UNC Cancer Epidemiology Seminar: Cancer Risk in New Users of Overactive Bladder Drugs

Transcription

1 February 19, 2016 UNC Cancer Epidemiology Seminar: Cancer Risk in New Users of Overactive Bladder Drugs James A. Kaye, MD, DrPH Senior Director, Epidemiology, RTI Health Solutions Collaborators: Andrea V. Margulis, Estel Plana, Jennifer Bartsch, Brian Calingaert, Susana Perez-Gutthann, Alejandro Arana rtihs.org Research Triangle Park Ann Arbor Barcelona Ljungskile Manchester Waltham

2 Disclosures All coauthors are full-time employees of RTI Health Solutions (RTI-HS), which received funding from Astellas Pharma to conduct this study The contract between RTI-HS and the sponsor includes independent publication rights Some of the findings to be discussed today were presented in an oral session at the 31st International Conference on Pharmacoepidemiology and Therapeutic Risk Management, Boston, August 2015 (Abstract #52) 2

3 Background January

4 Background Mirabegron, a beta-3 adrenergic agonist Introduced in 2012 by Astellas Pharma in the US and EU Clinical trials ( 1 year duration) suggested modestly increased risk of several cancers Relative risk (RR) for any malignancy for patients treated with mirabegron vs. tolterodine: 1.83 (95% CI, ) in all patients in global phase 2/3 program (5,863 mirabegron-exposed) 2.45 (95% CI, ) in patients treated for 12 weeks in global phase 2/3 program Cancers were various types occurring commonly in the general population Nonclinical studies had not identified mutagenic or genotoxic effects CI = confidence interval; EU = European Union; US = United States. 4

5 Background RTI-HS and several research partners are collaborating on a multidatabase postauthorization safety program: US: Optum Research Database (Optum) US: Comprehensive Health Insights (Humana) UK: Clinical Practice Research Datalink (CPRD) (analysis by RTI-HS) Denmark: Danish linked national registries (University of Southern Denmark) Sweden: Swedish linked national registries (Centre for Pharmacoepidemiology, Karolinska Institutet) Pilot studies of new users of anticholinergic drugs for overactive bladder (OAB) completed Drug utilization studies Cancer incidence rates estimated and explored Acute cardiovascular outcomes also assessed This presentation focuses on cancer incidence rates in the UK (CPRD) 5

6 Study Design Cohort of adult new users of antimuscarinic OAB drugs (2004 to 2012) CPRD data sources: All practices: GP electronic medical records with selected free text (additional information for validation of cancer diagnoses) Linkable practices: data also include National Cancer Data Repository (NCDR) and Hospital Episode Statistics (HES) Study exposures: Oxybutynin, tolterodine, solifenacin, trospium, fesoterodine, darifenacin Cancer outcomes: Sex-specific composites of 10 most commonly occurring cancers (other than nonmelanoma skin cancer), and individual cancers: Colorectal, pancreas, lung, melanoma, bladder, kidney, non-hodgkin lymphoma Prostate (men) Breast and uterus (women) GP = general practitioner. 6

7 Study Design Eligibility: First use of an OAB medication 12 months continuous enrollment before index prescription Exclusions: Prior cancer diagnosis other than nonmelanoma skin cancer HIV infection/medication Validation subcohort sampled from linked and nonlinked practices Results presented here are for all practices 7

8 Study Design Person-time censored after study or nonstudy cancer diagnosis Person-time also censored after double mastectomy in breast cancer analyses or hysterectomy in uterine cancer analyses Cancer rates analyzed by exposure to each study drug Ever exposed (vs. not yet exposed) Exposed to single OAB drug Cumulative exposure Cancer rates also stratified by time since cohort entry 6-month and 12-month intervals explored Standardized incidence rates per 1,000 person-years, with 95% CIs Age and sex distribution of entire follow-up time of study cohort used as the standard CIs = confidence intervals. 8

9 Patient Characteristics, by OAB Drug at Cohort Entry Oxybutynin (n = 40,651) Tolterodine (n = 37,506) Solifenacin (n = 33,120) Trospium (n = 6,071) Fesoterodine (n = 2,344) Darifenacin (n = 151) Variable n (%) n (%) n (%) n (%) n (%) n (%) Age at cohort entry (years) Mean (SD) , , , , , , , , , , , , , , , , , , , , , , , , Sex Male 13, , , , Female 27, , , , , Calendar year at cohort entry , , , , , , , , , , , , , , , , , , , , , , , , , , , , Note: A total of 69 patients (not shown in table) had prescriptions for more than one study OAB drug at cohort entry. 9

10 Composite Cancer Incidence Rates by Ever Use of OAB Drugs Males a Incidence rates per 1,000 person-years were standardized to the sex-specific age distribution of the total study population persontime. Events Patients Person-time (Years) Standardized Incidence Rate a (95% CI) Any OAB drug 1,917 36, , (16.2, 17.7) Oxybutynin ,599 45, (17.0, 19.5) Tolterodine ,149 54, (14.3, 16.4) Solifenacin ,512 29, (15.3, 18.3) Trospium 181 3,179 10, (13.7, 18.5) Fesoterodine 40 1,494 2, (12.1, 23.2) Darifenacin (8.3, 39.4) Females Any OAB drug 2,200 83, , (7.4, 8.0) Oxybutynin , , (7.5, 8.5) Tolterodine 1,083 32, , (7.3, 8.2) Solifenacin ,247 97, (7.0, 8.2) Trospium 240 7,918 29, (6.7, 8.7) Fesoterodine 49 4,395 7, (5.1, 9.2) Darifenacin , (3.0, 12.7) 10

11 Incidence Rates for Individual Study Cancers, Males, Ever Treated With Any OAB Drug Note: 36,157 patients contributed 113,293 person-years of follow-up time for all cancers listed. a Incidence rates per 1,000 person-years were standardized to the sex-specific age distribution of the total study population person-time. Events Standardized Incidence Rate a (95% CI) Bladder (2.6, 3.2) Colorectal (1.8, 2.3) Kidney (0.4, 0.6) Lung (1.6, 2.2) Melanoma (0.3, 0.6) Non-Hodgkin lymphoma (0.4, 0.7) Pancreatic (0.3, 0.6) Prostate (7.7, 8.8) 11

12 Incidence Rates for Individual Study Cancers, Females, Ever Treated With Any OAB Drug Events Standardized Incidence (95% CI) Rate a Bladder (0.6, 0.8) Colorectal (1.0, 1.2) Kidney (0.2, 0.3) Lung (0.9, 1.1) Melanoma (0.4, 0.6) Non-Hodgkin lymphoma (0.2, 0.4) Pancreatic (0.3, 0.4) Uterus, body (0.6, 0.8) Breast (2.9, 3.3) Note: 83,702 patients contributed 286,071 person-years of follow-up time for all cancers listed except for breast (83,681 patients, 286,005 person-years) and uterus (62,163 patients, 203,953 person-years). a Incidence rates per 1,000 person-years were standardized to sex-specific age distribution of the total study population person-time. 12

13 Incidence Rates for Prostate Cancer, Males, Ever Treated With Each OAB Drug Events Standardized Incidence Rate a (95% CI) Any OAB drug (7.7, 8.8) Oxybutynin (7.9, 9.6) Tolterodine (6.5, 8.0) Solifenacin (7.2, 9.3) Trospium (6.2, 9.5) Fesoterodine (5.9, 14.4) Darifenacin (1.4, 22.5) a Incidence rates per 1,000 person-years were standardized to the sex-specific age distribution of the total study population person-time. 13

14 Incidence Rates for Bladder Cancer, Males, Ever Treated With Each OAB Drug Events Standardized Incidence Rate a (95% CI) Any OAB drug (2.6, 3.2) Oxybutynin (2.8, 3.9) Tolterodine (2.2, 3.0) Solifenacin (2.5, 3.8) Trospium (1.6, 3.5) Fesoterodine (1.1, 5.9) Darifenacin (0.6, 20) a Incidence rates per 1,000 person-years were standardized to the sex-specific age distribution of the total study population person-time. 14

15 Incidence Rates for Bladder Cancer, Females, Ever Treated With Each OAB Drug Events Standardized Incidence Rate a (95% CI) Any OAB drug (0.6, 0.8) Oxybutynin (0.7, 1.0) Tolterodine (0.5, 0.8) Solifenacin (0.7, 1.1) Trospium (0.5, 1.2) Fesoterodine (0.5, 2.3) Darifenacin (0.0, 4.7) a Incidence rates per 1,000 person-years were standardized to the sex-specific age distribution of the total study population person-time. 15

16 Prostate Cancer Rates by Time Since Entry, Males 16

17 Bladder Cancer Rates by Time Since Entry, Males 17

18 Colorectal Cancer Rates by Time Since Entry, Males 18

19 Lung Cancer Rates by Time Since Entry, Males 19

20 Bladder Cancer Rates by Time Since Entry, Females 20

21 Breast Cancer Rates by Time Since Entry, Females 21

22 Colorectal Cancer Rates by Time Since Entry, Females 22

23 Lung Cancer Rates by Time Since Entry, Females 23

24 Prostate Cancer Incidence Rates for the Most Frequently Prescribed OAB Drugs, by Cumulative Dose Events Patients Persontime (Years) Incidence Rate a 95% CI Oxybutynin ,369 16, , > 200 to 1, ,887 17, , > 1, ,004 10, , 7.49 Tolterodine ,076 21, , 9.68 > 200 to 1, ,589 21, , 8.42 > 1, ,270 10, , 6.82 Solifenacin ,438 8, , > 200 to 1, ,054 13, , 9.58 > 1, ,544 7, , 6.78 a Incidence rates per 1,000 person-years were standardized to the sex-specific age distribution of the total study population person-time. 24

25 Bladder Cancer Incidence Rates for the Most Frequently Prescribed OAB Drugs, by Cumulative Dose, Males Events Patients Persontime (Years) Standardized Incidence Rate a 95% CI Oxybutynin ,369 16, , 5.48 > 200 to 1, ,887 17, , 4.41 > 1, ,004 10, , 2.95 Tolterodine ,076 21, , 3.60 > 200 to 1, ,589 21, , 3.45 > 1, ,270 10, , 2.99 Solifenacin ,438 8, , 5.14 > 200 to 1, ,054 13, , 4.69 > 1, ,544 7, , 3.24 a Incidence rates per 1,000 person-years were standardized to the sex-specific age distribution of the total study population person-time. 25

26 Bladder Cancer Incidence Rates for the Most Frequently Prescribed OAB Drugs, by Cumulative Dose, Females Events Patients Persontime (Years) Standardized Incidence Rate a 95% CI Oxybutynin ,278 44, , 1.37 > 200 to 1, ,777 39, , 1.22 > 1, ,282 23, , 0.87 Tolterodine ,298 58, , 1.03 > 200 to 1, ,047 52, , 0.75 > 1, ,234 25, , 0.86 Solifenacin ,946 29, , 1.62 > 200 to 1, ,193 42, , 1.10 > 1, ,022 23, , 1.13 a Incidence rates per 1,000 person-years were standardized to the sex-specific age distribution of the total study population person-time 26

27 Prostate Cancer (C61): European Age-Standardized Incidence Rates per 100,000 Population, Males, Great Britain Prepared by Cancer Research UK - original data sources are available from 27

28 Prostate-Specific Antigen Testing Among Patients With Prostate Cancer, by Year Time Period Year prior to cohort entry date First year of follow-up Second year Third year Fourth year Fifth year Sixth year Seventh year Eighth year Number of Patients Patients With PSA Test During Time Period Note: 36,157 patients contributed 113,293 person-years of follow-up time for all cancers listed. a Incidence rates are standardized to sex-specific age distribution of the total study population person-time. Ninth year PSA = prostate-specific antigen %

29 Prostate Cancer Incidence Rates (per 1,000 Person-Years) by Time Since Cohort Entry, Stratified by Prior Overactive Bladder Diagnosis (Cohort Entry 2004 to 2006) No Prior OAB Diagnosis Prior OAB Diagnosis Time Since Cohort Entry (Years) Events Incidence Rate (95% CI) Events Incidence Rate (95% CI) 0 to (15.8, 23.0) (6.3, 12.1) > 1 to (4.4, 9.0) (2.4, 6.7) > 2 to (4.4, 9.2) (2.5, 7.1) > 3 to (5.3, 10.9) (2.5, 7.4) > 4 to (3.4, 8.4) (3.1, 8.7) > 5 to (2.2, 6.8) (3.4, 9.8) > 6 to (3.3, 9.6) (1.1, 6.5) > 7 to (1.2, 8.3) (2.0, 11.7) > 8 to (0.6, 16.6) (0.1, 16.3) Total (7.5, 9.5) (4.5, 6.4). 29

30 Bladder Cancer Incidence Rates (per 1,000 Person-Years) by Time Since Cohort Entry, Stratified by Prior Overactive Bladder Diagnosis (Cohort Entry 2004 to 2006) No Prior OAB Diagnosis Prior OAB Diagnosis Time Since Cohort Entry (Years) Events Incidence Rate (95% CI) Events Incidence Rate (95% CI) 0 to (2.8, 4.9) (0.8, 1.8) > 1 to (1.0, 2.5) (0.5, 1.4) > 2 to (0.6, 1.9) (0.3, 1.1) > 3 to (0.8, 2.4) (0.5, 1.5) > 4 to (0.5, 2.0) (0.3, 1.2) > 5 to (0.1, 1.2) (0.2, 1.1) > 6 to (0.3, 1.8) (0.3, 1.4) > 7 to (0.1, 2.1) (0.0, 0.9) > 8 to (0.2, 6.8) (0.1, 3.8) Total (1.3, 1.9) (0.6, 1.0) 30

31 Discussion High rates of prostate and bladder cancer soon after cohort entry Incidence rates declined markedly over time Other cancer rates were generally stable during observed follow-up time Time courses of elevated prostate and bladder cancer rates (and lack of increased screening for prostate cancer after cohort entry) are more consistent with protopathic bias (reverse causality) or detection bias than with causal effect Protopathic bias if treated symptoms are a manifestation of cancer Detection bias if symptoms treated with OAB drugs are unrelated to cancer but workup reveals cancer Also, OAB drugs may be used after genitourinary procedures Inverse relations between cumulative dose and rates of prostate and bladder cancer are consistent with this explanation But how quickly can drugs cause cancer anyway? 31

32 Conjugated Estrogen and Endometrial Cancer Increased risk of endometrial carcinoma among users of conjugated estrogens. Ziel and Finkel. N Engl J Med 1975;293:

33 Incidence of Non-Hodgkin Lymphoma in Cadaver Renal Transplant Recipients Lymphomas after solid organ transplantation: A Collaborative Transplant Study report. Opelz and Döhler. Am J Transplant 2003;4:

34 Squamous Cell Skin Cancers in Patients With Melanoma Treated With Vemurafenib Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. Sosman et al. N Engl J Med 2012;366: Multicenter, single-arm phase 2 clinical trial 132 patients with BRAF V600-mutant metastatic melanoma (constitutively active mitogen-activated protein kinase [MAPK] pathway) Vemurafenib (protein kinase inhibitor with specificity for BRAF V600E), 960 mg orally twice daily until toxicity or disease progression 34 patients (26%) developed squamous cell skin cancer or keratoacanthoma at median 8 weeks (range, 2 to 36 weeks) 34

35 Discussion Challenge to distinguish a genitourinary cancer signal (if one should exist) from the noise related to the OAB drug indication Studies of cancer outcomes should not arbitrarily exclude early person-time from evaluation Especially when cancer signal is obtained from short-term clinical trials OAB drug prescribing physicians should be aware of the possibility of an undiagnosed cancer in patients presenting with OAB symptoms 35

36 Discussion EPIC cross-sectional telephone survey on lower urinary tract symptoms in general population in five countries noted this issue Identified 1,434 cases of OAB; matched case-control analysis (1:1) Bladder or prostate cancer in 37 cases (2.6%) and 14 controls (1.0%) Coyne, et al. BJU International 2008;101:

37 Discussion 37

38 Summary Rates of prostate and bladder cancer are relatively high soon after initiating use of OAB medications and decline thereafter, suggesting protopathic bias These findings complicate investigation of any potential causal relation between exposure to OAB medications and prostate or bladder cancer Physicians prescribing drugs for OAB symptoms should be aware that these may be manifestations of a genitourinary cancer 38