Targeted Oncology (2021) 16:357–367 https://doi.org/10.1007/s11523-021-00807-4 ORIGINAL RESEARCH ARTICLE Real‑World Safety and Efficacy Outcomes with Abiraterone Acetate Plus Prednisone or Prednisolone as the First‑ or Second‑Line Treatment for Metastatic Castration‑Resistant Prostate Cancer: Data from the Prostate Cancer Registry Anders Bjartell1,2 · 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 · Simon Chowdhury17 Accepted: 6 March 2021 / Published online: 7 April 2021 © The Author(s) 2021 Abstract Background Despite standard-of-care androgen-deprivation therapy and an increasing number of treatment options, the mor- tality rate for prostate cancer remains high. Progress to metastatic castration-resistant prostate cancer (mCRPC) necessitates additional treatments. Abiraterone acetate plus prednisone or prednisolone (AAP) prolongs survival in chemotherapy-naive and docetaxel-experienced patients. Objective To evaluate the real-world safety and efficacy of AAP as first-line and second-line [post-docetaxel only (AAP- PD)] treatment in patients with mCRPC. Patients and methods The Prostate Cancer Registry (PCR) was a prospective, international, observational study of patients with mCRPC in routine clinical practice. Men aged ≥ 18 years with confirmed mCRPC were included. Baseline character- istics, safety (treatment-emergent adverse events, treatment-emergent severe adverse events), and efficacy [progression-free survival (PFS) and overall survival (OS)] were analyzed. Results At baseline, patients who received first-line AAP (n = 754) were generally older than patients who received AAP- PD (n = 354); median age was 76 years and 70 years, respectively. However, the rate of visceral metastasis was higher in the AAP-PD cohort than in the AAP cohort (17.7% vs. 9.6%, respectively). Demographics and disease characteristics of patients with baseline cardiovascular disease were similar to those of the overall registry population. Efficacy outcomes were similar for all patients, regardless of the line of AAP therapy. For first-line AAP and AAP-PD, respectively, the median PFS was 8.9 and 5.8 months for all patients and 9.1 and 6.0 months for patients with cardiovascular comorbidities; median OS was 27.1 and 23.4 months for all patients, and 27.4 and 23.1 months for patients with cardiovascular comorbidities. There were no unexpected adverse events in any patient subgroup. Conclusions These real-world data complement the findings from randomized controlled trials, indicating that first- and second-line AAP is well tolerated and effective in patients with mCRPC, including those with underlying CV comorbidities. Trial Registration Number NCT02236637, registered 8 September 2014. * Anders Bjartell anders.bjartell@med.lu.se Extended author information available on the last page of the article Vol.:(0123456789) 358 A. Bjartell et al. toxicity of therapies evaluated in RCTs [12]. The extent to Key Points which clinical study results can be extrapolated to the real- world population is difficult to determine, as RCTs usually The Prostate Cancer Registry was the first and largest have lower generalizability (i.e., external validity). There- prospective, international, observational study of patients fore, real-world studies of patients with mCRPC in routine with metastatic castration-resistant prostate cancer clinical practice are useful to complement and extend the (mCRPC) in routine clinical practice. evidence from RCT-derived data [14, 15] as they can sup- These data extend the findings from randomized clinical port initial treatment choices and treatment sequencing deci- trials, which include patients meeting well-defined inclu- sions for all patient groups. sion and exclusion criteria. The Prostate Cancer Registry (PCR) (NCT02236637) was initiated in 2013 as the first and largest prospective, Real-world data from this registry confirm the efficacy international, observational study of patients with mCRPC and safety of first- and second-line abiraterone acetate in routine clinical practice and independent of treatment in patients with mCRPC, including a subset who had used. A recent analysis of data from the PCR showed, for cardiovascular comorbidities. the first time, that three major treatments for mCRPC (abira- terone acetate plus prednisone/prednisolone, enzalutamide, and docetaxel) are as effective in subpopulations of patients with comorbidities (cardiovascular disease or diabetes) or visceral metastases at baseline as in the wider patient popu- lation when used as first-line treatment [16]. To further the 1 Background understanding of the characteristics, disease management, and outcomes of patients with mCRPC, this analysis of final Prostate cancer is the second most common cancer in men, data from the PCR evaluated the safety of AAP as first-line having accounted for 13.5% of new cases in 2018 [1]. The and second-line [post-docetaxel only (AAP-PD)] treatment latest data show that an estimated 1.3 million men were diag- in patients with mCRPC. We chose to analyze second-line nosed with prostate cancer in 2018 [2], 450,000 new cases AAP after first-line docetaxel (i.e., vs. other treatments) of which were in Europe; this represents 20% of all cancers because this treatment sequence was approved for use in diagnosed in men [3]. For patients with metastatic disease, patients with mCRPC following the results of the pivotal androgen deprivation therapy is the cornerstone of treat- phase 3 COU-AA-301 study [10]. ment; however, many patients progress to metastatic castra- tion-resistant prostate cancer (mCRPC), necessitating addi- tional treatments [4]. Despite the efficacy of an increasing 2 Methods number of treatment options for mCRPC [5–9], the mortality rate associated with prostate cancer remains substantial. A 2.1 Aim, Study Design, and Setting mortality rate of 7% globally has been reported [2]; with 107,000 deaths from prostate cancer in 2018, it was the fifth The methodology for this analysis of patient record data most common cause of cancer-related death in Europe [3]. from the multicenter PCR of men with mCRPC has been In placebo-controlled, randomized trials, abiraterone described previously [16]. The current analysis was con- acetate plus prednisone or prednisolone (collectively, AAP) ducted to evaluate the safety and clinical outcomes of prolonged survival in patients with chemotherapy-naive patients receiving AAP-PD as part of the PCR, including mCRPC [8] as well as in those with mCRPC previously a subgroup of patients with baseline cardiovascular dis- treated with docetaxel [10]. Randomized controlled trials ease. Cardiovascular comorbidities included hypertension, (RCTs) are necessary for the development and approval of angina pectoris, history of myocardial infarction, arrhyth- new therapies; however, because of stringent methodol- mia, thromboembolic disease, transient ischemic attack, and ogy, which often excludes patients who may be at higher cerebrovascular accident. The PCR included patients treated risk, they do not reflect real-world clinical practice [11]. In with AAP, enzalutamide, docetaxel, other chemotherapy, particular, the inclusion and exclusion criteria may lead to and radium-223. under-representation of certain patient subgroups, such as The data for the PCR were collected at 199 academic patients with comorbidities or challenging disease charac- and non-academic centers of various size specializing in the teristics, who are more difficult to treat [12]. Ethnic repre- treatment of prostate cancer by both oncologists and urolo- sentation in RCTs may also differ from real-world settings, gists in a range of settings in 16 countries. At the start of which can affect outcomes [13]. This may contribute to an the PCR, AAP and enzalutamide were not routinely avail- overestimation of clinical benefit and underestimation of able for patients with mCRPC in all 16 countries. Patient Abiraterone for Metastatic Castration-Resistant Prostate Cancer: Real-World Outcomes 359 enrollment took place between 2013 and 2016 and the study to progression; or (4) new mCRPC treatment started due to end date was 9 July 2018. Patient demographics and disease progression. characteristics were collected at baseline, and patients were followed for up to 3 years. 2.4 Statistical Methods Data are presented descriptively. Missing data imputation 2.2 Patients methods were not applied; thus, there were no sensitivity analyses, and the comorbidity subgroup was constructed Eligible patients were men with mCRPC aged ≥ 18 years based on medical criteria. with a histologically or cytologically confirmed diagnosis of prostate adenocarcinoma with mCRPC, as defined previ- ously [16]. 3 Results 2.3 Variables and Data Measurement 3.1 Patient and Dosing Characteristics Observational methodology was used to capture data. The Overall, 3003 patients were included in the PCR. Among treating physicians made treatment decisions at their discre- patients who received treatment for mCRPC as part of rou- tion, per routine clinical practice, and only data available tine care, AAP was received as first-line therapy by 754 from clinical practice were collected. Prior disease history and as AAP-PD therapy by 394 (OSM, Fig. 1). Almost all and management data were collected at study inclusion. patients in the AAP and AAP-PD groups received concomi- Clinical data were collected at study inclusion, at the start tant corticosteroids (98.9% and 98.2%, respectively). Patient and end of treatments, and prospectively every 3 months demographics and disease characteristics at study entry are during routine follow-up (at least every 3 months per pro- shown in Table 1. Patients who received first-line AAP were tocol) over the 3-year study period, with clinical trial levels generally older than those who received AAP-PD (median of monitoring quality. age, 76 years vs. 70 years, respectively). In addition, more For this analysis, outcomes were evaluated for all patients patients in the AAP-PD group had visceral metastases than receiving AAP-PD and for those with cardiovascular comor- in the first-line AAP group (17.7% vs. 9.6%, respectively). bidities receiving AAP-PD, as part of the PCR. Data from Median levels of prostate-specific antigen and lactic acid the analysis of first-line AAP in all patients and in those dehydrogenase were also higher in the AAP-PD cohort. with cardiovascular comorbidities, as previously published The proportion of patients with an ECOG PS of 1 and M1 by Chowdhury et al. [16], are included for comparative stage at diagnosis was also higher among those who received purposes. Patients who received AAP-PD comprised two AAP-PD; more than 50% of patients in all groups had ECOG groups: (1) those who were receiving AAP at the start of PS ≥ 1 at baseline. the PCR and had received docetaxel as first-line mCRPC The majority of patients (> 70%) had comorbidities at treatment prior to PCR participation, and (2) those who were baseline (Table 2). A total of 66.8% of patients treated with receiving first-line docetaxel at the start of the PCR and went on to receive AAP as a second-line therapy during the study 12 11.2 11.1 period [Supplementary Fig. 1, Online Supplementary Mate- rial (OSM)]. 10 9.0 8.7 Months (median) Safety outcomes are reported as treatment-emergent 8 adverse events (TEAEs) or treatment-emergent severe adverse events (TESAEs). Efficacy outcomes are reported as 6 progression-free survival [PFS; assessed by radiologic and/ 4 or clinical methods (including prostate-specific antigen)] and overall survival (OS). Change in Eastern Cooperative Oncol- 2 ogy Group performance status (ECOG PS) from baseline to 0 the end of treatment was also reported. PFS was calculated AAP AAP-PD in months from the start of AAP treatment to disease pro- All patients Patients with CV comorbidities gression or death. Progression, which was based on available data, was defined (in order of importance) as: (1) evidence Fig. 1  Treatment duration (first-line data included for comparative purposes). aMedian duration of treatment by Kaplan-Meier estimates of radiographic progression by investigator’s assessment; and censoring of patients with ongoing treatment at end of Registry. (2) evidence of clinical progression by investigator’s assess- AAP abiraterone acetate plus prednisone/prednisolone, AAP-PD AAP ment; (3) first- or second-line mCRPC treatment stopped due after docetaxel, CV cardiovascular 360 A. Bjartell et al. Table 1  Demographics and disease characteristics at study entry AAPa AAP-PD All patient Patients with CV All patients Patients with CV (N = 754) comorbidities (N = 394) comorbidities (n = 504) (n = 234) Age, y, median (range) 76.0 (43–98) 77.0 (50–94) 70.0 (46–89) 72.0 (48–89) Time from initial prostate cancer diagnosis to 5.0 (0–29) 5.3 (0–29) 3.7 (0–20) 4.3 (0–18) study inclusion, y, median (range) Site of lesion, n (%) (n = 612) (n = 402) (n = 345) (n = 202) Node 249 (40.7) 167 (41.5) 155 (44.9) 96 (47.5) Liver and lung 7 (1.1) 5 (1.2) 7 (2.0) 4 (2.0) Liver only 13 (2.1) 7 (1.7) 25 (7.2) 17 (8.4) Lung only 39 (6.4) 25 (6.2) 29 (8.4) 19 (9.4) Local recurrence 85 (13.9) 54 (13.4) 70 (20.3) 42 (20.8) Bone 463 (75.7) 296 (73.6) 261 (75.7) 155 (76.7) Other 52 (8.5) 31 (7.7) 37 (10.7) 21 (10.4) Presence of bone metastases (baseline), n (%) (n = 550) (n = 374) (n = 271) (n = 169) Any 487 (88.5) 328 (87.7) 238 (87.8) 145 (85.8) ≥5 203 (36.9) 134 (35.8) 113 (41.7) 75 (44.4) Visceral metastases (baseline), n (%) (n = 612) (n = 402) (n = 345) (n = 202) Liver only 13 (2.1) 7 (1.7) 25 (7.2) 17 (8.4) Lung only 39 (6.4) 25 (6.2) 29 (8.4) 19 (9.4) Liver and lung 7 (1.1) 5 (1.2) 7 (2.0) 4 (2.0) Biological parameters, median (range) Prostate-specific antigen, ng/mL 34.40 (0.0–10,710.0) 34.00 (0.1–10,710.00) 50.45 (0.0 –2108.0) 52.4 (0.1 –1445.0) Lactic acid dehydrogenase, U/L 268.0 (3–3870) 255.0 (3–3870) 307.0 (40.0 –3537.0) 291.0 (103.0 –1553.0) Alkaline phosphatase, U/L 111.0 (1–2890) 112.5 (1–2890) 103.2 (1.0 –1850.0) 104.0 (1.0 –1433.0) Hemoglobin, g/dL 12.9 (7–17) 12.7 (7–16) 12.5 (7.0 –17.0) 12.4 (7.0 –16.0) Gleason score at initial diagnosis, n (%) (n = 674) (n = 448) (n = 367) (n = 220) 2–6 100 (14.8) 71 (15.8) 44 (12.0) 31 (14.1) 7 230 (34.1) 154 (34.4) 106 (28.9) 63 (28.6) 8–10 344 (51.0) 223 (49.8) 217 (59.1) 126 (57.3) M stage at initial diagnosis, n (%) (n = 732) (n = 488) (n = 388) (n = 230) Mx 161 (22.0) 114 (23.4) 73 (18.8) 44 (19.1) M0 315 (43.0) 217 (44.5) 138 (35.6) 89 (38.7) M1, M1a, M1b, M1c 256 (35.0) 157 (32.2) 177 (45.6) 97 (42.2) ECOG performance status, n (%) (n = 715) (n = 477) (n = 371) (n = 221) 0 340 (47.6) 218 (45.7) 133 (35.8) 72 (32.6) 1 318 (44.5) 214 (44.9) 208 (56.1) 127 (57.5) 2 48 (6.7) 6 (7.5) 26 (7.0) 19 (8.6) 3 9 (1.3) 9 (1.9) 4 (1.1) 3 (1.4) 4 0 0 0 0 AAP abiraterone acetate plus prednisone/prednisolone, AAP-PD AAP after docetaxel, CV cardiovascular, ECOG Eastern Cooperative Oncology Group a Included for comparative purposes first-line AAP had cardiovascular disease compared with group; the proportions of patients with renal and neurologi- 59.4% of those treated with AAP-PD; the profiles of car- cal comorbidities and diabetes were similar between cohorts. diovascular disease characteristics for patients were simi- The recommended daily dose of abiraterone was 1,000 lar in both treatment cohorts. There was a slightly higher mg; this was the dose received by ≥ 98% of patients in all rate of respiratory and hepatic disease in the first-line AAP analysis groups. Treatment duration was longer for patients Abiraterone for Metastatic Castration-Resistant Prostate Cancer: Real-World Outcomes 361 Table 2  Comorbidities at study entry AAPa AAP-PD All patients Patients with CV All patients Patients with CV (N = 754) comorbidities (N = 394) comorbidities (n = 504) (n = 234) Comorbid disease requiring treatment, n (%) 566 (75.1) 504 (100.0) 276 (70.1) 234 (100.0) Cardiovascular 504 (66.8) 502 (99.6) 234 (59.4) 231 (98.7) Hypertension 411 (54.5) 411 (81.5) 194 (49.2) 187 (79.9) Angina pectoris 34 (4.5) 34 (6.7) 20 (5.1) 19 (8.1) Myocardial infarction 48 (6.4) 48 (9.5) 25 (6.3) 25 (10.7) Arrhythmia 62 (8.2) 62 (12.3) 29 (7.4) 26 (11.1) Thromboembolic disease 21 (2.8) 21 (4.2) 10 (2.5) 8 (3.4) Cerebrovascular accident 19 (2.5) 19 (3.8) 8 (2.0) 8 (3.4) Transient ischemic attack 14 (1.9) 14 (2.8) 8 (2.0) 8 (3.4) Other cardiovascular 139 (18.4) 139 (27.6) 61 (15.5) 61 (26.1) Respiratory 60 (8.0) 46 (9.1) 25 (6.3) 19 (8.1) Chronic obstructive pulmonary disease 41 (5.4) 31 (6.2) 15 (3.8) 12 (5.1) Other respiratory 20 (2.7) 16 (3.2) 12 (3.0) 8 (3.4) Renal 52 (6.9) 43 (8.5) 24 (6.1) 16 (6.8) Chronic renal disease 31 (4.1) 27 (5.4) 11 (2.8) 10 (4.3) Other renal 21 (2.8) 16 (3.2) 14 (3.6) 7 (3.0) Hepatic 17 (2.3) 15 (3.0) 5 (1.3) 4 (1.7) Chronic hepatic disease 9 (1.2) 8 (1.6) 3 (0.8) 3 (1.3) Other hepatic 8 (1.1) 7 (1.4) 2 (0.5) 1 (0.4) Neurological 66 (8.8) 52 (10.3) 32 (8.1) 28 (12.0) Peripheral sensory impairment 2 (0.3) 1 (0.2) 5 (1.3) 4 (1.7) Memory impairment 5 (0.7) 3 (0.6) 1 (0.3) 1 (0.4) Cognitive disorder 4 (0.5) 3 (0.6) 3 (0.8) 2 (0.9) Convulsion 3 (0.4) 3 (0.6) 2 (0.5) 1 (0.4) Other neurological 27 (3.6) 15 (3.0) 8 (2.0) 7 (3.0) Infections 6 (0.8) 5 (1.0) 5 (1.3) 1 (0.4) Other infection 6 (0.8) 5 (1.0) 5 (1.3) 1 (0.4) Diabetes 121 (16.0) 101 (20.0) 66 (16.8) 52 (22.2) Non-insulin-dependent diabetes 87 (11.5) 75 (14.9) 53 (13.5) 44 (18.8) Insulin-dependent diabetes 34 (4.5) 26 (5.2) 14 (3.6) 9 (3.8) AAP abiraterone acetate plus prednisone/prednisolone, AAP-PD AAP after docetaxel, CV cardiovascular a Included for comparative purposes receiving first-line AAP than for those receiving AAP-PD; duration of follow-up in the Registry for the subgroup of within the cohorts, the treatment duration was similar for patients with cardiovascular comorbidities treated with first- all patients and those with cardiovascular comorbidities line AAP and AAP-PD was 23.4 (0–41) months and 22.2 (Fig. 1). The median [95% confidence interval (CI)] dura- (1–41) months, respectively. tion of treatment according to Kaplan-Meier analysis was 11.2 (9.8–12.2) months with AAP as first-line treatment and 3.2 Safety 8.7 (7.10–10.3) months with AAP-PD. For patients with car- diovascular comorbidities, the median (95% CI) duration of No unexpected AEs were observed in the analysis in the treatment was 11.1 (9.50–12.70) months with AAP as first- overall patient population or in the subgroup with cardio- line treatment and 9.0 (6.9–10.6) months with AAP-PD. The vascular comorbidities. TEAEs were more common among median (range) duration of follow-up in the PCR was 24.5 patients who received first-line AAP than among those (0–43) months for all patients treated with first-line AAP who received AAP-PD (Table 3). Among all 754 patients and 22.9 (1–41) months for AAP-PD. The median (range) who received first-line AAP, TEAEs were reported in 487 362 A. Bjartell et al. Table 3  Treatment-emergent adverse events reported in ≥ 5% of patients AAP AAP-PD All patients Patients with CV comor- All patients Patients with CV (N = 754) bidities (N = 394) comorbidities (n = 504) (n = 234) Number of patients with at 487 (64.6) 338 (67.1) 222 (56.3) 132 (56.4) least one TEAE, n (%) Preferred term, n (%) Fatigue 56 (7.4) 37 (7.3) 22 (5.6) 17 (7.3) Asthenia 54 (7.2) 39 (7.7) 22 (5.6) 14 (6.0) Edema peripheral 51 (6.8) 34 (6.7) – – Back pain 57 (7.6) 41 (8.1) – – Diarrhea – 26 (5.2) – – Anemia – – 31 (7.9) 15 (6.4) Hematuria – 27 (5.4) – – AAP abiraterone acetate plus prednisone/prednisolone, AAP-PD AAP after docetaxel, CV cardiovascular, TEAE treatment-emergent adverse event (64.6%); these were classified as mild, moderate, or severe patients and patients with cardiovascular comorbidities in in 24.8%, 34.1%, and 41.1% of cases, respectively. Of note, the AAP-PD group, 29.7% and 29.9%, respectively, had the incidences of cardiac and vascular TEAEs reported TESAEs. The proportions of patients experiencing the most were similar between all groups and neither hypokalemia common TESAEs were similar among patients with cardio- nor hypertension were reported in ≥ 5% of patients in any vascular comorbidities and the overall population in both treatment group (OSM, Table 1). TEAEs that led to treat- treatment cohorts. ment discontinuation occurred in 10.3% of patients. In the Compared with baseline, ECOG PS at the end of treat- subgroup of patients with cardiovascular comorbidities who ment had improved or remained unchanged in 59.3% of received first-line AAP, TEAEs were observed in 338 of 504 patients who received AAP and in 66.1% of patients in the (67.1%); these were classified as mild, moderate, or severe in AAP-PD cohort (Fig. 2). The proportions of patients with 24.3%, 34.6%, and 41.1% of cases, respectively. TEAEs that cardiovascular comorbidities whose ECOG PS improved led to treatment discontinuation occurred in 9.5% of patients. were similar. A slightly higher proportion of patients in the In the cohort of patients who received AAP-PD, TEAEs AAP cohort reported a worsening of ECOG PS than in the were reported in 222 of 394 patients (56.3%); these were AAP-PD cohort (40.7% vs. 33.6%, respectively). classified as mild, moderate, or severe in 20.3%, 38.3%, and The 6-month total mortality rates were similar between 41.4% of cases, respectively. TEAEs that led to treatment the total patient population and the subpopulation with car- discontinuation occurred in 11.7% of these patients. In the diovascular comorbidities among patients who received first- subgroup with cardiovascular comorbidities who received line AAP (~9%) and AAP-PD (~14%). AAP-PD, TEAEs were observed in 132 of 234 patients (56.4%); these were classified as mild, moderate, or severe 3.3 Efficacy in 19.7%, 38.6%, and 41.7% of cases, respectively. TEAEs that led to treatment discontinuation occurred in 11.4% of Efficacy outcomes with first-line AAP were similar between these patients. In both treatment cohorts, the proportions of the total patient group and the subgroup of patients with patients experiencing the most common TEAEs were similar baseline cardiovascular comorbidities. According to among patients with cardiovascular comorbidities and the Kaplan-Meier estimates, the median (95% CI) PFS was 8.90 overall population. (7.8–9.7) months for all patients and 9.10 (7.5–10.4) months A total of 496 of 1,490 patients who received AAP for patients with cardiovascular comorbidities (Fig. 3a). The (33.3%) in the PCR reported at least one TESAE (OSM, median (95% CI) OS was 27.1 (25.3–28.9) months for all Table 2). Overall, TESAEs were more common among patients and 27.4 (23.0–30.3) months for patients with car- patients who were treated with first-line AAP than those diovascular comorbidities (Fig. 4a). Efficacy outcomes with who received AAP-PD. Among all patients and patients with AAP-PD were similar between the total patient group and cardiovascular comorbidities in the first-line AAP group, the subgroup of patients with baseline cardiovascular comor- 34.7% and 37.3%, respectively, had TESAEs. Among all bidities (Fig. 4b). According to Kaplan-Meier estimates, Abiraterone for Metastatic Castration-Resistant Prostate Cancer: Real-World Outcomes 363 60 53.9 54.1 51.2 49.0 43.0 40.7 40 Patients (%) 33.6 33.0 Improvement 20 No change 12.2 12.4 Worsening 8.1 8.0 0 All patients Patients with CV All patients Patients with CV (N=602) comorbidities (N=304) comorbidities (n=400) (n=185) AAP AAP-PD Fig. 2  Change in Eastern Cooperative Oncology Group performance status during treatment. AAP abiraterone acetate plus prednisone/predniso- lone, AAP-PD AAP after docetaxel, CV cardiovascular the median (95% CI) PFS was 5.8 (5.2–6.6) months for in both treatment cohorts, slight differences were observed, all patients and 6.0 (5.0–8.0) months for patients with car- such as a higher proportion of patients with an ECOG PS of diovascular comorbidities (Fig. 3b). The median (95% CI) 0 in the first-line AAP group than in the group that received OS was 23.4 (20.1–30.6) months for all patients and 23.1 AAP-PD and a higher proportion with an ECOG PS of 1 in (19.4–30.0) months for patients with cardiovascular comor- the AAP-PD group than in the first-line AAP group. bidities (Fig. 4b). Data from the PCR demonstrated that AAP, whether given as first- or second-line treatment, was not associated with any unexpected adverse events, even in patients with 4 Discussion underlying cardiovascular comorbidities. Severe TEAEs were reported in approximately 40% of patients in all groups. This analysis of real-world outcomes of patients with This is lower than reported from the COU-AA-302 clinical mCRPC in the PCR showed that first- and second-line AAP study, in which grade 3 or 4 adverse events were reported in is effective for treating mCRPC in a large group of patients, 48% of patients in the abiraterone-prednisone group, despite among whom specific comorbidities were not excluded. the fact that patients were not selected so they generally had There were some notable differences in the baseline more severe disease at baseline and so AEs may be expected demographics and disease characteristics between patients to be more prevalent [17]. Overall, more AEs were observed who received first-line AAP and AAP second-line post with first-line than second-line AAP. This may be because docetaxel. In general, patients who received AAP-PD were patients in the first-line AAP group were not deemed eligible younger than those who received first-line AAP. This obser- for docetaxel due to their frailty, which, in turn, may have vation was reported in an earlier analysis of the PCR [16] made them more prone to AEs. and indicates that a patient’s age—as an indicator of fit- PFS and OS were numerically longer for patients who ness—could influence the physician’s decision to start treat- received first-line AAP compared with those in the AAP-PD ment with docetaxel versus other first-line treatments. Rates treatment cohort, which is consistent with the results from of liver and/or lung lesions, and local recurrence of lesions, RCTs [8, 10]. However, almost no differences in PFS and OS were higher in the AAP-PD group versus the first-line AAP between the overall populations and in the subpopulations group. Median prostate-specific antigen and lactic acid dehy- of patients with cardiovascular comorbidities were seen in drogenase values were also higher than in the first-line AAP either the first- or second-line AAP therapy cohort. These group, as was the number of patients with stage M1 mCRPC. outcomes showing consistent efficacy between the subgroup This finding is consistent with docetaxel being more fre- of patients with cardiovascular disease and the overall treat- quently used as a first-line treatment for patients who are at ment populations indicate that AAP is also effective in this a more advanced disease stage. At baseline, the majority of patient subgroup irrespective of whether it is given as a first- patients had an ECOG PS of 0 or 1, indicative of a relatively or second-line treatment. fit population included in the PCR. Although there were The safety and efficacy outcomes of this Registry similar proportions of patients with ECOG PS of 0, 1, and 2 complement the data from phase 3 RCTs that evaluated 364 A. Bjartell et al. Fig. 3  Progression-free survival a 100 All patients in all patients treated with a Patients with AAP and b AAP-PD among CV comorbidities those with and without cardio- Survival probability (%) 80 vascular comorbidities (first-line data included for comparative purposes). AAP abiraterone 60 acetate plus prednisone/pred- nisolone, AAP-PD AAP after docetaxel, CV cardiovascular 40 20 0 0 10 20 30 40 Progression-free survival (months) Number at risk All 754 513 329 235 165 122 86 52 0 CV 504 336 224 155 110 80 53 31 0 b 100 All patients Patients with CV comorbidities Survival probability (%) 80 60 40 20 0 0 10 20 30 40 Progression-free survival (months) Number at risk All 394 215 127 67 42 25 16 6 0 CV 234 127 74 37 20 13 8 3 0 first- and second-line treatment with AAP in patients with This study benefits from a number of strengths, including mCRPC [8, 10], supporting the clinical utility of AAP for the size and scope of the PCR, which allow a wealth of data to the treatment of patients with mCRPC. In our analysis, the be collected. Importantly, the Registry includes patients often median OS of 27.1 months among patients who received excluded from clinical studies (such as those with cardiovas- AAP was shorter than the 34.7 months achieved in an RCT cular comorbidities, among whom abiraterone or docetaxel of chemotherapy-naive men [8]. Conversely, the OS of are not contraindicated). However, some limitations should 23.4 months observed for patients who received AAP-PD be acknowledged. The long duration of data collection for the was longer than the 14.8 months reported from an RCT PCR spanned a period that witnessed substantial advances in of patients who had also received second-line abiraterone mCRPC treatment over time. AAP and enzalutamide were not after docetaxel [10]. The differences in survival outcomes routinely indicated for mCRPC in all 16 countries included observed in the PCR and in RCTs most likely reflect differ- in the PCR for the entire duration of the study, which would ences in inclusion/exclusion criteria, highlighting the need have affected the choice of initial therapy. In this observational for both interventional and non-interventional studies to study, data were collected at routine clinical visits, which may provide a comprehensive evaluation of treatment effects. not have occurred at regular intervals for all patients, and Abiraterone for Metastatic Castration-Resistant Prostate Cancer: Real-World Outcomes 365 Fig. 4  Overall survival in all a 100 All patients patients treated with a AAP and b AAP-PD among those Patients with with and without cardiovascular CV comorbidities 80 comorbidities (first-line data Survival probability (%) included for comparative pur- poses). AAP abiraterone acetate plus prednisone/prednisolone, 60 AAP-PD AAP after docetaxel, CV cardiovascular 40 20 0 0 10 20 30 40 Time to death (months) Number at risk All 754 692 597 509 420 339 245 142 3 0 CV 504 458 391 335 271 221 158 91 1 0 b 100 All patients Patients with CV comorbidities 80 Survival probability (%) 60 40 20 0 0 10 20 30 40 Time to death (months) Number at risk All 394 331 253 202 148 92 66 28 0 CV 234 194 152 126 89 51 38 14 0 patients may not have been consecutively enrolled. In addition, 5 Conclusions the criteria for progression reflected routine clinical practice at the treating physician’s discretion, and so were not the same These real-world data provide a comprehensive analysis of as the strict criteria that are generally used in RCTs. Initiation the characteristics and clinical outcomes of a large cohort of second-line treatment after disease progression was at the of men with mCRPC. These data complement and extend discretion of the treating physician and not according to a strict those obtained from RCTs and may be useful for informing protocol. 366 A. Bjartell et al. clinical practice, especially with regard to the management manuscript, and had final responsibility for the decision to submit for of mCRPC in patients who would generally be considered publication. Simon Chowdhury was involved in data collection, con- tributed to data interpretation, and reviewed the manuscript. NL was ineligible for interventional studies, making them more involved in patient recruitment/data collection, data interpretation, and generalizable to real-world patients with mCRPC than to reviewing the manuscript. PM was involved in data collection and con- those included in RCTs. Importantly, these results confirm tributed to data analysis, interpretation, and review of the manuscript. that abiraterone, when used as first-line therapy or second- TP was involved in data collection and contributed to review of manu- script drafts. FG-V was involved in data collection, contributed to data line treatment after docetaxel, is effective and well toler- interpretation, reviewed the manuscript, and participated as co-inves- ated in patients with mCRPC. tigator in the PCR. AB was involved in data collection and contributed to review of manuscript drafts. GK was involved in data collection and Supplementary Information The online version contains supplemen- contributed to review of manuscript drafts. EK was involved in data tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 11523-0​ 21-0​ 0807-4. collection, data interpretation, and reviewing the manuscript. DS was involved in data collection and contributed to study design, data analy- Acknowledgments The authors acknowledge Kate Bradford, PhD, of sis, data interpretation, and reviewing the manuscript. SF was involved Parexel who provided editorial assistance in the development of the in data collection and contributed to review of manuscript drafts. VM manuscript. was involved in data collection and contributed to review of manuscript drafts. FL and RW contributed to study design, data analysis, data interpretation, and reviewing the manuscript. ML contributed to data Funding Open access funding provided by Lund University. analysis, data interpretation, and reviewing the manuscript. LC was involved in data collection, contributed to data interpretation, reviewed Declarations the manuscript, and participated as a co-investigator in the PCR. Funding This study was funded by Janssen EMEA. Janssen EMEA Ethics approval The study was approved by the ethics committees of contributed to the study design; the collection, analysis, and interpreta- every country that participated. The study was conducted in accordance tion of data; the writing of the report; and the decision to submit the with the Declaration of Helsinki. paper for publication. Consent to participate All patients provided written informed consent. Conflicts of interest Simon Chowdhury has participated in speaker Consent for publication Not applicable. bureaus and acted as a consultant for Johnson & Johnson, Astellas, Sa- nofi, and Clovis, and has received research grants from Clovis. Anders Code availability Not applicable. Bjartell has received remuneration from Janssen, Astellas, Sandoz, Ipsen, AstraZeneca, Merck, and Bayer for lectures and for participa- tion in advisory boards, and from Ferring and Astellas for investigator- Open Access This article is licensed under a Creative Commons Attri- initiated trials. Nicolaas Lumen has participated in advisory boards for bution-NonCommercial 4.0 International License, which permits any Astellas, Janssen, and Bayer, receives grants from Astellas, Janssen, non-commercial use, sharing, adaptation, distribution and reproduction Bayer, Sanofi, Ferring, and Ipsen, and receives speaker honoraria from in any medium or format, as long as you give appropriate credit to the Bayer, Astellas, Janssen, GSK, and Ipsen. Pablo Maroto has participat- original author(s) and the source, provide a link to the Creative Com- ed in advisory boards for Janssen, Astellas, and Bayer. Thomas Paiss mons licence, and indicate if changes were made. The images or other reports no conflicts of interest. Francisco Gomez-Veiga has received third party material in this article are included in the article’s Creative remuneration from Bayer, Astellas, Janssen, and Amgen for lectures Commons licence, unless indicated otherwise in a credit line to the and for participation in advisory boards. Alison Birtle has participat- material. If material is not included in the article’s Creative Commons ed in advisory boards and provided educational meeting support for licence and your intended use is not permitted by statutory regula- Janssen, Astellas, Sanofi Genzyme, Bayer, and Roche. Gero Kramer tion or exceeds the permitted use, you will need to obtain permission reports no conflicts of interest. Ewa Kalinka has received honoraria directly from the copyright holder. To view a copy of this licence, visit from Janssen and Medivation/Pfizer. Dominique Spaëth reports no http://​creat​iveco​mmons.​org/​licen​ses/​by-​nc/4.​0/. conflicts of interests. Susan Feyerabend reports no conflicts of inter- est. Vsevolod Matveev has participated in advisory boards for and re- ceived speaker honoraria from Astellas, Bayer, Janssen, and Sanofi. Florence Lefresne is an employee of Janssen Pharmaceutica N.V. and holds stock in Johnson & Johnson. Martin Lukac is an employee of References Parexel International Czech Republic s.r.o, on behalf of Janssen Phar- maceutica N.V., Beerse, Belgium. Robert Wapenaar is an employee of 1. World Health Organization. GLOBOCAN 2018: all cancers. Janssen-Cilag B.V. and holds stock in Johnson & Johnson. Luis Costa https://​gco.​iarc.​fr/​today/​data/​facts​heets/​cance​rs/​39-​All-​cance​rs-​ has participated in advisory boards for Janssen, Astellas, and Bayer, fact-​sheet.​pdf. Accessed 17 May 2019. and has received speaker honoraria from Janssen and Bayer. 2. 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Authors and Affiliations Anders Bjartell1,2 · 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 · Simon Chowdhury17 1 10 Department of Urology, Skåne University Hospital Malmö, Centre d’Oncologie de Gentilly, Nancy, France Jan Waldenströms gata 5, SE 205 02 Malmö, Sweden 11 Studienpraxis Urologie, Nürtingen, Germany 2 Department of Translational Medicine, Medical Faculty, 12 N.N. Blokhin National Cancer Research Center, Moscow, Lund University, Malmö, Sweden Russia 3 Department of Urology, Ghent University Hospital, Ghent, 13 EMEA Oncology, Janssen Pharmaceutica N.V., Beerse, Belgium Belgium 4 Department of Medical Oncology, Hospital de la Santa Creu 14 Parexel International Czech Republic s.r.o, on behalf i Sant Pau, Autonomous University of Barcelona, Barcelona, of Janssen Pharmaceutica N.V., Beerse, Belgium Spain 15 5 Janssen-Cilag B.V., Breda, The Netherlands Urologie team Ulm, Ulm, Germany 16 6 Oncology Division, Faculdade de Medicina, Hospital de Urology Department and Kidney Transplant Unit, Santa Maria, Instituto de Medicina Molecular, Universidade Translational Research Group of Urology GITUR‑IBSAL, de Lisboa, Lisbon, Portugal Salamanca University Hospital, Salamanca, Spain 17 7 Guy’s and St Thomas’ NHS Foundation Trust and Sarah Royal Preston Hospital, Preston, UK Cannon Research Institute, London, UK 8 Department of Urology, Medical University of Vienna, Vienna, Austria 9 Clinic of Oncology, Polish Mother’s Memorial Hospital, Research Institute, Lodz, Poland