Stesura Seveso 393Archivio Italiano di Urologia e Andrologia 2021; 93, 4 ORIGINAL PAPER No conflict of interest declared. Since 1941, when Charles Huggins and colleagues uncov- ered the hormonal dependence of metastatic prostate cancer, androgen deprivation therapy has been the thera- peutical mainstay for metastatic prostate cancer. After decades of absent novelties, we assisted to the intro- duction of novel hormonal agents for the treatment of castration-resistant metastatic prostate cancer. Abiraterone and enzalutamide were the first two novel hormonal agents approved for the treatment of metastat- ic prostate cancer and are now widely used. Abiraterone is an inhibitor of CYP17A1, an enzyme essential in the process of androgen synthesis. Enzalutamide competi- tively inhibits androgen binding to the androgen receptor (AR), nuclear translocation of the AR, DNA binding and coactivator recruitment. Both abiraterone and enzalu- tamide are first line treatments for metastatic castration- resistant prostate cancer (mCRPC), but there is a lack of quality evidence regarding which is associated with better outcomes and who would benefit the most with one or another of these drugs. Our propose was to evaluate the clinical outcomes of patients submitted to either abiraterone or enzalutamide for castration-resistant metastatic prostate cancer in our center. PATIENTS AND METHODS Patients eligible for this study had a diagnosis of metastat- ic castration-resistant prostate cancer defined as castrate serum testosterone < 50 ng/mL and biochemical progres- sion (three consecutives rises in prostatic specific antigen (PSA) at least one week apart resulting in two 50% increas- es over the nadir, and a PSA > 2 ng/mL) or radiological pro- gression (appearance of new lesions: either two or more new bone lesions or a soft lesion using Response Evaluation Criteria in Solid Tumours (RECIST)) and initiated treatment with either abiraterone or enzalutamide between January 1, 2016 and December 31, 2019. Follow-up extended from January 1, 2016 until December 31, 2020. In 2019, we treated 358 patients diagnosed with prostate cancer, repre- senting roughly 5.5% cases nationwide. Individual clinical cases were discussed in bi-weekly onco- urology meetings. Patients with clinical criteria of poor prognosis (symptoms, short period of response under Introduction: Prostate cancer is the most common cancer in men, accounting for 15% of all diagnosed cancers and is the sixth leading cause of cancer- related deaths amongst men worldwide. Abiraterone and enza- lutamide were the first two novel hormonal agents approved for the treatment of metastatic prostate cancer but there is a lack of quality evidence regarding which is associated with better outcomes and who would benefit the most with one or another of these drugs. Objective: To evaluate the clinical outcomes of real-world patients submitted to treatment with novel hormonal agents, enzalutamide and abiraterone, for castration resistant metastat- ic prostate cancer in an academic center. Patients and methods: We retrospectively reviewed patients treated for castration-resistant prostate cancer with either abi- raterone or enzulatamide between January 1, 2016 and December 31, 2019. The primary endpoints were biochemical response, biochemical progression, radiological progression, clinical deterioration (attributed to disease progression) and death. Results: Enzalutamide had a higher biochemical response rate than abiraterone in patients with mCRPC (77.1% vs 58.1%, p = 0.016). Achieving a biochemical response was associated with a lower risk of biochemical progression (OR: 0.248, p = 0.017) and death (OR: 0.302, p = 0.038). Conclusions: Enzalutamide conferred higher biochemical response rate than abiraterone in patients with mCRPC. Despite the trend to better performance of other endpoints in the enzalutamide group, it did not achieve statistical signifi- cance. Well-designed prospective studies are needed to elucidate the comparative efficacies of these agents. KEY WORDS: Prostate cancer; Abiraterone; Enzalutamide; Castration-resistant. Submitted 7 June 2021; Accepted 15 August 2021 INTRODUCTION Prostate cancer is the most common cancer in men, accounting for 15% of all diagnosed cancers and being the sixth leading cause of cancer-related deaths amongst men worldwide. Metastatic prostatic cancer can be roughly divided in two main clinical stages: hormone-sensitive and castration- resistant prostate cancer. Novel hormonal agents for metastatic Castration-Resistant Prostate Cancer: comparing outcomes. A single-center retrospective study Roberto Saldanha Jarimba 1, Miguel Nobre Eliseu 1, João Pedroso Lima 1, Vasco Quaresma 1, Pedro Moreira 1, Pedro Coelho Nunes 1, 2, Edgar Tavares da Silva 1, 2, Arnaldo José Figueiredo 1, 2 1 Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; 2 Faculty of Medicine, University of Coimbra, Portugal. DOI: 10.4081/aiua.2021.4.393 Summary Archivio Italiano di Urologia e Andrologia 2021; 93, 4 R. Saldanha Jarimba, M. Nobre Eliseu, J. Pedroso Lima, et al. 394 androgen deprivation therapy (ADT), high metastatic bur- den, visceral metastasis or poor prognostic genetic muta- tions) were treated with taxane-based chemotherapy. The decision to begin treatment with a novel hormonal agent was taken either as first line therapy in patients with less aggressive features (asymptomatic, durable response under previous ADT, low metastatic burden and no visceral metastases) or as second line therapy in patients that pro- gressed under first line therapy with taxane-based chemoterapy. In the absence of contraindication for either pharmaceutical drugs, patients were sequentially assigned to either enzalutamide or abiraterone group. The database used was anonymized and unstructured. Data were originally extracted from electronic medical records. Demographic and clinicopathological features (International Society of Urological Pathology (ISUP) score, M1 ab inition or progression after local treatment status, previous period of classical androgen deprivation thera- py, PSA level, previous treatment of taxane-based chemotherapy and localization of metastasis) were regis- tered at baseline. Data reported adverse events (AEs) was also available. Per local protocol, stable patients with metastatic prostate cancer under novel hormonal agents are followed with clinical and analytical evaluation including PSA measure- ment every 3 months by a staff expert. Occurrence of bio- chemical response (defined as a reduction of ≥ 50% of pretreatment PSA level after 12 weeks of treatment), PSA progression (three consecutives rises in PSA at least one week apart resulting in two 50% increases over the nadir, and a PSA > 2 ng/mL), radiological progression (appear- ance of new lesions: either two or more new bone lesions or a soft lesion using RECIST) diagnosed either by com- puted tomography (CT) scan, bone scintigraphy or G68 - prostate-specific membrane antigen (PSMA) - positron emis- sion tomography (PET), clinical deterioration and/or death and the time of their occurrence were available. The primary endpoints of this study were biochemical response, biochemical progression, radiological progres- sion, clinical deterioration (attributed to disease progres- sion) and death. Safety was a secondary endpoint. Follow-up was stopped when the drug was suspended due to adverse reactions or disease progression. There was no crossover. Statistical analysis Descriptive statistics of patient and pathological charac- teristic were calculated for all patients included in the present study, as well as by administered agent. We used a chi-square univariate analysis to assess the sta- tistical significance of the difference between rate response in the abiraterone and enzalutamide group. Further, we used a binary logistic regression, adjusted to clinicopathological features, to quantify this association. A Cox-regression was performed to uncover predictive co-variates of biochemical progression, radiological pro- gression and overall survival. A survival analysis using a Kaplan-Meier method was used to evaluate the risk of biochemical progression, radi- ological progression and overall survival and a log-rank test applied to test for significant differences. All analyses were conducted using IBM SPSS statistics version 23. All comparisons were made using 2-sided tests, with p < 0.05 considered statistically significant. RESULTS A total of 91 patients who initiated a novel hormonal agent, either abiraterone or enzalutamide, between January 2016 and December 2019 were included in the study. 56 (61.5%) patients were treated with abiraterone and the remaining 35 (38.5%) with enzalutamide. 45 (49.5%) patients were diagnosed with metastatic prostate cancer ab inition. 74.7%, 53.8% and 6.6% had bone, lym- phatic, and visceral metastasis, respectively. Almost 30% of patients had been previously submitted to taxane-based chemotherapy. Mean age of the cohort was 74.4 (± 8.26) years, while the mean pretreatment PSA level was 231.51 (± 380.15) ng/mL and previous classical androgen depri- vation therapy duration was 74.13 (± 54.87) months. Median follow-up time was 18.34 months. All covariates, as age, pretreatment PSA level, ISUP score, M1 ab inition or progression after local treatment status, previous period of classical androgen deprivation thera- py, previous treatment of taxane-based chemotherapy and localization of metastasis were similar between the groups. Baseline demographic and clinicopathological features are shown in Table 1. Biochemical response Overall, rate of biochemical response was 61.5% in mCRPC patients. It was found to be significantly higher in the enza- lutamide group than in the abiraterone group, with a rate response of 77.1% and 58.1%, respectively (p = 0.016). In binary logistic regression adjusted to clinicopathological features, enzalutamide was associated with a higher proba- Table 1. Baseline demographic and clinicopathological characteristics by drug of mCRPC patients. Demographic and pathological features Total Abiraterone Enzalutamide P (n = 91) (n = 56) (n = 35) Age (years) 74.44 ± 8.26 75.00 ± 7.01 73.54 ± 9.980 0.416 Pretreatment PSA level (ng/ml) 231.51 ± 380.16 215.40 ± 372.82 257.94 ± 401.65 0.717 Previous ADT (months) 74.13 ± 54.87 77.53 ± 61.66 68.82 ± 42.50 0.882 Follow-up (months) 18.34 ± 9.81 17.16 ± 8.71 20.68 ± 11.20 0.276 ISUP 0.612 1 9 (10%) 4 (7.3%) 5 (14.3%) 2 18 (20%) 13 (23.6%) 5 (14.3%) 3 25 (27.8%) 16 (29.1%) 9 (25.7%) ≥ 4 19 (21.1%) 12 (21.8%) 7 (20%) N/A 19 (21.1%) 10 (18.2%) 9 (25.7%) Status 0.934 M1 ab inition 45 (50.6%) 28 (50.9%) 17 (50%) Post local treatment 44 (49.4%) 27 (49.1%) 17 (50%) Metastasis Bone 68 (74.7%) 39 (69.6%) 29 (82.9%) 0.158 Ganglionar 49 (53.8%) 30 (53.6%) 19 (54.3%) 0.947 Visceral 6 (6.2%) 4 (6.5%) 2 (5.7%) 0.788 Post docetaxel 27 (29.7%) 15 (26.8%) 12 (34.3%) 0.446 ADT: androgen deprivation therapy; PSA: prostate-specific antigen; N/A: not admitted. 395Archivio Italiano di Urologia e Andrologia 2021; 93, 4 Novel hormonal agents for metastatic castration-resistant prostate cancer: Comparing outcomes bility of biochemical response (OR: 3.485, p = 0.021). Biochemical response was associated with lower probabili- ty of biochemical progression (OR: 0.248, p = 0.017) and death (OR: 0.302, p = 0.038), adjusted to clinicopatholog- ical features. Subgroup analyses showed no statistically significant dif- ference between biochemical responses in the docetaxel- naïve patients between abiraterone and enzalutamide (56.1% vs 73.9%, p = 0.158), but enzalutamide had a higher response rate than abiraterone in patients previ- ously submitted to docetaxel (83.3% vs 40%, p = 0.019). In the subgroup of patients with metastatic prostate can- cer ab inition, that progressed to mCRPC and were doc- etaxel-naïve, the period of previous classical hormonal therapy was inversely associated with biochemical response (OR: 0.928, p = 0.035). Biochemical progression mCRPC patients submitted to treatment with enzalu- tamide and abiraterone had a biochemical progression- free survival (bPFS) of 19.2 and 30.2 months, respective- ly. The difference failed to achieve statistical significance (p = 0.284). The Kaplan-Meier curves for bPFS are showed in the Figure 1. In patients who achieved a bio- chemical response, the bPFS was similar in both enzalu- tamide group and abiraterone group (24.0 vs 24.3 months, p = 0.651). No covariate factor was identified as predictor of bPFS in multivariate analysis. Figure 1. Biochemical progression based on administered drug. Figure 2. Radiological progression based on administered drug. Archivio Italiano di Urologia e Andrologia 2021; 93, 4 R. Saldanha Jarimba, M. Nobre Eliseu, J. Pedroso Lima, et al. 396 Radiological progression Overall, in the mCRPC group the rPFS in patients sub- mitted to enzalutamide was 41.2 months vs 28.57 months in the abiraterone group, but with no statistical significance (p = 0.363). The Kaplan-Meier curves for rPFS are showed in the Figure 2. Among biochemical responders, patients submitted to abiraterone had a rPFS of 32.2 months and patients treated with enzalutamide had a rPFS of 29.34 months. No statistically significant differences was achieved (p = 0.791). No covariate factor was identified as predictor of rPFS in multivariate analysis. Overall survival All cause time-to-death, in mCRPC patients, was 37.5 months in enzalutamide group and 26 months in abi- raterone group, without achieving a statistically signifi- cant difference (p = 0.277). The Kaplan-Meier curves for overall survival (OS) are showed in the Figure 3. In patients in whom biochemical response was achieved, the abiraterone group had a OS of 31.27 months vs 27.30 months in the enzalutamide group, but without statisti- cally significant difference (p = 0.994). In patients that failed to meet biochemical response crite- ria, OS was 31.15 months and 17.58 months in enzalu- tamide and abiraterone group, respectively. A statistically significant difference was not achieved (31.18 vs 17.58, p = 0.121). No covariate factor was identified as predic- tor of OS in multivariate analysis. AEs associated with treatment with abiraterone or enzalutamide Overall, 14 patients (14.4%) experienced drug-related adverse events (AEs), 10 (16.1%) in abiraterone group and 4 (11.4%) in enzalutamide group. The common AEs that occurred in this series were as follows: fatigue (60%) and diarrhea (20%) in abiraterone group and fatigue (100%) in enzalutamide group. Only 2 AEs ≥ grade 3 were registered, 1 in each group, causing the suspension of the drug. DISCUSSION Novel hormonal agents are now a cornerstone in the treatment of castration-resistant prostate cancer. Both enzalutamide and abiraterone with prednisolone are approved therapies for men with mCRPC. These two drugs have shown clinical efficacy in multicenter phase III RCTs (1-4), yet there is a lack of evidence regarding comparative outcomes of men submitted to treatment with either of the two drugs. Findings from previous ret- rospective studies suggest survival advantages toward enzalutamide compared with abiraterone and pred- nisolone in the treatment of men with mCRPC (5), although both drugs were effective, with PSA rate response over 50%. Our analysis is consistent with prior data for better biochemical response with enzalutamide in men with mCRPC. We found that patients in the enza- lutamide group had a significantly higher biochemical response than the abiraterone group, with a rate response of 51.8% and 77.1%, respectively (p = 0.016). This seems particularly relevant in patients previously submitted to taxane-based chemotherapy. In a multivariate analysis, enzalutamide was associated with a higher probability of rate response compared with abiraterone (OR: 3.485, p = 0.021). Biochemical response was associated with a lower probability of biochemical progression (OR: 0.248, p = 0.017) and death (OR: 0.302, p = 0.038). This data suggests that the higher rate of biochemical response of enzalutamide is associated with better outcomes. Respective to other endpoints (biochemical progression, radiological progression, and overall survival), there was a trend toward advantage of enzalutamide over abiraterone with no statistical significance. Data showed that in patients who achieved biochemical response, the apparent advantage of enzalutamide over abiraterone disappears. Patients who did not achieve a biochemical response had a trend to longer survival when treated to enzalutamide vs abiraterone, albeit not statistically different. As suggested in previous studies (6, 7), this may support an early change of therapeutical strategy when biochemical response is not achieved with abiraterone. Figure 3. Overall survival based on administered drug. 397Archivio Italiano di Urologia e Andrologia 2021; 93, 4 Novel hormonal agents for metastatic castration-resistant prostate cancer: Comparing outcomes Miyake et al., retrospectively reviewed 280 docetaxel- naïve mCRPC patients. A higher PSA response rate for patients treated with enzalutamide when compared with abiraterone (70.7% vs 53.1%) was found, in line with our results. On the other hand, a better bPFS in enzalutamide group was also found, which our study failed to find. In this study, because of the drug choice was at physician discretion, there was a preference of abiraterone over enzalutamide in patients with less favorable clinicopatho- logical features based in the results of COU-AA-302 and PREVAIL trials, respectively (8). Heo et al. performed a retrospective study that evaluated the outcomes of patients diagnosed with mCRPC treated with abiraterone and enzalutamide in post-docetaxel set- ting. 54 patients were evaluated (25 in abiraterone group and 29 in enzalutamide group) and a PSA rate response was seen 36% and 52% for abiraterone and enzalutamide, respectively. In our cohort the PSA rate response was sim- ilar for abiraterone (40%), but enzalutamide had a high- er response rate than reported in this study (83.3%) in this subset of patients (9). Both drugs were well tolerated, with low incidence of drug-related grade ≥ 3 events. Only two patients had their treatment suspended. The type of AEs registered were in line with ones reported in COU-AA-302 and PREVAIL trials. Norris et al. retrospectively studied 198 mCRPC patients submitted to treatment with abiraterone and enzalu- tamide. Significantly higher PSA response rates were observed in the enzalutamide (51%) than abiraterone (36%). In our cohort the overall PSA response rate were higher, 51.8% and 77.1% in abiraterone and enzalu- tamide, respectively. There was no significant difference in OS between the groups with median OS of 15.3 months in abiraterone group versus 22.2 months in the enzalutamide group. The OS survival in our study was also higher for enzalutamide (37.5 months for enzalu- tamide and 27.30 months for abiraterone). These differ- ences can be partially explained by the proportion of patients that were treated in post-docetaxel setting in each study, being the majority of patients in Norris et al. cohort and only 30% in ours. As seen in our cohort, high- er PSA response rates were seen in the pre-docetaxel group compared to the post-docetaxel (10). Garcia et al. performed a retrospective observational study reviewing 48 patients with mCRPC (26 in abi- raterone group and 22 in enzalutamide). Most patients had been submitted to docetaxel. The primary endpoint was biochemical response. Unlike our study, no statisti- cally difference in biochemical response between abi- raterone and enzalutamide was observed (53.85% and 58.85% for abiraterone and enzalutamide groups, respec- tively). A low number of patients treated can impair the statistical power of this study (11). Khalaf et al. retrospectively analyzed 210 patients (106 in abiraterone and 104 in enzalutamide groups), older than 80 years who received novel hormonal agents for first- line treatment of mCRPC. As in our cohort, the biochem- ical response was higher in patients treated with enzalu- tamide than abiraterone (77.9% vs 43.4%) but no OS advantage was observed. In our study the PSA response rates of docetaxel-naïve patients were similar with the ones reported in this study (56.1% and 73.9% for abi- raterone and enzalutamide, respectively) (12). Our study has some strengths: similar groups regarding clinicopathological characteristics and a relatively uni- form distribution between abiraterone and enzalutamide groups (61.5% vs 38.5%). A 1:1 proportion between abi- raterone and enzalutamide was not achieved due to the numerous contraindications to enzalutamide. The approval of abiraterone for treatment of mCRPC was conceded before enzalutamide by national regulatory agency, contributing to the discrepancy in the number of patients in each group. Some limitations of this study must however be noted. As a real-life study, the results can be biased by not random- ized allocation of patients to different treatments. Adverse events were not systematically evaluated due to retro- spective nature of this study, making security perform- ance assessment inaccurate. 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Correspondence Roberto Saldanha Jarimba robertojarimba@chuc.min-saude.pt Serviço de Urologia, Centro Hospitalar e Universitário de Coimbra Rua Professor Mota Pinto 3004-561, Coimbra (Portugal) Miguel Nobre Eliseu, MD João Pedroso Lima, MD Vasco Quaresma, MD Pedro Moreira, MD Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra (Portugal) Pedro Coelho Nunes, MD Edgar Tavares da Silva, MD Arnaldo José Figueiredo, MD Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra & Faculty of Medicine, University of Coimbra, Coimbra (Portugal)