Targeted Oncology (2020) 15:301–315 https://doi.org/10.1007/s11523-020-00720-2 ORIGINAL RESEARCH ARTICLE Real‑World Outcomes in First‑Line Treatment of Metastatic Castration‑Resistant Prostate Cancer: The Prostate Cancer Registry Simon Chowdhury1 · Anders Bjartell2 · Nicolaas Lumen3 · Pablo Maroto4 · Thomas Paiss5 · Francisco Gomez‑Veiga6 · Alison Birtle7 · Gero Kramer8 · Ewa Kalinka9 · Dominique Spaëth10 · Susan Feyerabend11 · Vsevolod Matveev12 · Florence Lefresne13 · Martin Lukac14 · Robert Wapenaar15 · Luis Costa16 Published online: 4 June 2020 © The Author(s) 2020 Abstract Background Metastatic prostate cancer has a 30% 5-year survival rate despite recent therapeutic advances. There is a need to improve the clinical understanding and treatment of this disease, particularly in the real-world setting and among patients who are under-represented in clinical trials. Objective We aimed to evaluate the characteristics and clinical outcomes of patients who received their first treatment for metastatic castration-resistant prostate cancer (mCRPC) in routine clinical practice, independent of treatment used, including subgroups with baseline cardiac disease, diabetes mellitus, or visceral metastases. Patients and methods Prospective, noninterventional analysis of patient record data in the multicenter Prostate Cancer Reg- istry (PCR) of men with mCRPC. The data were collected in 16 countries with the aim of recruiting more than 3000 patients between 2013 and 2016. The study end date was 9 July 2018. Data evaluated included baseline characteristics, treatment exposure, and efficacy outcomes [overall survival (OS) and time to progression (TTP)] of patients treated with abiraterone acetate plus prednisone or prednisolone (collectively, “abiraterone”), enzalutamide, or docetaxel. Descriptive outcomes are reported from the overall patient population and subgroups of patients with baseline cardiovascular disease, diabetes mel- litus, or visceral metastases. The treatment effects for time to progression were compared for the overall patient population. Results The study enrollment period lasted 2.5 years, and each patient was followed for a maximum of 3 years. A total of 1874 patients in the PCR had not received previous mCRPC treatment at baseline, although they had received androgen- deprivation therapy. Prevalent co-morbidities included cardiovascular disease in 65.4% and diabetes mellitus in 17.4% of patients. Baseline characteristics suggested that patients with more advanced disease received docetaxel treatment. In the overall patient population, the median time to progression with abiraterone, enzalutamide, and docetaxel as first-line mCRPC therapy was 9.6, 10.3, and 7.6 months, respectively, and median OS was 27.1, 27.1, and 27.9 months, respectively. Outcomes in the subgroups of patients with cardiovascular disease or diabetes mellitus were similar to those of the whole population in the analysis. As expected, patients with visceral metastases had shorter TTP and OS than patients in the overall population. Conclusions This analysis shows, for the first time, the effectiveness in parallel of first-line abiraterone, enzalutamide, and docetaxel in mCRPC, including in patients with co-morbidities such as cardiovascular disease or diabetes mellitus or in patients with visceral metastases. These real-world findings from the PCR provide meaningful information to help manage mCRPC, particularly in patients under-represented in clinical studies. Trial Registration ClinicalTrials.gov identifier NCT02236637; registered September 2014. Electronic supplementary material The online version of this article (https​://doi.org/10.1007/s1152​3-020-00720​-2) contains supplementary material, which is available to authorized users. * Simon Chowdhury simon.chowdhury@gstt.nhs.uk Extended author information available on the last page of the article Vol.:(0123456789) 302 S. Chowdhury et al. wealth of data on all mCRPC treatments from this critical Key Points period in a wide range of countries and patients, including groups under-represented in clinical research. Thus, the PCR The Prostate Cancer Registry collected real-world data contains important data reflecting clinical practice in these on the clinical characteristics, management, and out- challenging subgroups of patients with mCRPC, for whom comes of more than 3000 men with metastatic castration- data on which to base treatment decisions are often lacking. resistant prostate cancer (mCRPC) from 2013–2016. This analysis of data in the PCR focuses on the char- This study found that the efficacy of three major first- acteristics and clinical outcomes of patients who received line treatments for mCRPC (abiraterone, enzalutamide, their first treatment for mCRPC in routine clinical practice and docetaxel) was similar between subpopulations of including subgroups with baseline cardiac disease, diabetes patients with co-morbidities and the wider patient popu- mellitus, or visceral metastases. Specifically, baseline patient lation. characteristics, treatment exposure, overall survival (OS), and time to progression were evaluated. These real-world data provide information on long-term outcomes for patients with metastatic castration-resistant prostate cancer. 2 Methods 2.1 Aim, Study Design, and Setting 1 Background This prospective, noninterventional analysis of patient record data from the multicenter PCR of men with mCRPC Prostate cancer is the second most common cancer and fifth was conducted to gain a greater understanding of real-world leading cause of death from cancer in men [1]. Worldwide, outcomes in a broad group of patients treated for mCRPC an estimated 1.1 million men were diagnosed with prostate to optimize future treatment of patients with this disease. cancer in 2012, representing 15% of all cancers diagnosed in We focused on the characteristics and clinical outcomes of men, and the disease caused 307,000 deaths [1]. In Europe, patients, including subgroups with baseline cardiac disease, 450,000 new cases of prostate cancer were diagnosed in diabetes mellitus, or visceral metastases, who received their 2018, and 107,000 deaths were reported [2]. Prostate cancer first treatment for mCRPC during participation in the PCR. survival rates vary widely according to stage. Outcomes for The data for the PCR were collected at 199 centers special- localized prostate cancer are very good, owing to effective izing in the treatment of prostate cancer by both oncologists radical surgery or radiation therapy [3]. However, the mor- and urologists in a range of settings (including hospitals, tality rate among men in whom the disease has progressed private clinics, outpatient departments, and universities) in to metastatic prostate cancer is substantial. Although several 16 countries: Austria, Belgium, France, Germany, Israel, options for treatment of metastatic castration-resistant pros- Italy, Luxembourg, Poland, Portugal, Russia, Slovenia, tate cancer (mCRPC) (abiraterone, enzalutamide, cabazi- Spain, Sweden, Switzerland, Turkey, and the UK. Patient taxel, radium-223, and sipuleucel-T) have shown a survival enrollment took place between 2013 and 2016. At the start benefit in phase 3 trials, evidence for optimal sequences or of the PCR, abiraterone acetate and enzalutamide were not combinations is lacking [4–6]. Expert opinion is helpful for routinely available in the mCRPC setting in all 16 coun- treatment decisions in routine clinical practice [7]; however, tries. The study duration was 5.5 years, with a maximum there is a substantial need to improve the understanding and patient follow-up of 3 years, and was designed specifically management of this disease—in particular, to avoid progres- to include more than one line of therapy where applicable. sion to disease states in which mortality rates are high and to The study end date was 9 July 2018. assess patients outside of a clinical trial setting. The Prostate Cancer Registry (PCR) (NCT02236637) 2.2 Patients was initiated in 2013 to collect real-world data on mCRPC treatments. This is the first and largest prospective, interna- Men aged ≥ 18 years with a histologically or cytologically tional, observational study of patients with mCRPC. The confirmed diagnosis of prostate adenocarcinoma with PCR aims to document the characteristics, management, mCRPC (disease progression despite testosterone < 50 ng/dL and outcomes of more than 3000 men in routine clinical and/or androgen deprivation therapy and/or history of orchi- practice, independent of treatment used. Enrollment took ectomy), enrolled at any time after diagnosis, under surveil- place between June 2013 and March 2016, when unprece- lance according to routine clinical practice, or who initiated dented progress was being made in the treatment of mCRPC a systemic treatment for mCRPC (as required) following in Europe. The PCR provided the opportunity to capture a baseline data collection at enrollment, were eligible. The Real-World Outcomes in Metastatic Castration-Resistant Prostate Cancer 303 PCR included patients treated with abiraterone acetate plus not be compared with those of abiraterone or enzalutamide. prednisone or prednisolone (collectively, “abiraterone”), Cause of death data were not collected. enzalutamide, docetaxel, other chemotherapy, and radium-223. Only treatment groups with adequate num- 2.4 Bias bers of patients (> 50) for reliable analysis were included. Patients treated with other chemotherapy or radium-223 To ensure a patient population representative of that seen in were excluded because the numbers were too low. clinical practice and to reduce selection bias, the protocol stated that all consecutive patients meeting the eligibility 2.3 Variables and Data Measurement criteria at a participating site and who agreed to participate according to local regulations were enrolled in the PCR, Treatment outcomes were duration of initial therapy and rea- irrespective of their treatment. sons for stopping initial mCRPC therapy. Appropriate treat- ment gaps for classifying subsequent therapy were 30 days for abiraterone or enzalutamide and 60 days for docetaxel, 2.5 Study Size which included any prolonged, temporary treatment dis- continuation. Efficacy outcomes were OS at 3 years after Of more than 3000 men included in the PCR, data from enrollment and time to progression. Criteria for disease pro- patients who were being treated with abiraterone, enzalu- gression on treatment (date of recording progression/assess- tamide, or docetaxel as first-line mCRPC therapy and who ment) were met if: (1) there was evidence of radiographic had not received previous systemic mCRPC treatment were progression by investigator’s assessment (Prostate Cancer included in this analysis. The PCR was designed to gener- Working Group 2 and Response Evaluation Criteria In Solid ate data for informative purposes. Thus, this sample size Tumors guidelines were recommended by the protocol); (2) was determined by pragmatic considerations, to provide data there was evidence of clinical progression by investigator’s from a large population that is representative of patients with assessment (date of the patient visit); (3) first-line mCRPC mCRPC in the Europe/Middle East region. treatment was stopped because of progression (date treat- ment stopped); or (4) new mCRPC treatment was started 2.6 Statistical Methods because of progression (date new treatment began). The treatment effects for time to progression with the therapies We only used descriptive statistics to present observed data of interest were compared for the entire analysis popula- from routine clinical practice. To manage confounding, we tion. We compared treatment outcomes in the whole analysis used propensity score methods for the comparative effec- population with those in subgroups of patients with base- tiveness analyses. We did not apply missing data imputa- line cardiovascular disease requiring treatment (including tion methods; thus, there were no sensitivity analyses, and at least one of the following co-morbidities: hypertension, subgroups were constructed based on medical criteria (i.e., angina pectoris, history of myocardial infarction, arrhyth- treatment received, co-morbidities). mia, thromboembolic disease, transient ischemic attack, cer- ebrovascular accident, and/or other cardiovascular event), diabetes mellitus, or visceral metastases (defined as lesions in the liver and/or lung). These patient subgroups are typi- 3 Results cally under-represented in clinical studies. Adverse events 3.1 Patients were collected only for those patients receiving abiraterone, as a regulatory requirement. At the end of study, 3003 patients were evaluated, 1874 We used observational methodology to capture data. (62.4%) of whom had received no previous mCRPC treat- The treating physician made treatment decisions at his or ment; of these, 1654 (88.3%) started a treatment documented her discretion, per routine clinical practice, and only data in the PCR (abiraterone, enzalutamide, docetaxel, other available from clinical practice were collected. We collected chemotherapy, radium-223, trial medication). Abiraterone, prior disease history and management data at study inclusion enzalutamide, or docetaxel as first-line mCRPC therapy was and clinical data at study inclusion and prospectively every received by 754, 227, and 602 patients, respectively, with a 3 months during routine follow-up (at least every 3 months median follow-up of 18.6 months. The number of patients per protocol) over the 3-year study period, with clinical- and study flow are presented in the Supplementary Material trial levels of monitoring quality (see Supplementary Fig. (Fig S2). S1). Because docetaxel is administered through a maximum number of cycles (typically 6–10 cycles as appropriate), out- comes influenced by duration of docetaxel treatment should 304 S. Chowdhury et al. 3.2 Overall and First‑Line mCRPC Treatment was from abiraterone to docetaxel followed by enzalutamide Population to docetaxel (Table 3). 3.2.1 Baseline Characteristics 3.2.3 Efficacy Outcomes Patient demographics and disease and biological charac- Kaplan–Meier estimates showed that the median (95% confi- teristics at study inclusion are shown in Table 1. Patients dence interval (CI)) time to progression was 9.6 (8.4–10.8), treated with docetaxel were younger than those treated with 10.3 (8.9–13.0), and 7.6 (7.0–8.0) months with abiraterone, abiraterone or enzalutamide (median age [range]: 69 [44–88] enzalutamide, and docetaxel, respectively (Fig. 1a, Table 4). vs. 76 [43–98] and 76 [53–91] years, respectively) and had a The treatment effects for time to progression comparing shorter median (range) time from initial diagnosis to study abiraterone versus docetaxel and enzalutamide versus doc- inclusion (2.6 [0–22] years vs. 5.0 [0–29] years and 4.5 etaxel were statistically significant (all p < 0.0001; hazard [0–24] years, respectively). At diagnosis, de novo metas- ratio < 1.0), while those comparing abiraterone versus enza- tases were reported in 35.0% of patients in the abiraterone lutamide were not significant (all p > 0.5; hazard ratios > 1.0) group compared with 42.3% in the enzalutamide group and (Table 5). The median (95% CI) OS was 27.1 (25.3–28.9), 50.1% in the docetaxel group. Median (range) time from 27.1 (21.8–32.7), and 27.9 (25.6–31.5) months in the initial to metastatic diagnosis was 2.5 (0–29), 0.9 (0–21), abiraterone, enzalutamide, and docetaxel groups, respec- and 0.1 (0–21) months for the abiraterone, enzalutamide, tively (Fig. 2a, Table 6). None of the differences between and docetaxel groups, respectively. In addition, a Gleason treatment groups for OS were significant (Table 7). score of 8–10 was reported in 51.0%, 60.6%, and 58.4% of patients in the abiraterone, enzalutamide, and docetaxel 3.3 Patients with Cardiovascular Disease groups, respectively. Details regarding treatment history at study inclusion are 3.3.1 Baseline Characteristics presented in Table 2. Overall, 10.1% and 21.3% of patients had undergone either radical prostatectomy or prostate radi- At baseline, cardiovascular disease was reported in 504 otherapy, respectively, since initial diagnosis (abiraterone, (66.8%), 161 (70.9%), and 351 (58.3%) patients in the 11.8% and 23.1%; enzalutamide, 9.5% and 23.3%; docetaxel, abiraterone, enzalutamide, and docetaxel, groups, respec- 9.5% and 23.3%; respectively) and 94.7% had received at tively; the most common cardiovascular co-morbidity was least one prior systemic anticancer therapy since diag- hypertension in all three treatment groups (54.5%, 56.8%, nosis (95.1%, 93.8%, and 94.2% for patients treated with and 48.0%, respectively), followed by specific cardiovas- abiraterone, enzalutamide, and docetaxel, respectively). cular co-morbidities of arrhythmia and history of myocar- Orchiectomy had been performed in 4.6%, 7.3%, and 5.3% dial infarction (Table 1). This cardiovascular disease group of patients, respectively. also had important concomitant co-morbidities for patients receiving abiraterone, enzalutamide, and docetaxel: diabetes 3.2.2 Treatment Exposure mellitus (types 1 and 2) was reported in 101 (20.0%), 36 (22.4%), and 84 (23.9%) patients; respiratory co-morbidi- The median (95% confidence interval [CI]) duration of ties were reported in 46 (9.1%), 23 (14.3%), and 38 (10.8%) treatment according to the Kaplan–Meier analysis was patients; and neurologic co-morbidities were reported in 52 11.2 (9.8–12.2) months with abiraterone, 13.0 (10.4–15.9) (10.3%), 17 (10.6%), and 37 (10.5%) patients, respectively months with enzalutamide, and 4.8 (4.4–5.0) months with (Supplementary Table S3A). docetaxel (Supplementary Table S1). In the abiraterone, Patients treated with abiraterone had a median (range) enzalutamide, and docetaxel groups, the most common rea- time from initial prostate cancer diagnosis to study inclu- son for stopping treatment was disease progression (72.8%, sion of 5.3 (0–29) years versus 4.9 (0–21) and 3.1 (0–22) 67.3%, and 27.0% of patients) (Supplementary Table S2). years for the enzalutamide and docetaxel groups, respec- The proportion of patients who discontinued treatment tively. Median (range) age at baseline was 77 (50–94), 77 because of toxicity was 7.1%, 13.5%, and 14.2% in these (59–91), and 71 (47–88) years, respectively (Supplementary groups, and death during treatment was reported in 7.2%, Table S3A), which was older than the ages reported in recent 11.1%, and 3.8% of patients, respectively (Supplementary registration studies [8, 9]. At diagnosis, 49.8%, 59.0%, and Table S2). In this first-line mCRPC treatment population, 56.6% of patients in the abiraterone, enzalutamide, and doc- 48.7%, 43.6%, and 70.8%, of abiraterone-, enzalutamide-, etaxel groups, respectively, had a Gleason score of 8–10 and docetaxel-treated patients, respectively, went on to (Supplementary Table S3A). Details regarding treatment receive a subsequent treatment; the most common switch history at study inclusion are presented in Supplementary Table S3B. Real-World Outcomes in Metastatic Castration-Resistant Prostate Cancer 305 Table 1  Patient demographics and disease and biological characteristics at study inclusion in the first-line mCRPC treatment population Characteristic Patients who had not received First-line treatment with previous mCRPC treatment at baseline N = 1874 Abiraterone N = 754 Enzalutamide N = 227 Docetaxel N = 602 Age, Mean (SD), years 73.1 (8.58) 75.3 (8.20) 74.9 (7.87) 68.8 (7.70) Median (range), years 74.0 (43–98) 76.0 (43–98) 76.0 (53–91) 69.0 (44–88) Age group, n (%) < 65 years 314 (16.8) 81 (10.7) 24 (10.6) 173 (28.7) 65–74 years 683 (36.4) 228 (30.2) 75 (33.0) 280 (46.5) ≥ 75 years 877 (46.8) 445 (59.0) 128 (56.4) 149 (24.8) Geographic distribution, n (%) N 1874 (100.0) 754 (100.0) 227 (100.0) 602 (100.0) Austria 12 (0.6) 2 (0.2) 2 (0.9) 2 (0.3) Belgium 129 (6.9) 60 (8.0) 25 (11.0) 28 (4.7) France 209 (11.2) 116 (15.4) 27 (11.9) 53 (8.8) Germany 240 (12.8) 128 (17.0) 19 (8.4) 61 (10.1) Israel 18 (1.0) 11 (1.5) 0 3 (0.5) Italy 238 (12.7) 157 (20.8) 2 (0.9) 70 (11.6) Luxembourg 8 (0.4) 1 (0.1) 0 6 (1.0) Poland 163 (78.7) 1 (0.1) 2 (0.9) 122 (20.3) Portugal 78 (4.2) 21 (2.8) 2 (0.9) 43 (7.1) Russia 79 (4.2) 16 (2.1) 2 (0.9) 27 (4.5) Slovenia 22 (1.2) 14 (1.9) 2 (0.9) 1 (0.2) Spain 141 (7.5) 85 (11.3) 17 (7.5) 24 (4.0) Sweden 149 (8.0) 18 (2.4) 47 (20.7) 38 (6.3) Switzerland 14 (0.8) 6 (0.8) 1 (0.4) 7 (1.2) Turkey 61 (3.3) 10 (1.3) 0 47 (7.8) United Kingdom 313 (16.7) 108 (14.3) 79 (34.8) 70 (11.6) ECOG performance status, n (%) N 1732 715 187 555 0 746 (43.1) 340 (47.6) 99 (52.9) 211 (38.0) 1 797 (46.0) 318 (44.5) 69 (36.9) 293 (52.8) ≥2 189 (10.9) 57 (8.0) 19 (10.2) 51 (9.2) Gleason score at initial diagnosis, n (%) N 1713 674 208 574 ≤6 216 (12.6) 100 (14.8) 25 (12.0) 61 (10.6) 7 548 (32.0) 230 (34.1) 57 (27.4) 178 (31.0) 8–10 949 (55.4) 344 (51.0) 126 (60.6) 335 (58.4) M stage at initial diagnosis, n (%) N 1830 732 222 591 Mx 353 (19.3) 161 (22.0) 40 (18.0) 100 (16.9) M0 682 (37.3) 315 (43.0) 88 (39.6) 195 (33.0) M1, M1a, M1b, M1c 795 (43.4) 256 (35.0) 94 (42.3) 296 (50.1) Time from initial prostate cancer diagnosis to start of the study N 1874 754 227 602 Median years (range) 3.8 (0–29) 5.0 (0–29) 4.5 (0–24) 2.6 (0–22) 306 S. Chowdhury et al. Table 1  (continued) Characteristic Patients who had not received First-line treatment with previous mCRPC treatment at baseline N = 1874 Abiraterone N = 754 Enzalutamide N = 227 Docetaxel N = 602 Presence of bone metastases (baseline), n (%) N 1396 550 184 451 Any 1253 (89.8) 548 (99.6) 164 (89.1) 405 (89.8) ≥5 548 (39.3) 203 (36.9) 60 (32.6) 192 (42.6) Visceral metastases (baseline), n (%) N 1484 612 163 517 Liver only 69 (4.6) 13 (2.1) 9 (5.5) 39 (7.5) Lung only 96 (6.5) 39 (6.4) 7 (4.3) 40 (7.7) Liver and lung 17 (1.1) 7 (1.1) 0 9 (1.7) Biological parameters PSA, ng/mL N 1833 733 226 588 Mean (SD) 143.66 (462.496) 125.54 (488.412) 79.82 (173.516) 181.05 (510.264) Lactic acid dehydrogenase, U/L N 732 331 77 242 Mean (SD) 344.5 (296.75) 330.3 (281.58) 283.5 (204.28) 367.1 (320.45) Hemoglobin, g/dL N 1618 651 199 530 Mean (SD) 12.6 (1.67) 12.7 (1.63) 12.9 (1.43) 12.5 (1.73) Alkaline phosphatase, U/L N 1365 575 191 414 Mean (SD) 209.6 (341.29) 192.1 (282.84) 181.8 (473.49) 223.7 (297.86) Co-morbidities requiring treatment, n (%) Any 1367 (72.9) 566 (75.1) 176 (77.5) 398 (66.1) Cardiovascular 1221 (65.2) 504 (66.8) 161 (70.9) 351 (58.3) Hypertension 1002 (53.5) 411 (54.5) 129 (56.8) 289 (48.0) Angina pectoris 115 (6.1) 34 (4.5) 12 (5.3) 35 (5.8) Myocardial infarction 133 (7.1) 48 (6.4) 21 (9.3) 32 (5.3) Arrhythmia 154 (8.2) 62 (8.2) 22 (9.7) 41 (6.8) Thromboembolic disease 55 (2.9) 21 (2.8) 8 (3.5) 18 (3.0) Cerebrovascular accident 48 (2.6) 19 (2.5) 3 (1.3) 17 (2.8) Transient ischemic attack 34 (1.8) 14 (1.9) 5 (2.2) 9 (1.5) Other cardiovascular 300 (16.0) 139 (18.4) 39 (17.2) 80 (13.3) Respiratory 160 (8.5) 60 (8.0) 27 (11.9) 48 (8.0) Chronic obstructive pulmonary 105 (5.6) 41 (5.4) 16 (7.0) 29 (4.8) disease Other respiratory 60 (3.2) 20 (2.7) 12 (5.3) 19 (3.2) Renal 143 (7.6) 52 (6.9) 24 (10.6) 42 (7.0) Chronic renal disease 82 (4.4) 31 (4.1) 16 (7.0) 21 (3.5) Other renal 62 (3.3) 21 (2.8) 8 (3.5) 21 (3.5) Hepatic 31 (1.7) 17 (2.3) 3 (1.3) 8 (1.3) Chronic hepatic disease 17 (0.9) 9 (1.2) 3 (1.3) 4 (0.7) Other hepatic 14 (0.7) 8 (1.1) 0 4 (0.7) Neurologic 157 (8.4) 66 (8.8) 17 (7.5) 41 (6.8) Peripheral sensory impairment 8 (0.4) 2 (0.3) 0 5 (0.8) Memory impairment 14 (0.7) 5 (0.7) 4 (1.8) 2 (0.3) Cognitive disorder 12 (0.6) 4 (0.5) 2 (0.9) 1 (0.2) Real-World Outcomes in Metastatic Castration-Resistant Prostate Cancer 307 Table 1  (continued) Characteristic Patients who had not received First-line treatment with previous mCRPC treatment at baseline N = 1874 Abiraterone N = 754 Enzalutamide N = 227 Docetaxel N = 602 Convulsion 5 (0.3) 3 (0.4) 0 0 Other neurologic 54 (2.9) 27 (3.6) 4 (1.8) 10 (1.7) Infections 11 (0.6) 6 (0.8) 3 (1.3) 1 (0.2) Other infection 11 (0.6) 6 (0.8) 3 (1.3) 1 (0.2) Diabetes mellitus 307 (16.4) 121 (16.0) 47 (20.7) 100 (16.6) Type 2 235 (12.5) 87 (11.5) 36 (15.9) 82 (13.6) Type 1 72 (3.8) 34 (4.5) 11 (4.8) 18 (3.0) Investigations Hypercholesterolemia 276 (14.7) 122 (16.2) 48 (21.1) 62 (10.3) ECOG Eastern Cooperative Oncology Group, M metastatic status, mCRPC metastatic castration-resistant prostate cancer, N number of evaluable patients for each specific parameter, PSA prostate-specific antigen, SD standard deviation Table 2  Treatment history at study inclusion in the first-line mCRPC treatment population Prior treatment, n (%) Patients who had not received previous First-line treatment with mCRPC treatment at baseline n = 1874 Abiraterone n = 754 Enzalutamide n = 227 Docetaxel n = 602 Orchiectomy since initial diagnosis 123 (6.6) 35 (4.6) 12 (5.3) 44 (7.3) Radical prostatectomy/prostate-specific radiotherapy since initial diagnosis Both radical prostatectomy and 160 (8.5) 79 (10.5) 18 (7.9) 52 (8.6) prostate-specific radiotherapy Radical prostatectomy only 190 (10.1) 89 (11.8) 21 (9.3) 57 (9.5) Prostate-specific radiotherapy only 399 (21.3) 174 (23.1) 46 (20.3) 140 (23.3) None 1125 (60.0) 412 (54.6) 142 (62.6) 353 (58.6) Prior systemic anticancer therapy Any 1774 (94.7) 718 (95.2) 213 (93.8) 567 (94.2) Endocrine therapy 1755 (93.6) 710 (94.2) 211 (93.0) 562 (93.4) Antiandrogen 1569 (83.7) 646 (85.7) 188 (82.8) 506 (84.1) GnRH agonist 1280 (68.3) 474 (62.9) 211 (93.0) 434 (72.1) Steroids 194 (10.4) 76 (10.1) 22 (9.7) 75 (12.5) GnRH antagonist 127 (6.8) 64 (8.5) 9 (4.0) 39 (6.5) Estrogens and derivatives 53 (2.8) 28 (3.7) 7 (3.1) 5 (0.8) Adrenal synthesis inhibitors 14 (0.7) 6 (0.8) 0 (0) 7 (1.2) Other 6 (0.3) 0 (0) 3 (1.3) 2 (0.3) Bone-targeted Any 455 (24.3) 163 (21.6) 32 (14.1) 176 (29.2) Zoledronic acid 330 (17.6) 120 (15.9) 20 (8.8) 126 (20.9) Denosumab 103 (5.5) 45 (6.0) 10 (4.4) 32 (5.3) Other 55 (2.9) 9 (1.2) 6 (2.6) 32 (5.3) Other 28 (1.5) 12 (1.6) 5 (2.2) 7 (1.2) GnRH gonadotropin-releasing hormone, mCRPC metastatic castration-resistant prostate cancer 3.3.2 Treatment Exposure for typically 6–10 cycles (Supplementary Table S1); these are similar to durations observed in the equivalent overall Median (95% CI) treatment durations were 11.1 (9.5–12.7) patient population treatment groups, in which docetaxel months with abiraterone, 12.7 (9.1–15.3) months with exposure was shorter than abiraterone and enzalutamide enzalutamide, and 4.6 (4.3–5.0) months with docetaxel exposures. In the abiraterone, enzalutamide, and docetaxel 308 S. Chowdhury et al. Table 3  Subsequent therapy for the first-line treatment population treatment groups, respectively (Supplementary Table S4A). The following important concomitant co-morbidity types n (%) Abiraterone Enzalutamide Docetaxel were reported in the diabetes mellitus group for patients First treatment set 754 227 602 receiving abiraterone, enzalutamide, and docetaxel, respec- Patients with a next 367 (48.7) 99 (43.6) 426 (70.8) tively: cardiovascular in 102 (84.3%), 36 (76.6%), and 85 ­therapya (85.0%) patients; neurologic in 13 (10.7%), 4 (8.5%), and Therapy 12 (12.0%) patients; and renal in 10 (8.3%), 12 (25.5%), Abiraterone – 17 (17.2) 191 (44.8) and 7 (7.0%) patients (Supplementary Table S4A). Details Docetaxel 178 (48.5) 42 (42.4) – regarding treatment history at study inclusion are presented Enzalutamide 99 (27.0) – 116 (27.2) in Supplementary Table S4B. Cabazitaxel 4 (1.1) 2 (2.0) 74 (17.4) Other chemotherapy 10 (2.7) 1 (1.0) 8 (1.9) 3.4.2 Treatment Exposure a If treatment was interrupted for less than 30 days (abiraterone or enzalutamide) or 60 days (docetaxel or cabazitaxel), it was defined as Median (95% CI) treatment duration was 11.5 (9.1–16.1), continuing. Next therapy could be started immediately following ces- 12.2 (8.2–17.5), and 4.3 (3.6–4.9) months in the abiraterone, sation of first-line treatment enzalutamide, and docetaxel (typically 6–10 cycles) treat- ment groups, respectively (Supplementary Table S1), which groups, the most common reason for stopping treatment was similar to that in treatment groups for the overall pop- was disease progression (72.0%, 62.7%, and 24.3% of ulation, in which docetaxel exposure was shorter than for patients, respectively) (Supplementary Table S2). Death abiraterone and enzalutamide. The most commonly reported during treatment was reported in 6.9%, 11.9%, and 5.6% reason for stopping treatment in abiraterone-, enzalutamide-, of patients in these treatment groups, respectively (Sup- and docetaxel-treated patients was disease progression plementary Table S2). (66.3%, 57.9%, and 24.0%, respectively), followed by toxic- ity (12.0%, 13.2%, and 19.0%, respectively) (Supplementary 3.3.3 Efficacy Outcomes Table S2). Death during treatment was reported in 9.8%, 18.4%, and 5.6% of patients, respectively (Supplementary According to Kaplan–Meier estimates, the median (95% CI) Table S2). time to progression was 9.7 (8.2–11.2), 9.8 (8.0–12.9), and 7.4 (6.6–7.9), months for abiraterone, enzalutamide, and 3.4.3 Efficacy Outcomes docetaxel, respectively (Fig. 1b, Table 4). The median (95% CI) OS was 27.4 (23.0–30.3), 26.1 (18.1–33.9), and 26.1 According to Kaplan–Meier estimates, the median (95% CI) (23.0–29.7) months in these treatment groups, respectively time to progression was 12.0 (9.8–16.4), 10.3 (5.5–14.7), (Fig. 2b, Table 6). and 7.7 (5.7–9.0) months with abiraterone, enzalutamide, and docetaxel, respectively (Fig. 1c, Table 4). The median 3.4 Patients with Diabetes Mellitus (95% CI) OS was 30.8 (21.7–not estimable [NE]), 27.1 (14.7–NE), and 24.3 (16.1–29.0) months in these treatment 3.4.1 Baseline Characteristics groups, respectively (Fig. 2c, Table 6). At baseline, 121 (16.0%), 47 (20.7%), and 100 (16.6%) 3.5 Patients with Visceral Metastases patients had diabetes mellitus in the abiraterone, enzaluta- mide, and docetaxel groups, respectively; in each treatment 3.5.1 Baseline Characteristics group, a lower proportion of those with diabetes mellitus had diabetes mellitus type 1 than diabetes mellitus type 2 Visceral metastases were reported in 59 patients (7.8%) in (71.9% vs. 28.1%, 76.6% vs. 23.4%, and 82.0% vs. 18.0% in the abiraterone group, 16 (7.0%) in the enzalutamide group, the abiraterone, enzalutamide, and docetaxel groups, respec- and 88 (14.6%) in the docetaxel group. The small number tively) (Table 1). of patients with visceral metastases in the enzalutamide The median (range) time from initial diagnosis to study group meant that meaningful analyses could not be per- start was 5.7 (0–29), 4.0 (0–18), and 5.4 (1–20) years in the formed (Table 1). Details regarding patient demographics abiraterone, enzalutamide, and docetaxel groups, respec- and disease and biological characteristics at study inclusion tively. Median (range) age at baseline was 77.0 (54–93), in patients with visceral metastases in the first-line treatment 77.0 (62–91), and 69.0 (51–88) years, respectively (Sup- population and treatment history are presented in Supple- plementary Table S4A). A Gleason score of 8–10 at diag- mentary Tables S5A and S5B, respectively. nosis was reported in 47.7%, 55.8%, and 49.0% of these Real-World Outcomes in Metastatic Castration-Resistant Prostate Cancer 309 a b 100 100 Abi Abi Patients who were progression free (%) Patients who were progression free (%) Enz Enz Doc Doc 80 80 60 60 40 40 20 20 0 0 0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40 Time to progression (months) Time to progression (months) Number at risk Number at risk Abi 754 505 325 231 162 120 83 51 0 Abi 504 332 222 152 110 80 51 31 0 Enz 227 145 102 74 51 30 15 6 0 Enz 161 102 68 51 34 22 9 2 0 Doc 602 381 161 50 23 15 8 5 0 Doc 351 209 82 18 7 4 2 2 0 c d 100 100 Abi Abi Patients who were progression free (%) Patients who were progression free (%) Enz Doc Doc 80 80 60 60 40 40 20 20 0 0 0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40 Time to progression (months) Time to progression (months) Number at risk Number at risk Abi 121 83 61 39 30 22 12 7 0 Abi 59 34 14 11 9 8 6 4 0 Enz 47 28 19 12 9 6 4 0 0 Doc 88 54 29 10 7 6 4 3 0 Doc 100 63 24 5 2 2 1 1 0 Fig. 1  Time to progression in the first-line treatment population (a), and cardiovascular (b), diabetes mellitus (c), and visceral metastases sub- groups (d). Abi abiraterone, Enz enzalutamide, Doc docetaxel 3.5.2 Treatment Exposure In this subgroup analysis, 10.4% and 11.6% of patients dis- continued abiraterone and docetaxel treatment, respectively, The median (95% CI) treatment duration in abiraterone- because of toxicity; the most common reason was disease and docetaxel-treated patients was 7.9 (5.5–10.9) and 4.3 progression (70.8% and 26.7%), with 10.4% and 4.7% of (3.5–5.1) months, respectively (Supplementary Table S1); patients dying (Supplementary Table S2). This compares the typical regimen for docetaxel treatment was 6–10 cycles. to 7.4%, 72.8%, and 7.2%, for toxicity, disease progression, 310 S. Chowdhury et al. Table 4  Time to progression in the first-line treatment population, including subgroups Kaplan–Meier estimates (patients with no progression at end Abiraterone Enzalutamide Docetaxel of Registry are censored) First-line treatment population, N 754 227 602 Median time to p­ rogressiona (95% CI), months 9.6 (8.4–10.8) 10.30 (8.9–13.0) 7.6 (7.0–8.0) Patients with cardiovascular disease, N 504 161 351 Median time to p­ rogressiona (95% CI), months 9.7 (8.2–11.2) 9.8 (8.0–12.9) 7.4 (6.6–7.9) Patients with diabetes mellitus, N 121 47 100 Median time to p­ rogressiona (95% CI), months 12.0 (9.8–16.4) 10.3 (5.5–14.7) 7.7 (5.7–9.0) Patients with visceral metastases, N 59 – 88 Median time to p­ rogressiona (95% CI), months 6.2 (4.8–8.1) – 7.8 (6.7–9.9) CI confidence interval a Criteria for disease progression were met if radiographic progression (progression date is date of the assessment); if no radiographic progres- sion documented then clinical progression per investigator’s assessment (progression date is date of the patient visit) was used as the criterion. If no progression was documented using the criteria specified, then stopping medication because of progression (progression date is date that the treatment was stopped) was used as the criterion. New treatment started because of progression (progression date is date that the new treatment began) was used if previous medication was not stopped because of progression Table 5  Unadjusteda and ­adjustedb treatment effect for time to progression in the first-line treatment population Dependent variable Unadjusted/adjusted Comparison Number of Hazard ratio (95% CI) p value observations Unadjusted and adjusted treatment effect, time to progression, abiraterone vs. docetaxel (first line) Time to progression Unadjusted Abiraterone vs. docetaxel n = 1356 0.599 (0.529–0.678) < 0.0001 Time to progression Unadjusted Abiraterone vs. docetaxel n = 1049 0.597 (0.519–0.686) < 0.0001 Time to progression Adjusted Abiraterone vs. docetaxel n = 1049 0.685 (0.586–0.800) < 0.0001 Unadjusted and adjusted treatment effect, time to progression, enzalutamide vs. docetaxel (first line) Time to progression Unadjusted Enzalutamide vs. docetaxel n = 829 0.548 (0.456–0.657) < 0.0001 Time to progression Unadjusted Enzalutamide vs. docetaxel n = 674 0.556 (0.455–0.678) < 0.0001 Time to progression Adjusted Enzalutamide vs. docetaxel n = 674 0.564 (0.455–0.698) < 0.0001 Unadjusted and adjusted treatment effect, time to progression, abiraterone vs. enzalutamide (first line) Time to progression Unadjusted Abiraterone vs. enzalutamide n = 981 1.031 (0.867–1.226) 0.7302 Time to progression Unadjusted Abiraterone vs. enzalutamide n = 751 1.009 (0.833–1.222) 0.9277 Time to progression Adjusted Abiraterone vs. enzalutamide n = 751 1.040 (0.851–1.271) 0.7000 CI confidence interval a The unadjusted analysis is a Cox proportional hazards model with treatment as only predictor b The adjusted analysis is similar to the unadjusted but is based on the propensity score method; potential confounders are: age, log of time from diagnosis to castration resistance, log of time from diagnosis to metastasis, log of time from metastasis to study start, log alkaline phosphatase, log prostate-specific antigen, log hemoglobin, Gleason score, diabetes, use of strong analgesics, use of weak analgesics, cardiovascular disease, ECOG status 2–3, ECOG status unknown, prior radical prostatectomy, T class 3, T class 4, T class unknown, N class 1, N class unknown, M class 1, M class unknown, bone lesions 5–20, bone lesions > 20, and bone lesions unknown and death, respectively, during treatment in the whole abi- and 20.40 (15.10–26.10) months in abiraterone- and raterone treatment group and 14.2%, 27.0%, and 3.8% in the docetaxel-treated patients, respectively – shorter than in the whole docetaxel group (Supplementary Table S2). respective overall patient populations (Fig. 2d, Table 6). 3.5.3 Efficacy Outcomes 4 Discussion In patients with visceral metastases, the median (95% CI) time to progression was 6.2 (4.8–8.1) and 7.8 (6.7–9.9) The data in the PCR provide the first opportunity to evalu- months with abiraterone and docetaxel, respectively (Fig. 1d, ate characteristics and outcomes of the largest cohort of Table 4). The median (95% CI) OS was 17.40 (13.60–22.70) patients with mCRPC receiving first-line treatment in Real-World Outcomes in Metastatic Castration-Resistant Prostate Cancer 311 a b 100 100 Abi Abi Enz Enz Doc Doc 80 80 Patients who survived (%) Patients who survived (%) 60 60 40 40 20 20 0 0 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 Time to death (months) Time to death (months) Number at risk Number at risk Abi 754 692 597 505 417 336 240 141 3 0 Abi 504 458 391 332 269 219 155 91 1 0 Enz 227 209 177 150 110 86 52 17 0 0 Enz 161 150 126 107 76 61 34 9 0 0 Doc 602 548 451 374 307 247 169 86 0 0 Doc 351 312 254 211 174 140 91 48 0 0 c d 100 100 Abi Abi Enz Doc Doc 80 80 Patients who survived (%) Patients who survived (%) 60 60 40 40 20 20 0 0 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 Time to death (months) Time to death (months) Number at risk Number at risk Abi 121 103 87 74 60 51 39 23 1 0 Abi 59 50 41 32 24 19 13 6 0 Enz 47 42 34 28 20 17 11 5 0 0 Doc 88 79 64 50 39 28 21 10 0 Doc 100 92 70 55 43 32 18 13 0 0 Fig. 2  Overall survival in the first-line treatment population (a), and cardiovascular (b), diabetes mellitus (c), and visceral metastases subgroups (d). Abi abiraterone, Enz enzalutamide, Doc docetaxel the real-world setting. Notably, they encompass informa- to inclusion in the study. In addition, a higher proportion tion from patients from 16 countries included in the PCR of patients in the docetaxel group had an Eastern Coop- between 2013 and 2016. erative Oncology Group score of 1, visceral metastases, In this analysis of a real-world setting, patients treated five or more bone metastases at baseline, and had de novo with docetaxel as their first-line systemic mCRPC treat- metastases at initial diagnosis. Biological parameters of ment were younger than those treated with abiraterone or prostate-specific antigen, lactate dehydrogenase, and alka- enzalutamide and had a shorter time from initial diagnosis line phosphatase levels also tended to be higher in patients 312 S. Chowdhury et al. Table 6  Overall survival in the first-line treatment population, including subgroups Abiraterone Enzalutamide Docetaxel First-line treatment population, N 754 227 602 Median overall survival (95% CI), months 27.1 (25.3–28.9) 27.1 (21.8–32.7) 27.9 (25.6–31.5) Patients with cardiovascular disease, N 504 161 351 Median overall survival (95% CI), months 27.4 (23.0–30.3) 26.1 (18.1–33.9) 26.1 (23.0–29.7) Patients with diabetes mellitus, N 121 47 100 Median overall survival (95% CI), months 30.8 (21.7–NE) 27.1 (14.7–NE) 24.3 (16.1–29.0) Patients with visceral metastases, N 59 – 88 Median overall survival (95% CI), months 17.40 (13.60–22.70) – 20.40 (15.10–26.10) Patients alive at end of Registry are censored CI confidence interval, N number of evaluable patients for each specific parameter, NE not estimable Table 7  Unadjusteda and ­adjustedb treatment effect for overall survival in the first-line treatment population Dependent variable Unadjusted/adjusted Comparison Number of Hazard ratio (95% CI) p value observations Unadjusted and adjusted treatment effect, overall survival, abiraterone vs. docetaxel (first line) Overall survival Unadjusted Abiraterone vs. docetaxel n = 1356 1.035 (0.891–1.202) 0.6520 Overall survival Unadjusted Abiraterone vs. docetaxel n = 1049 0.994 (0.841–1.176) 0.9462 Overall survival Adjusted Abiraterone vs. docetaxel n = 1049 1.105 (0.920–1.328) 0.2843 Unadjusted and adjusted treatment effect, overall survival, enzalutamide vs. docetaxel (first line) Overall survival Unadjusted Enzalutamide vs. docetaxel n = 829 1.047 (0.843–1.301) 0.6763 Overall survival Unadjusted Enzalutamide vs. docetaxel n = 674 1.064 (0.841–1.347) 0.6039 Overall survival Adjusted Enzalutamide vs. docetaxel n = 674 1.075 (0.837–1.380) 0.5727 Unadjusted and adjusted treatment effect, overall survival, abiraterone vs. enzalutamide (first line) Overall survival Unadjusted Abiraterone vs. enzalutamide n = 981 0.983 (0.798–1.211) 0.8741 Overall survival Unadjusted Abiraterone vs. enzalutamide n = 751 0.927 (0.737–1.165) 0.5147 Overall survival Adjusted Abiraterone vs. enzalutamide n = 751 1.000 (0.788–1.270) 0.9986 CI confidence interval a The unadjusted analysis is a Cox proportional hazards model with treatment as only predictor b The adjusted analysis is similar to the unadjusted, but is based on the propensity score method; potential confounders are: age, log of time from diagnosis to castration resistance, log of time from diagnosis to metastasis, log of time from metastasis to study start, log alkaline phosphatase, log prostate-specific antigen, log hemoglobin, Gleason score, diabetes, use of strong analgesics, use of weak analgesics, cardiovascular disease, ECOG status 2–3, ECOG status unknown, prior radical prostatectomy, T class 3, T class 4, T class unknown, N class 1, N class unknown, M class 1, M class unknown, bone lesions 5–20, bone lesions > 20, and bone lesions unknown treated with docetaxel than in those who received the other of abiraterone was 1000 mg once daily [11], and the usual treatment options. Together, these findings suggest that the dose of enzalutamide is 160 mg taken at the same time patients treated with docetaxel had more advanced dis- once daily [12]. In general, treatment duration was not ease and poorer prognosis. These differences in baseline influenced by the presence of cardiovascular disease or characteristics are not unexpected, given the observational diabetes mellitus in this study. methodology used to capture the treatment decisions made In this real-world analysis, which includes patients at the discretion of the treating physician. The clinical effi- who are under-represented in prostate cancer clinical tri- cacy and safety of docetaxel therapy in prostate cancer was als, median OS of those enrolled in the PCR treated with achieved with a recommended dose of 75 mg/m2 every first-line abiraterone, enzalutamide, or docetaxel as mCRPC 3 weeks over 10 cycles [10]; the median duration of doc- therapy was 27.1, 27.1, or 27.9 months, respectively, com- etaxel treatment was approximately 4 months in the patient pared with a median OS of 34.7 months for patients treated groups in the analysis. In contrast, the recommended dose with abiraterone acetate in the phase 3 COU-AA-302 study Real-World Outcomes in Metastatic Castration-Resistant Prostate Cancer 313 in asymptomatic or mildly symptomatic patients with subgroups under-represented in clinical trials, and a dura- chemotherapy-naive prostate cancer [13] and 18.9 months tion that allows mature data to be collected during a period with three-times-weekly docetaxel in patients with meta- that has seen a number of advances in mCRPC treatment. static hormone-refractory prostate cancer in the phase 3 Furthermore, this is the largest data set on abiraterone treat- TAX 327 study [9]. However, at the time of the TAX 327 ment in patients with CRPC with visceral metastases in the study, subsequent treatment options for mCRPC were lim- real-world setting. However, several limitations exist. This ited, which may have influenced the OS rates in this study. is an observational study, and there is no randomization to In the FIRSTANA study, which evaluated cabazitaxel ver- allow direct treatment comparisons. In addition, because sus docetaxel treatment in chemotherapy-naïve patients with treatment followed clinical practice, duration of exposure mCRPC, median OS was 24.3 months for docetaxel [14], varied between treatments based on treatment cycles. Thus, which is similar to our findings. This study was initiated at the results for duration of treatment and reason for stopping a time when novel hormonal treatments were being used treatment or number of deaths during the treatment period clinically to treat mCRPC after docetaxel. cannot be compared between docetaxel and abiraterone or In the phase 3 PREVAIL study of enzalutamide in docetaxel and enzalutamide because of the possible influ- patients with disease progression despite androgen- ence of the dosing regimens of the drugs; docetaxel has a deprivation therapy, median OS was longer, at 32.4 months shorter dosing regimen, being administered in 6–10 cycles, [8]. However, the older age, presence of certain baseline compared with the daily regimens of abiraterone acetate and characteristics (visceral metastases, ECOG status of 2 and enzalutamide, which are administered until the point of dis- above), and longer disease duration before treatment of ease progression. Data were also collected at routine clinical patients in the PCR compared with those in the clinical tri- visits, which may not have occurred at regular intervals for als is likely to have affected treatment outcomes. Similarly, all patients. The commercial availability of the treatments shorter OS in renal cancer has been reported for sunitinib in in participating countries, different treatment practices and the non-clinical trial setting (18.7 months) compared with settings, and timing of enrollment should also be taken into the first-line clinical setting (26.4 months) [15]. Treatment consideration; the treatment options available in each coun- outcomes for mCRPC did not appear to be compromised try of the PCR varied according to availability of different by cardiovascular disease and diabetes mellitus in the pre- drugs, which may have influenced findings. sent study; however, in patients with visceral metastases, OS was approximately 7 months shorter than in the overall population. 5 Conclusions Data from the PCR provide information on patient sub- groups that are poorly represented in pivotal trials. Nota- This analysis shows for the first time the effectiveness in par- bly, the PCR provides information on many patients with allel of three major treatments in first-line mCRPC therapy: cardiovascular co-morbidities and patients with both car- abiraterone, enzalutamide, and docetaxel. More importantly, diovascular and diabetic co-morbidities. The PCR does not the efficacy of these treatments was similar among subpopu- provide information on the severity of the co-morbidities lations of patients with co-morbidities such as cardiovas- or whether patients’ conditions related to co-morbidities at cular disease or diabetes mellitus compared with the wider baseline were well controlled by concomitant medications patient group. For the subpopulation of patients with vis- at baseline, which may affect their outcomes. Other than dis- ceral metastases, outcomes were as expected considering the ease progression, toxicity was the next most common reason poor prognosis for this subgroup. This real-world analysis of for stopping systemic mCRPC treatment in patients with long-term efficacy outcomes of patients in the PCR provides cardiovascular disease (8.9% and 16.7% of patients treated meaningful data to support physicians in managing different with abiraterone and enzalutamide, respectively). This was patient groups with mCRPC, which is associated with poor also a reason for stopping treatment in patients with diabetes prognosis and mortality. Because the PCR includes patients mellitus (12.0% and 13.2% stopped abiraterone and enzalu- from several countries and represents real-world practice, tamide, respectively). In addition, the higher incidence of these results apply to most men with mCRPC. treatment-limiting toxicity in patients with diabetes mellitus compared with the overall population and in patients with Acknowledgements The authors acknowledge Edwin Martens who provided statistical support for the Propensity Score method analysis, cardiovascular disease suggests that extra care should be Emma Lee who facilitated author liaison and project support for this taken in treating these men. manuscript, and Parexel, which provided editorial assistance in the This study benefits from a number of strengths, includ- development of this manuscript. ing robust monitoring providing clinical trial-level qual- ity data, the size and scope of the Registry, allowing for a Author contributions SC was involved in data collection, had full access to all the data in the study, provided review of the manuscript, large amount of data to be collected, inclusion of patient 314 S. Chowdhury et al. and had final responsibility for the decision to submit for publication. A ://www.janss​en.com/clini​cal-trial​s/trans​paren​cy. As noted on this site, Bjartell was involved in data collection, contributed to data interpreta- requests for access to the study data can be submitted through Yale tion, reviewed the manuscript, and participated as co-investigator. NL Open Data Access (YODA) Project site at https​://yoda.yale.edu. was involved in patient recruitment/data collection, data interpretation, and reviewing the manuscript. PM was involved in data collection, contributed to data analysis and interpretation and review of the manu- Open Access This article is licensed under a Creative Commons Attri- script. TP was involved in data collection and contributed to review of bution-NonCommercial 4.0 International License, which permits any manuscript drafts. FGV was involved in data collection, contributed non-commercial use, sharing, adaptation, distribution and reproduction to data interpretation, reviewed the manuscript, and participated as co- in any medium or format, as long as you give appropriate credit to the investigator. A Birtle was involved in data collection and contributed original author(s) and the source, provide a link to the Creative Com- to review of manuscript drafts. GK was involved in data collection and mons licence, and indicate if changes were made. The images or other contributed to review of manuscript drafts. EK was involved in data third party material in this article are included in the article’s Creative collection, data interpretation, and reviewing the manuscript. DS was Commons licence, unless indicated otherwise in a credit line to the involved in data collection, contributed to study design, data analysis, material. If material is not included in the article’s Creative Commons data interpretation, and reviewing the manuscript. SF was involved in licence and your intended use is not permitted by statutory regula- data collection and contributed to review of manuscript drafts. VM was tion or exceeds the permitted use, you will need to obtain permission involved in data collection and contributed to review of manuscript directly from the copyright holder. To view a copy of this licence, visit drafts. FL and RW contributed to study design, data analysis, data http://creat​iveco​mmons​.org/licen​ses/by-nc/4.0/. interpretation, and reviewing the manuscript. ML contributed to data analysis, data interpretation, and reviewing the manuscript. LC was involved in data collection, contributed to data interpretation, reviewed the manuscript, and participated as a co-investigator. References 1. World Health Organization. Globocan 2018: all cancers. https​:// Funding This study was funded by Janssen EMEA. Janssen EMEA gco.iarc.fr/today/​ data/factsh​ eets/​ cancer​ s/39-All-cancer​ s-fact-sheet​ contributed to the study design, the collection, analysis, and interpreta- .pdf. Last update: 2018. Accessed May 17, 2019. tion of data, the writing of the report, and the decision to submit the 2. Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bet- paper for publication. tio M, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018. Eur J Compliance with ethical standards Cancer. 2018;103:356–87. 3. American Society of Clinical Oncology. Prostate cancer: statistics. Conflicts of interest Simon Chowdhury has participated in speaker https​://www.cance​r.net/cance​r-types​/prost​ate-cance​r/stati​stics​. bureaus and acted as a consultant for Johnson & Johnson, Astellas, Sa- Last update: Jan 2019. Accessed May 17, 2019. nofi, and Clovis and has received research grants from Clovis. Anders 4. Basch E, Loblaw DA, Oliver TK, Carducci M, Chen RC, Frame Bjartell has received remuneration from Janssen, Astellas, and Bayer JN, et al. Systemic therapy in men with metastatic castration- for lectures and for participation in advisory boards. Nicolaas Lumen resistant prostate cancer: American Society of Clinical Oncology has participated in advisory boards for Astellas, Janssen, and Bayer, re- and Cancer Care Ontario clinical practice guideline. J Clin Oncol. ceives grants from Astellas, Janssen, Bayer, Sanofi, Ferring, and Ipsen, 2014;32:3436–48. and receives speaker honoraria from Bayer, Astellas, Janssen, GSK, 5. Lorente D, Mateo J, Perez-Lopez R, de Bono JS, Attard G. and Ipsen. Pablo Maroto has participated in advisory boards for Jans- Sequencing of agents in castration-resistant prostate cancer. Lan- sen, Astellas, and Bayer. Thomas Paiss reports no conflicts of interest. cet Oncol. 2015;16:e279–e292292. Francisco Gomez-Veiga has received remuneration from Bayer, Astel- 6. Nuhn P, De Bono JS, Fizazi K, Freedland SJ, Grilli M, Kantoff las, Janssen, and Amgen for lectures and for participation in advisory PW, et al. Update on systemic prostate cancer therapies: manage- boards. Alison Birtle has participated in advisory boards and provided ment of metastatic castration-resistant prostate cancer in the era educational meeting support for Janssen, Astellas, Sanofi Genzyme, of precision oncology. Eur Urol. 2019;75:88–99. Bayer, and Roche. Gero Kramer reports no conflicts of interest. Ewa 7. Gillessen S, Attard G, Beer TM, Beltran H, Bossi A, Bristow R, Kalinka has received honoraria from Janssen and Medivation/Pfizer. et al. Management of patients with advanced prostate cancer: the Dominique Spaëth reports no conflicts of interests. Susan Feyerabend report of the Advanced Prostate Cancer Consensus Conference reports no conflicts of interest. Vsevolod Matveev participated in ad- APCCC 2017. Eur Urol. 2018;73:178–211. visory boards for and received speaker honoraria from Astellas, Bayer, 8. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Janssen, and Sanofi. Florence Lefresne is an employee of Janssen Higano CS, et al. Enzalutamide in metastatic prostate cancer Pharmaceutica N.V. and holds stock in Johnson & Johnson. Martin before chemotherapy. N Engl J Med. 2014;371:424–33. Lukac is an employee of Parexel International Czech Republic s.r.o, 9. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, on behalf of Janssen Pharmaceutica N.V., Beerse, Belgium. Robert et al. Docetaxel plus prednisone or mitoxantrone plus prednisone Wapenaar is an employee of Janssen-Cilag B.V. and holds stock in for advanced prostate cancer. N Engl J Med. 2004;351:1502–12. Johnson & Johnson. Luis Costa has participated in advisory boards for 10. Taxotere SPC. https​://www.ema.europ​a.eu/docum​ents/produ​ Janssen, Astellas, and Bayer, and has received speaker honoraria from ct-infor ​matio​n/taxot​ere-epar-produ​ct-infor ​matio​n_en.pdf. Last Janssen and Bayer. update: Accessed May 17, 2019. 11. Zytiga SPC. https:​ //www.medici​ nes.org.uk/emc/files/​ pil.2381.pdf. Ethics approval and consent to participate The study was approved by Last update: Feb 2019. Accessed May 17, 2019. the ethics committees of every country that participated. The study was 12. Xtandi SPC. https:​ //www.medici​ nes.org.uk/emc/files/​ pil.3203.pdf. conducted in accordance with the Declaration of Helsinki. Last update: Oct 2018. Accessed May 17, 2019. 13. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg Availability of data and material The data sharing policy of Janssen CN, et al. Abiraterone acetate plus prednisone versus placebo plus Pharmaceutical Companies of Johnson & Johnson is available at https​ prednisone in chemotherapy-naive men with metastatic castration- resistant prostate cancer (COU-AA-302): final overall survival Real-World Outcomes in Metastatic Castration-Resistant Prostate Cancer 315 analysis of a randomised, double-blind, placebo-controlled phase 15. Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard 3 study. Lancet Oncol. 2015;16:152–60. S, et al. Final results from the large sunitinib global expanded- 14. Oudard S, Fizazi K, Sengelov L, Daugaard G, Saad F, Hansen S, access trial in metastatic renal cell carcinoma. Br J Cancer. et al. Cabazitaxel versus docetaxel as first-line therapy for patients 2015;113:12–9. with metastatic castration-resistant prostate cancer: a randomized phase III trial-FIRSTANA. J Clin Oncol. 2017;35:3189–97. Affiliations Simon Chowdhury1 · Anders Bjartell2 · Nicolaas Lumen3 · Pablo Maroto4 · Thomas Paiss5 · Francisco Gomez‑Veiga6 · Alison Birtle7 · Gero Kramer8 · Ewa Kalinka9 · Dominique Spaëth10 · Susan Feyerabend11 · Vsevolod Matveev12 · Florence Lefresne13 · Martin Lukac14 · Robert Wapenaar15 · Luis Costa16 1 9 Guy’s and St Thomas’ NHS Foundation Trust and Sarah Clinic of Oncology, Polish Mother’s Memorial Hospital– Cannon Research Institute, Westminster Bridge Rd, Research Institute, Lodz, Poland Lambeth, London SE1 7EH, UK 10 Centre d’Oncologie de Gentilly, Nancy, France 2 Department of Urology, Skåne University Hospital Malmö, 11 Studienpraxis Urologie, Nürtingen, Germany Malmö, Sweden 12 3 N.N. Blokhin National Cancer Research Center, Moscow, Department of Urology, Ghent University Hospital, Russia C. Heymanslaan 10, 9000 Ghent, Belgium 13 4 EMEA Oncology, Janssen Pharmaceutica N.V., Beerse, Department of Medical Oncology, Hospital de la Santa Belgium Creu i Sant Pau, Autonomous University of Barcelona, 14 08025 Barcelona, Spain Parexel International Czech Republic s.r.o, on behalf 5 of Janssen Pharmaceutica N.V., Beerse, Belgium Urologie Team Ulm, Ulm, Germany 15 6 Janssen-Cilag B.V., Breda, the Netherlands Urology Department and Kidney Transplant Unit, 16 Translational Research Group of Urology GITUR‑IBSAL, Oncology Division, Hospital de Santa Maria, Instituto de Salamanca University Hospital, Salamanca, Spain Medicina Molecular, Faculdade de Medicina, Universidade 7 de Lisboa, 1649‑035 Lisbon, Portugal Royal Preston Hospital, Preston, UK 8 Department of Urology, Medical University of Vienna, Vienna, Austria