented by duration, by age cohort, and by stage. Incidence • All annual incidence rates were obtained directly from population-based national cancer registries: – l’Institut de veille sanitaire/l’Institut national du cancer (France)11 – Robert Koch Institut (Germany)12 – Istituto superiore di sanità (Italy)13 – GLOBOCAN 2002, 2008 (Spain, EU-5)1,14 – Cancer Research U.K.15 – and Austrian National Cancer Register16 • The model assumes that diagnosis rates will have stabilized during the projection period and will not continue to grow. • Age-adjusted incidence rates in 2010 are generated for each country (Table 1). The model assumes that these age-specific PC incidence rates will not continue to increase and will remain constant through the projection period, with age demographics driving growth in incidence.17 Table 1. Age-adjusted PC Incidence Rates in Each EU-5 Country, 2010 and 2026 (per 100,000 Males in the Population) France Germany Italy Spain U.K. 2010 227.4 159.6 133.7 116.7 126.0 2026 286.4 209.3 167.6 151.5 150.1 PSA Levels/Tumor Burden Limited data: Literature (U.S.) or IMS Oncology Analyser™ (EU-5) Metastasis Treatment rates: Literature and IMS Oncology Analyser™ (EU-5) Androgen Deprivation Therapy (ADT) Graph adapted from: Smith MR. Eur Urol Suppl 2009; 8(11): 821-838. *Data gaps in understanding of disease burden (prevalence) indicated. Stage Distribution • Stage distribution data from cancer registries demonstrate how increased PSA testing in Europe has led to diagnosis of PC at earlier stages. – Munich Cancer Registry integrated with recent Schleswig-Holstein registry data (Germany)18,19 – Munich Cancer Registry (Germany) integrated with Stage IV data from literature (France,20 Italy21 [no data for Spain, Italy data used]) – Northern Ireland Cancer Registry Cancer Services Audit (U.K.)22 ADT Treatment • For country-specific inputs, IMS Oncology Analyser™ “evidence of ADT” data were used.23 – IMS Oncology Analyser™ routinely captures data on patients treated by participating physicians: from 2005 to 2011, there are up to 58,000 patients per year treated by nearly 822 physicians in EU-5.23 – The model utilizes the average country-specific ADT rates, as reported for 17,842 M0 PC patients in EU-5 between January 1, 2005 and December 31, 2011. Recurrence and Progression • IMS Oncology Analyser™ data from 2005-2011 reveal country-level trends in • Based on literature, the model assumed that 35% of patients with Stage ADT in EU-5 (Figure 3). I, II, and III disease have PSA relapses (estimates range from 12% to • Overall, ADT rates from IMS Oncology Analyser™ for EU-5 are consistent with 59% in studies of newly diagnosed patients 5 to 15 years after radical the “any ADT” rate of approximately 45% reported in the literature from U.S. prostatectomy or radiotherapy).28,29 studies.24,25 – 44.8% in first year of diagnosis: 36% T1, 46% T2, and 76% T324 • This assumption is consistent with a recent study of PSA-level data from – 43.2% in first year of diagnosis among T1 and T2 cases25 electronic medical records in the U.S., which found CRPC among 36% of patients with M0 disease treated with ADT. Survival – Pirolli et al (2012)30 defined CRPC consistent with clinical trials using • Historically, survival for patients with PC in Europe is lower than survival for sequential rises in PSA (PSA1 < PSA2 < PSA3), with data on 1,818 men patients in the U.S. from 328 oncology and urology clinics in the U.S. with M0 PC and ≥ 1 • As diagnosis and treatment of PC in Europe have been improving compared to PSA recorded during a 1-year period (March 2010 to March 2011) and historical trends, survival in Europe will improve to the same extent as in the recently treated with ADT for ≥ 6 months. U.S. • Accordingly, the model is based on country-specific survival data from EUROCARE-4,26 adjusted to SEER survival curves or trends observed in the U.S.27 Figure 4. Five-Year Prevalence of PC During Projection Period, Based on Recent Cancer Registry Data 60.0% 40.0% 20.0% 0.0% EU-5 France Germany Italy Spain U.K. 2005 50.0% 37.5% 55.6% 27.3% 41.6% 73.6% 2006 47.9% 34.4% 45.2% 22.9% 47.1% 73.3% 1,200,000 1,000,000 100,000 800,000 80,000 400,000 200,000 0 EU-5 France Germany Italy Spain U.K. 2008 793,742 210,880 224,793 143,308 78,442 136,319 2010 911,161 258,591 258,063 154,271 93,524 146,711 2012 2014 2016 2018 2020 2022 2024 2026 973,145 1,012,641 1,054,885 1,097,035 1,137,975 1,179,383 1,221,401 1,263,952 284,755 298,947 314,819 330,280 344,443 357,855 370,683 383,159 274,212 283,198 292,400 301,919 311,707 321,919 332,300 342,691 160,080 165,850 171,739 177,612 183,437 189,515 195,896 202,586 101,614 106,104 111,034 116,041 121,098 126,621 132,795 139,598 152,484 158,542 164,892 171,184 177,291 183,472 189,727 195,918 600,000 40,000 200,000 20,000 EU-5 France Germany Italy Spain U.K. 2008 662,750 173,165 198,320 114,991 61,610 114,665 2010 768,274 215,232 229,275 124,993 74,579 124,195 2012 823,643 238,521 244,284 130,130 81,593 129,114 2014 858,272 250,971 252,431 135,216 85,426 134,228 2016 895,841 265,136 260,767 140,522 89,719 139,696 2018 933,233 278,976 269,317 145,782 94,067 145,090 2020 2022 969,281 1,005,728 291,626 303,645 278,041 287,154 150,935 156,295 98,407 103,119 150,273 155,516 2024 1,042,695 315,174 296,420 161,908 108,369 160,824 2026 1,080,111 326,398 305,699 167,781 114,148 166,085 41.2% 28.8% 40.0% 20.5% 49.3% 56.9% 300,000 250,000 200,000 150,000 • This model provides the first understanding of number of men living in Europe with M0 CRPC. • Although M0 CRPC represents a small subset of the overall PC population (Figure 7), the model predicts an increase in the prevalence of CRPC over the next 14 years. • As men with M0 CRPC have an increased risk of developing metastases (particularly to bone) resulting in a shortened lifespan, these findings highlight the need for clinical trials to establish standards of care for these patients, and for new therapeutic options. LIMITATIONS 100,000 50,000 274,212 244,284 22,017 Italy 160,080 130,130 6,288 Spain 101,614 81,593 9,548 U.K. 152,484 129,114 16,760 Austria 21,065 17,170 1,511 • The prevalence model is dependent on the accuracy and precision of the source data (e.g., incidence data from population-based cancer registries), which may decrease with each population segment in the model, with great statistical variation driven by the ADT assumptions. • Further research is underway in 2012 to validate ADT rates for EU-5 (from IMS Oncology Analyser™), as well as to provide current data on ADT rates in additional European countries. 1. Ferlay J et al. GLOBOCAN. 2008. http://globocan.iarc.fr, Lyon, IARC, 2010. 2. Jemal A et al. CA Cancer J Clin. 2011; 61: 69-90. 3. Quinn M, Babb P. BJU Int. 2002; 90: 162-173. 4. Neppl-Huber C et al. Ann Oncol. 2012; 23(5): 1325-1334 (Epub 2011 Sep 28). 5. Kvåle R et al. J Natl Cancer Inst. 2007; 99: 1881-1887. 6. Shulman MJ, Benaim EA. J Urol. 2004; 172: 141-145. 7. Smith MR et al. J Clin Oncol. 2005; 23: 2918-2925. 8. Bubendorf L et al: Hum Pathol. 2000; 31: 578-583. 9. Sathiakumar N et al. PC Prostatic Dis. 2011; 14: 177-183. 10. Verdecchia A et al. Stat Med. 2002; 21: 3511-3526. 11. Institut national du cancer (INCa), Projections de l'incidence et de la mortalité par cancer en France en. 2011, http://www.invs.sante.fr, 2011. 12. Robert Koch Institut. Cancer in Germany. 2005/2006: Incidence and Trends, http://www.rki.de, 2010. 13. Istituto superiore di sanità, AIRTUM database, http://www.registri-tumori.it/, 2006. 14. Ferlay J et al. GLOBOCAN 2002. Lyon, IARC, 2004. 15. Cancer Research U.K., CancerStats, http://info.cancerresearchuk.org/cancerstats/, 2011. 16. STATISTICS AUSTRIA, Austrian National Cancer Register (as of 13 September 2011). Compiled on 10 October 2011. 2008 44.0% 35.9% 41.5% 25.1% 55.0% 54.7% 2009 46.3% 34.6% 44.9% 24.8% 57.3% 62.1% 2010 41.8% 33.4% 29.5% 22.0% 59.5% 53.3% 2011 41.6% 30.3% 20.4% 23.1% 63.5% 55.0% 2005-2011 44.8% 33.4% 41.6% 23.6% 52.3% 62.2% 60,000 400,000 0 2007 Figure 6. Five-Year Prevalence of M0 CRPC During Projection Period, Modeled Using Country-Level IMS Oncology Analyser™ ADT Treatment Rates (see Figure 3) 120,000 Figure 7. Five-Year Prevalence of PC, M0 PC, and M0 CRPC in 2012, Modeled Using Country-Level Rates From IMS Oncology Analyser™ (EU-5) or Literature Treatment Rates With ADT (Austria) 284,755 238,521 18,001 80.0% 1,200,000 600,000 # CRPC 100.0% 1,400,000 800,000 35% Figure 3. Trend Analysis of “Evidence of ADT” Among Patients with M0 PC Represented In IMS Oncology Analyser™23 Figure 5. Five-Year Prevalence of M0 PC During Projection Period, Modeled From Cancer Registry Data 1,000,000 # Treated with ADT Recurrence and progression: Literature, 35% PSA relapse rate applied to relapse curve (results in19% to 25% range over projection period due to increases in survival) 0 EU-5 France Germany Italy Spain U.K. 2008 48,576 10,971 14,908 4,486 6,032 12,178 2010 62,112 15,166 18,994 5,379 8,101 14,472 2012 72,613 18,001 22,017 6,288 9,548 16,760 2014 82,448 20,145 24,766 7,373 10,701 19,463 2016 89,810 21,930 26,709 8,145 11,615 21,411 2018 93,836 23,123 27,663 8,495 12,205 22,350 2020 98,136 24,345 28,768 8,861 12,858 23,305 2022 2024 2026 102,690 106,461 110,290 25,548 26,495 27,419 29,985 30,958 31,926 9,260 9,593 9,941 13,584 14,278 15,047 24,313 25,138 25,957 DISCLOSURES REFERENCES Germany # Non-metastatic Treatment rates: Literature, 45% “any ADT”, consistent with 44.6% “evidence of ADT” per IMS Oncology Analyser™ for Germany Recurrence and progression: Metastatic disease # CRPC CONCLUSIONS PC M0 PC M0 CRPC # Not treated with ADT # Treated with ADT Recurrence and progression: Literature, 35% PSA relapse rate applied to relapse curve (results in19% to 25% range over projection period due to increases in survival) Time France Stage distribution: Stage IV metastatic data from Munich Cancer Registry (Germany) integrated with Stage IV data from literature (Italy, no data available for Austria) Metastatic # Non-metastatic 81.5% 45% CRPC 0 # Men living with PC in 2012 Incidence: Austrian National Cancer Register incidence rates applied to UN population projections Mortality: Cancer registry, data by stage and diagnosis year with adjustment to recent trends Survival: EUROCARE-4 survival data for Austria with adjustment to recent trends in SEER Stage distribution: Cancer registry, non-metastatic (stage I-III, IV M0) Start of ADT • For EU-5 countries, the model projects that 5-year prevalence of PC will increase from approximately 1.0 million in 2012 to as high as 1.3 million in 2026 (Figure 4). • M0 PC, which comprises about 85% of all PC 5-year prevalence, will increase from approximately 0.8 million in 2012 to 1.1 million by 2026 (Figure 5). • M0 CRPC is projected to exceed 70,000 with a projected increase to 110,000 patients by 2026 (Figure 6). • In 2012, projected prevalence of M0 CRPC in EU-5 is approximately 7% of the total PC prevalence using “evidence of ADT” rates per IMS Oncology Analyser™ in the M0 setting. – Figure 7 summarizes estimates for EU-5 and Austria using the same methodology, although ADT rates for Austria are based on the published literature (45%). Inflow Survival: Cancer registry, data by stage and diagnosis year with adjustment to recent trends Prevalance not available* RESULTS Outflow # Men living with PC in 2012 Incidence: Cancer registry, new cases from previous 5 years B: Data Sources Contributing to Assumptions in Patient Flow Prevalence Model: Austrian Example Men METHODS PC diagnosis Inflow Men To estimate the prevalence of PC, M0 PC, and M0 CRPC by country in key European countries (EU-5), and for each year from 2008 to 2026 (the projection period). • Prevalence: 5-year limited-duration prevalence is provided and refers to the number of men diagnosed with PC in the previous 5 years and alive on index date (December 31) of projection year of interest. • EU-5 countries: France, Germany, Italy, Spain, and United Kingdom (U.K.) • To illustrate the model, data from Austria have been presented. Cancer registry data: Incidence, some prevalence1 A. Country-level Data “Inflows” and “Outflows” in the Patient Flow Prevalence Model by Population Segment for 2012. Castration-Resistant Death Castration-Sensitive Men STUDY OBJECTIVE Figure 2. Disease States of Interest in Treatment Paradigm Figure 1. Hypothetical Patient Diagnosed with M0 PC Illustrating States and Treatments Over Time Coinciding with Elevated PSA Levels and Leading to Metastasis and Death* Men • Prostate cancer (PC) is the second most common cancer diagnosed among men, with approximately 900,000 men diagnosed each year worldwide (13.8% of all cancer incidence), and constitutes the third most common cause of cancer-related death in men in developed countries.1,2 • In Europe, the incidence of reported PC has increased dramatically over the last two decades as a result of widespread prostate-specific antigen (PSA) screening.3,4 Although the specific timing differs by country, mortality has declined in tandem with increased incidence trends, and the vast majority of men present with localized disease with no metastases.3-5 • During an initial hormone- or castration-sensitive phase, a rise in PSA levels can occur after a variable time interval following primary surgical or radiation treatment, prompting initiation of androgen-deprivation therapy (ADT) (Figure 1). ADT can substantially control disease and decline serum PSA levels in almost all patients.6 • Although PCs are initially castration sensitive and respond to ADT,7 nearly all patients progress to castration-resistant PC (CRPC), a disease state defined by rising PSA levels during effective ADT in the absence of metastases. • CRPC patients are at increased risk for developing clinically apparent metastatic disease, particularly to bone.6,7 Patients with PC and bone metastases have a significantly shortened lifespan compared with patients without metastases.8,9 Survival has been reported as 1 to 2 years.9 • Non-metastatic (M0) CRPC is a growing public health burden that has not been adequately quantified. • We report results of a model to estimate the prevalence of M0 CRPC in major populations in Europe. 3 Center for Observational Research, Amgen Inc., Thousand Oaks, California, USA; 2Center for Observational Research, Amgen Ltd, Uxbridge, UK; 3Plan A Inc., Mountain View, California, USA METHODS (Continued) BACKGROUND 3 % ADT for Men with M0 PC 1 2 17. United Nations, World Population Prospects: The 2010 Revision. 2011. 18. Munich Cancer Registry, Spezielle Auswertungen C61: Prostatakarzinom, http://www.tumorregistermuenchen.de, 2010. 19. Rohde V et al. Urol Int. 2009, 83: 134-140. 20. Flamand V et al. Prog Urol. 2008; 18: 53-59. 21. Bono AV et al. Eur Urol. 1996; 30 Suppl 1: 2-6; discussion 19-21. 22. Gavin A et al. Cancer Services Audit. 1996 & 2001, Prostate, 2005. 23. IMS Oncology Analyzer™ analyses, IMS Health (and Amgen Inc.), 2011-2012. 24. Gilbert SM et al. Urol Oncol. 2009; 29(6): 647-653 (Epub 2009 Nov 19). 25. Shahinian VB et al. N Engl J Med. 2010; 363: 1822-1832. 26. Istituto superiore di sanità, EUROCARE-4, http://www.eurocare.it, 2009 27. Surveillance, Epidemiology, and End Results (SEER), SEER*Stat Database: Incidence—SEER 9 Regs Research Data, Nov 2010 Sub (1973–2008), www.seer.cancer.gov, 2011. 28. Pound CR et al. JAMA. 1999; 281: 1591-1597. 29. Amling CL et al. J Urol. 2000; 164: 101-105. 30. Pirolli M et al. J Clin Oncol (suppl). 2012; 30 (abstr 1581). • This study was funded by Amgen Inc. • Alex Liede and Oliver Günther are employees of Amgen Inc. and have received stock or stock options. • Brian Bennett and Steven Wong are consultants at Plan A. ACKNOWLEDGEMENTS • IMS Health provided analyses of IMS Oncology Analyser™ for this study. • We would like to thank Albert Y. Rhee, Amgen Inc. for assistance with the poster. European Society for Medical Oncology, Vienna, Austria; Sept 28 – Oct 2, 2012