Received: 11 April 2022 | Accepted: 16 August 2022 DOI: 10.1002/nau.25031 CLINICAL ARTICLE Effect of LHRH analogs on lower urinary tract symptoms associated with advanced prostate cancer in real clinical practice: ANALUTS study Juan Morote1 | Antonio Gómez‐Caamaño2 | Raúl Poza de Celis3 | Francisco Gómez‐Veiga4 | Juan P. Ciria5 | Jesús Calleja6 | Javier Extramiana7 | Maria Pérez‐Sampietro8 | Valerie Perrot9 | Javier C. Angulo10 | ANALUTS Study Group 1 Department of Urology, Vall d'Hebrón Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain 2 Department of Radiation Oncology, Hospital Clínico Universitario de Santiago de Compostela, La Coruña, Spain 3 Department of Radiation Oncology, Hospital Txagorritxu HUA, Álava, Spain 4 Department of Urology, Complexo Hospitalario Universitario A Coruña, Spain 5 Department of Radiation Oncology, Hospital Universitario Donostia, San Sebastián, Spain 6 Department of Urology, Hospital Clínico Universitario Valladolid, Valladolid, Spain 7 Department of Urology, Hospital Txagorritxu HUA, Álava, Spain 8 Ipsen Pharma, Barcelona, Spain 9 Ipsen Pharma, Boulogne, France 10 Clinical Department, Hospital Universitario de Getafe, Universidad Europea de Madrid, Madrid, Spain Correspondence Javier C. Angulo, Clinical Department, Abstract Hospital Universitario de Getafe, Aims: To estimate the prevalence of lower urinary tract symptoms (LUTS) in Universidad Europea de Madrid, Madrid, Spain. patients with prostate cancer scheduled to receive LHRH analogs, and to Email: javier.angulo@salud.madrid.org assess the effectiveness of LHRH analogs on LUTS in patients presenting moderate/severe symptoms. Funding information Methods: Prospective, noninterventional, multicenter study conducted at 28 Ipsen Pharma S.A.U. centers in Spain and Portugal. LUTS were evaluated using the International Prostate Symptom Score (IPSS) at baseline, 24 and 48 weeks after initiation of treatment. Subanalyses were performed according to age and concomitant treatment (radiotherapy, alpha‐blockers, and antiandrogens). Results: A total of 354 patients were treated with LHRH analogs for 48 weeks. The percentage of patients with moderate/severe LUTS (IPSS > 7) decreased from 60.2% (n = 213/354) at baseline to 52.8% (n = 187/354) at Week 48. Among patients with moderate/severe LUTS at baseline: 73.7% (n = 157/213) still had moderate/severe See Acknowledgment for the list of contributors. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. © 2022 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC. 1824 | wileyonlinelibrary.com/journal/nau Neurourol Urodyn. 2022;41:1824–1833. MOROTE ET AL. | 1825 LUTS at Week 48; percentage reductions of patients with LUTS at Week 48 were statistically significant (p < 0.05) overall and by age or concomitant treatment, except for alpha‐blockers (84.2% patients receiving them still had moderate/severe LUTS at Week 48). All IPSS items, including quality of life for urinary symptoms, improved throughout the study. The only predictor of response to treatment with LHRH analogs that improved IPSS by 3 points after 48 weeks was baseline testosterone levels. Lower baseline testosterone levels were associated with greater improvement in IPSS after treatment with LHRH analogs (odds ratio 0.998, 95% confidence interval 0.996–1.000, p = 0.0277). Conclusion: LHRH analogs have a positive effect in patients with locally advanced or metastatic prostate cancer presenting moderate/severe LUTS regardless of age or concomitant treatment received (radiotherapy, antiandro- gens, or alpha‐blockers). KEYWORDS androgen deprivation, concomitant, hormonal therapy, quality of life, radiotherapy 1 | INTRODUCTION are known to improve LUTS in these patients.11–13 However, the prevalence of LUTS in patients with Lower urinary tract symptoms (LUTS) is a recent term advanced prostate cancer is not well known and the for what used to be known as prostatism.1 LUTS occur effect of ADT on LUTS merits further investigation. when men experience disturbances to their urinary flow, The intention of this study is to investigate the either in the form of storage symptoms (i.e., nocturia, incidence of LUTS in patients with prostate cancer frequency, and urgency) or voiding symptoms (i.e., appointed to receive treatment with LHRH analogs, hesitancy, intermittency, and weakened stream). Bearing without a history of surgery or radiotherapy. In addition, these definitions in mind, the majority of literature on the effect of LHRH analogs on the improvement of LUTS this subject refers to the LUTS complex generically as symptoms after 48 weeks of treatment is investigated. related to benign prostatic enlargement. However, it may also be present in patients with prostate cancer. In fact, 40% of the patients screened annually for prostate cancer 2 | METHODS showed moderate/severe urinary symptoms, and local prostate cancer treatment obviously affects LUTS.2 2.1 | Study design In comparison with age‐matched controls, external beam radiotherapy (ERBT) may cause incontinence, A prospective noninterventional study has been conducted stress incontinence and urinary pain, thus affecting at 28 centers in Spain and Portugal between July 2015 and quality of life (QoL); however, major long‐term deterio- September 2018 to investigate the prevalence of LUTS in ration is not observed after 4 years of treatment.3 Use of patients with prostate cancer and the effect of LHRH analogs α1‐adrenoreceptor antagonists is often considered in on the improvement of these symptoms over time. patients treated with radiation therapy, either prophylac- The decision to receive LHRH analogs derived from tically or at the earliest sign of LUTS deterioration.4 routine clinical practice and was taken before enrollment in Patients treated with brachytherapy have a much higher the study. Any LHRH analog was considered. Follow‐up incidence of detrusor overactivity, prostatic and urethral visits were also in line with current practice at each hospital. strictures, and prostatic urethral stones, thus worsening End of study visit was 48 ± 4 weeks after baseline visit. LUTS.5,6 Also, α1‐adrenoreceptor antagonists tend to be Patients were screened for the presence of LUTS by the used to improve LUTS in these patients.7,8 completion of the International Prostate Symptom Score Androgen deprivation therapy (ADT) using LHRH (IPSS) that was evaluated at baseline, at 24 weeks, and at 48 analogs is a first‐line treatment of symptomatic meta- weeks after the start of the treatment with LHRH analogs. static prostate cancer.9,10 Also, different agents including All other procedures performed were in accordance with LHRH agonists, LHRH antagonists, and antiandrogens routine clinical practice. According to the standards of 1826 | MOROTE ET AL. radiotherapy available in participant institutions, differences at week 48, and the determination of predictive factors in radiotherapy protocols that could have impacted the of response to LHRH analogs, considering as a course of LUTS over time are not to be expected. response variable a reduction of total IPSS of at least The study was approved by the ethics committees of 3 points.14 participating centers. Demographics and baseline characteristics were recorded for the study population: age, tumor stage (TNM classification), time since first prostate cancer 2.2 | Participants diagnosis, Gleason score, prior and concomitant treat- ments, PSA and testosterone levels, uroflowmetry, and Inclusion criteria to participate in the study were adult prostate volume. patients who had been diagnosed with prostate cancer and The IPSS consists of seven questions: four questions were scheduled to receive an LHRH analog therapy; that deal with voiding symptoms (incomplete emptying, completion of IPSS questionnaire no more than 6 months intermittency, weak stream, and straining to void) and before the initial visit and before starting LHRH analogs; three questions about storage symptoms (frequency, and patients mentally fit for completing self‐administered urgency, and nocturia). Each question is scored from 0 IPSS and written informed consent. to 5 points. The total IPSS is calculated as the sum of the Exclusion criteria included any prostate surgery or seven symptom question scores and ranges between 0 pelvic radiotherapy performed before the study initiation; and 35. Four categories of total IPSS were defined: none testosterone <50 ng/dL at first IPSS questionnaire; or no symptoms (total score 0); mild symptoms (total participation in any other clinical study within the last score 1–7); moderate symptoms (total score 8–19); and 2 months before study entry; and a life expectancy of less severe symptoms (total score 20–35).14 The eighth than 12 months. As this was a non‐interventional study, question of the IPSS questionnaire is relative to QoL no specific withdrawal criteria were specified. due to urinary symptoms (“If you were to spend the rest To avoid bias in recruitment, investigators were not of your life with your urinary condition the way it is now, allowed to choose the patients but were asked to include all how would you feel about that?”). This question is valued consecutive patients to achieve the recruitment target for the from 0 to 6. center during a period. However, if consecutive inclusions No safety data were recorded in the clinical database were not feasible, investigators have authorized to space the and no statistical analyses of safety were planned in this inclusions until achievement of the recruitment target. study. Investigators were asked to report serious adverse Three populations were defined. The enrolled population events (regardless of causal relationship) and adverse was composed of all patients who signed informed consent drug reactions as in real‐world clinical practice. form. The study population was patients with given informed consent and with total IPSS baseline data (V1) and without prior surgery or radiotherapy. Total IPSS 2.4 | Statistical analysis baseline was defined as IPSS assessment prior, to the same date as or a maximum of 1 day after the first LHRH analog Primary objectives were to estimate the prevalence of injection. The effectiveness population (EP) were patients LUTS in patients with prostate cancer scheduled to from the study population that received LHRH analogs for receive LHRH analogs as part of prostate cancer 48 weeks and with total IPSS data at 24 weeks (V2) or 48 management, and to assess the effectiveness of LHRH weeks (V3). analogs on urinary symptoms in patients with prostate cancer presenting moderate/severe LUTS (IPSS > 7). Secondary objectives were to assess the QoL due to 2.3 | Endpoint variables urinary symptoms and to investigate the predictive factors of response to LHRH analogs. The primary effectiveness endpoints included assessment It was intended to enroll and collect data from 458 of the number and percentage of patients with prostate patients with prostate cancer requiring treatment with cancer and LUTS at baseline (V1), and the percentage of LHRH analogs. As this was an exploratory noninterven- patients suffering from prostate cancer with moderate/ tional observational study, the sample size was mainly severe LUTS (IPSS > 7) at baseline (V1) and at 24 weeks based on feasibility. However, with this sample size, a (V2) and 48 weeks (V3). two‐sided 95% confidence interval (CI) for a single Secondary endpoints included the assessment of proportion using the exact method (Clopper–Pearson) the changes in the IPSS categories for each visit, the would extend 4.72% from the observed proportion for an assessment of IPSS QoL due to urinary symptoms item expected prevalence of 50%. MOROTE ET AL. | 1827 The prevalence of LUTS analysis was based on the 60.2% (n = 213/354). According to age (>75 or ≤75 study population. The number and percentage of patients years) or concomitant treatment, the proportion of having moderate/severe LUTS at baseline were presented patients with moderate/severe LUTS at baseline was using descriptive statistics including 95% CI for the similar (Table 2). percentage. The proportion of patients with moderate/severe The primary effectiveness analysis was performed on LUTS in the overall EP decreased from 60.2% (n = 213/ the EP, firstly on overall patients and secondly on 354) at baseline to 52.8% (n = 187/354) after 48 weeks of patients presenting moderate/severe LUTS at baseline. treatment with LHRH analogs (Figure 2A). This A subgroup analysis was performed according to age and reduction was not statistically significant. In the concomitant treatment received. The number and different subgroups, the reduction was statistically percentage of patients with moderate/severe LUTS at significant only in patients of the overall EP without week 48 were presented using descriptive statistics. To concomitant radiotherapy (63.5%–51.9%, p = 0.0095), compare the proportion of patients with LUTS at Week without concomitant oral anti‐androgens (63.1%–51.7%, 48 versus the proportion of patients with moderate/ p = 0.0095), and without alpha‐blockers (57.6%–48.9%, severe LUTS at baseline, paired McNemar exact test p = 0.0103) (Table 2). was used. Considering only patients with moderate/severe Secondary effectiveness analyses were performed on LUTS at baseline, after 48 weeks of treatment with the EP and patients presenting moderate/severe LUTS at LHRH analogs 73.7% (n = 157/213) still had moderate/ baseline. For each potential predictive factor, a null severe LUTS (Figure 2A). In this group of patients, the hypothesis that the regression coefficient for the factor is reduction was statistically significant (p < 0.05) whatever zero was tested using a logistic regression model. A the age group or concomitant treatment received but threshold entry of 0.2 was considered for the stepwise with a lower decrease in patients receiving alpha‐ multiple regression model. For quantitative factors, the blockers (84.2% patients receiving them still had moder- odds ratio is presented for a one‐unit increase. ate/severe LUTS) (Table 2). All statistical tests were exploratory and two‐sided at the 5% level of significance. The 95% CI of the proportions was calculated. Approximate binomial CI 3.3 | Changes in IPSS and quality of life was produced using the Agresti‐Coull method. Statistical due to urinary symptoms evaluation was performed using the Statistical Analysis System (SAS)® (version 9.4). All IPSS items, including QoL due to urinary symptoms, improved throughout the study. In the overall EP, the mean total IPSS decreased from 11.03 ± 7.85 at baseline 3 | RESUL TS to 8.99 ± 6.60 at Week 48 (p < 0.0001). 3.1 | Baseline patient characteristics A total of 488 patients were screened in 25 sites in Spain and 3 sites in Portugal. Of them, 19 (3.9%) were not enrolled as they did not meet entry criteria. Of the 469 enrolled patients, 18 were excluded because protocol violation or other reasons. Thus, the study population was comprised of 451 patients (96.2% of enrolled patients) and an overall EP of 354 patients (75.5%) (Figure 1). Table 1 shows baseline patient characteristics for the study population. 3.2 | Prevalence of LUTS and effectiveness of LHRH analogs The proportion of patients with moderate/severe F I G U R E 1 Patient disposition in the study. IPSS, International LUTS (IPSS > 7) at baseline in the study population Prostate Symptom Score; LHRH, luteinizing hormone‐releasing was 61% (n = 275/451), and in the overall EP was hormone; LUTS, lower urinary tract symptoms 1828 | MOROTE ET AL. T A B L E 1 Baseline patient Variable N % characteristics in the study Age, mean ± SD (years) 74.4 ± 7.1 population (n = 451) TNM (n = 451) T < 3, N0/NX, M0/MX 22 4.9 T ≥ 3, N0/NX, M0/MX 332 73.6 Any T, N1, M0/MX 32 7.1 Any T, any N, M1 65 14.4 Time since diagnosis, median (min; max) (months) 1.8 (0.0; 106.0) Gleason score, median (min; max) 7.0 (4.0; 10.0) Gleason score (n = 451) ≤6 66 15.1 3+4 99 22.6 4+3 84 19.2 8 87 19.9 9–10 102 23.3 No data 13 Previous treatments (n = 451) Oral antiandrogens 163 36.1 Alpha‐blockers 44 9.8 5‐α‐reductase inhibitor 21 4.7 Concomitant treatments (n = 451) Oral antiandrogens 200 44.3 Radiotherapy 195 43.2 Alpha‐blockers 73 16.2 Anticholinergics 8 1.8 Beta‐3 agonist 5 1.1 PSA, mean ± SD (ng/ml) (n = 439)* 36.3 ± 82.6 Testosterone, mean ± SD (ng/ml) (n = 217)* 414.6 ± 221.7 Maximum flow, mean ± SD (ml/s) (n = 101)* 12.6 ± 7.3 Post‐void residual volume, mean ± SD (ml) (n = 67)* 31.6 ± 40.1 Bladder volume, mean ± SD (ml) (n = 89)* 183.6 ± 101.7 Prostate volume, mean ± SD (ml) (n = 53)* 43.0 ± 18.9 Total IPSS, mean ± SD Overall effectiveness population (n = 354) 11.03 ± 7.85 Effectiveness population with moderate/severe LUTS at 15.77 ± 6.53 baseline (n = 213) Abbreviations: IPSS, International Prostate Symptom Score; PSA, prostate‐specific antigen; SD, standard deviation. *Number of patients with available data for the parameter. MOROTE ET AL. | 1829 TABLE 2 Patients with lower urinary tract symptoms (LUTS) at baseline (V1) and week 48 (V3) visits Effectiveness population with moderate/ Overall effectiveness population (n = 354) severe LUTS at baseline (n = 213) Baseline Week 48 Baseline Week 48 Subgroups (V1) (%) (V3) (%) p Value (V1) (%) (V3) (%) p Value All patients 60.2 52.8 0.0487 100 73.7 <0.0001 >75 years 65.3 57.7 0.0961 100 77.0 <0.0001 ≤75 years 55.4 47.0 0.1325 100 69.2 <0.0001 With radiotherapy 56.6 52.4 0.5327 100 74.7 <0.0001 Without radiotherapy 63.5 51.9 0.0095 100 72.0 <0.0001 With oral anti‐androgens 56.9 52.6 0.5327 100 72.9 <0.0001 Without oral 63.1 51.7 0.0095 100 73.6 <0.0001 anti‐androgens With alpha‐blockers 71.9 67.9 1.0000 100 84.2 0.0313 Without alpha‐blockers 57.6 48.9 0.0103 100 70.6 <0.0001 p Value: Paired McNemar exact test. In the EP with moderate/severe LUTS at baseline, volume change and IPSS change from baseline in these mean total IPSS decreased from 15.77 ± 6.53 at baseline patients (Person coefficient 0.28; p = 0.5). to 11.75 ± 6.39 at Week 48 (p < 0.0001). The reduction was statistically significant whatever the age group or concomitant treatment received. Both voiding 3.4 | Predictive factors of response to (8.47 ± 4.61 to 5.73 ± 4.03) and storage (7.30 ± 3.21 to LHRH analogs 6.04 ± 3.20) items decreased from baseline to Week 48. A reduction in IPSS score of ≥ 3 in this population was Because only one factor fulfilled the criteria for inclusion observed in 55.5% of the cases, and the proportion of into the stepwise procedure, no stepwise multiple logistic patients with improvement in total IPSS score ≥ 25% regression modeling could be applied. The only predictor baseline was 50.8%. of response to treatment with LHRH analogs that After 48 weeks of treatment with LHRH analogs, QoL improved IPSS by 3 points after 48 weeks was baseline due to urinary symptoms improved in both overall EP testosterone levels. The level of testosterone at the start of and patients with moderate/severe LUTS at baseline. treatment has an inverse relationship with the improve- Most patients are between categories 1–4 (delighted, ment in IPSS of more than 3 points that occurs at the end pleased, mostly satisfied, and equally satisfied/dissatis- of treatment (Table 3). Age, PSA levels at baseline, fied with urinary symptoms) (Figure 2B). Gleason score at baseline, time since diagnosis, or According to IPSS categories, the percentage of concomitant treatment were not considered predictors patients with mild IPSS (score 1–7) increased slightly of treatment response. in the overall EP from baseline to Week 48 (37.6%–44.1%) and increased significantly in the population of patients with moderate/severe LUTS at 4 | DISCUSSION baseline (0%–25.8%). Patients with moderate IPSS (score 8–19) did not change in the overall EP This non‐interventional study was designed to character- (44.6%–43.2%) and decreased in the group of patients ize and investigate the frequency of LUTS in patients with moderate/severe LUTS at baseline (74.2%–58.7%). scheduled to receive LHRH analogs as part of prostate Only patients with severe IPSS (score 20–35) decreased cancer management, and also to measure the overall in both groups (15.5%–9.6% and 25.8%–15.0%, respec- effect of LHRH analogs in prostate cancer patients tively) (Figure 2C,D). presenting moderate/severe LUTS (IPSS > 7). Changes in prostate size were available in a small The prevalence of LUTS in the overall population cohort in the EP (n = 52). Median (Q1–Q3) prostate ranges from 4.8% for severe symptoms to 18.5% for volume changed from 42 (26–56) baseline to 28 moderate symptoms and increases with age.15 In a (22–41) ml. There was no correlation between prostate previous report in Belgian patients with prostate cancer, 1830 | MOROTE ET AL. F I G U R E 2 Changes in IPSS and QoL during the study: (A) Evolution of patients with moderate/severe LUTS (IPSS > 7) after 48 weeks of treatment with LHRH analogs in the overall effectiveness population (n = 354) and in the population of patients with moderate/severe LUTS at baseline (n = 213); (B) Distribution of IPSS QoL categories after 48 weeks of treatment with LHRH analogs in the overall effectiveness population (n = 354) and in the population with moderate/severe LUTS at baseline (n = 213). (C) Proportion of patients with mild, moderate, and severe LUTS during the study in overall effectiveness population (n = 354); (D) Proportion of patients with mild, moderate and severe LUTS during the study in the effectiveness population with moderate to severe LUTS at baseline (n = 213). IPSS, International Prostate Symptom Score; LHRH, luteinizing hormone‐releasing hormone; LUTS, lower urinary tract symptoms; QoL, quality of life. *IPSS assessment at 48 weeks is at last available visit. For the vast majority of the patient (324/354) it is at 48 weeks but for the 30 remaining patients, it is at 24 weeks. 61.5% had moderate/severe LUTS,16 and in an observa- triptorelin in reducing moderate or severe LUTS in tional grouped analysis of several countries, the preva- patients with prostate cancer. Following the administra- lence of moderate/severe LUTS was 52.1%.17 These tion of the drug, the proportion of patients with results are similar to those in our study, with a moderate/severe LUTS at baseline was reduced to prevalence of moderate/severe LUTS at baseline in the 75.9% at Week 24 and to 67.2% at Week 48.19 In other EP population of 60.2%. However, another study reported study, 31.3% of patients showed a clinically meaningful a prevalence of moderate/severe LUTS in Chinese improvement in LUTS after 24 weeks of treatment with patients of 93.2%.18 These data highlight the differences goserelin plus bicalutamide. Total IPSS showed a in severity of LUTS between European and Chinese significant decrease from baseline at Weeks 12 and 24. populations. While IPSS voiding score also decreased significantly Several trials have assessed the impact of ADT on from baseline to Weeks 12 and 24, IPSS storage score did LUTS in patients with prostate cancer. A grouped not change significantly.20 Although the effect of LHRH analysis of several non‐interventional studies initiated analogs observed in our study was somewhat smaller in clinical practice assessed the effectiveness of (80.5% and 73.7% of patients with moderate/severe LUTS MOROTE ET AL. | 1831 T A B L E 3 Logistic regression analysis Univariate analysis* of the predictive factors of response to LHRH analogs in the effectiveness Factor Odds ratio (95% CI) p Value population with moderate/severe lower Age 0.996 (0.959–1.034) 0.8262 urinary tract symptoms at baseline PSA at baseline (ng/ml) 1.000 (0.997–1.004) 0.9014 Gleason score at baseline 1.010 (0.777–1.313) 0.9409 Time since diagnosis (months) 0.994 (0.964–1.021) 0.6385 Concomitant radiotherapy versus no 0.742 (0.418–1.315) 0.3071 Concomitant alpha‐blockers versus no 0.759 (0.371–1.551) 0.4471 Concomitant anti‐androgens versus no 1.074 (0.604–1.911) 0.8085 Testosterone at baseline (ng/dL) 0.998 (0.996–1.000) 0.0277 Note: Response is defined as improvement in total IPSS ≥ 3. Abbreviations: CI, confidence interval; IPSS, International Prostate Symptom Score; LHRH, luteinizing hormone‐releasing hormone; PSA, prostate‐specific antigen. *97 observations were eliminated due to the absence of values. at baseline still have these symptoms at 24 and 48 weeks, that study had previously received hormonal therapy respectively), both IPSS voiding and storage scores and radiotherapy. decreased significantly. We could not demonstrate a Another study described that only IPSS value was symptomatic improvement caused by the decrease in independently associated with a meaningful IPSS prostate volume. response.20 In our study, the only predictor of response The reduction of LUTS observed in the overall EP was to treatment with LHRH analogs that improved IPSS by only significant in patients without concomitant treat- 3 points after 48 weeks was baseline testosterone levels. ment. This could be explained, at least in part, because Lower baseline testosterone levels were associated with the percentage of patients with LUTS at baseline was greater improvement in IPSS after treatment with LHRH lower when they received concomitant treatment. The analogs. We cannot explain how testosterone level before only exception was among those receiving alpha‐ LHRH analogs administration predicts IPSS response in blockers. The percentage of patients with LUTS at these patients. However, there is some related experi- baseline who received concomitant alpha‐blockers was ence. A study performed on 50 Korean males revealed higher than those who did not. Despite the fact that with serum testosterone levels negatively correlate with IPSS the use of alpha‐blockers there was a lower reduction of and transitional prostate volume.22 Another prospective moderate/severe LUTS, according to the regression study performed in Taiwan with 1752 middle‐age men analysis, none of the concomitant treatments was a enrolled revealed high testosterone level is significantly predictor of response to LHRH analogs (improvement of associated with the presence of moderate/severe LUTS.23 at least 3 points of the IPSS score). The worse outcome On the other hand, both human clinical trials and animal observed in patients who received concomitant alpha‐ studies have shown that testosterone replacement blockers is possibly due to the fact that they had worse therapy can improve LUTS, possibly by increasing baseline characteristics. In any case, all patients experi- bladder capacity and compliance and decreasing detrusor enced an improvement in LUTS as they all received pressure at maximum flow rate (Qmax).24,25 However, LHRH analogs, regardless of age and concomitant future studies are needed to better understand the treatment. relationship between testosterone level and male LUTS. Our study also described an improvement in QoL The main limitation of this study lies in the nature of due to urinary symptoms. Percentage of patients rating its non‐interventional observational design, so that no QoL as “mostly satisfied,” “pleased,” and “delighted” conclusions could be drawn according to the particular was 55.4% in the population with moderate/severe LHRH analog chosen. Also, it is not possible to draw LUTS at 48 weeks. In another study that assessed the appropriate conclusions according to the subgroups, effect of triptorelin, this percentage was of 53.9% at since the number of patients in some of them is very Week 24 and 77.3% at Week 48.21 However, the sample small. Besides, discrimination between the positive size of this study at Week 48 was smaller (n = 22) than influence of alpha‐adrenergic blockers vs LHRH analogs in our study (n = 213). In addition, some patients in on LUTS is another limitation. It should also be taken 1832 | MOROTE ET AL. into account that the same patient could have received Ciudad Real, Ciudad Real); Luis Campos (Hospital de more than one concomitant treatment. São José, Lisboa); Roberto Castañeda (Hospital Althaia, Manresa); Lluís Cecchini (Hospital del Mar, Barcelona); Venancio Chantada (Hospital Universitario de A 5 | CONCLUSION Coruña, A Coruña); Arnaldo Figuereido (Hospitais da Universidade de Coimbra, Coimbra); Asier Leiba The prevalence of moderate/severe LUTS in patients (Hospital Universitario Infanta Sofía, San Sebastián de with prostate cancer in the Iberian Peninsula is similar to los Reyes), Francisco Javier Madrid (Hospital Universi- that described in other studies. LHRH analogs have a tario del Sureste, Arganda del Rey); José Carlos positive effect in patients with locally advanced or Martínez (Hospital Universitario Nuestra Señora de metastatic prostate cancer presenting moderate/severe Candelaria, Santa Cruz de Tenerife); Jesús Muñoz LUTS regardless of age or concomitant treatment (Hospital Parc Taulí, Sabadell); Rui Prisco (Hospital received. In addition, the QoL due to urinary symptoms Pedro Hispano, Senhora da Hora); Carlos Olivier improved in these patients, suggesting a symptomatic (Hospital Universitario de La Princesa, Madrid); Miguel relief upon treatment with LHRH analogs. Lower Ángel Rado (Hospital Universitario de León, León); José baseline testosterone levels were associated with greater Manuel Ruiz (Hospital de L'Esperit Sant, Santa Coloma improvement in IPSS after treatment with LHRH de Gramenet); Josep Segarra (Hospital Joan XXIII, analogs. Tarragona); José Suarez (Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat); José Ángel Taber- AUTHOR CONTRIBUTIONS nero (Hospital Universitario La Paz, Madrid); María Juan Morote: Data analysis and interpretation, critical Luisa Vázquez (Hospital do Meixoeiro, Vigo). The revision of the article and final approval of the version to authors wish to thank Content Ed Net (Madrid) and be published. Antonio Gómez‐Caamaño: Data analysis Fernando Sánchez Barbero PhD for their support on the and interpretation, critical revision of the article and final preparation of this manuscript, which was sponsored by approval of the version to be published. Javier C. Ipsen Pharma S.A.U. (Spain) in accordance with Good Angulo: Conception and design of the study, data Publication Practice guidelines. The study was funded collection, data analysis and interpretation, critical by Ipsen Pharma S.A.U. revision of the article and final approval of the version to be published. Raúl Poza de Celis: Data collection, C O NF L I C T O F I N T E R E S T S critical revision of the article and final approval of the Juan Morote, Antonio Gómez‐Caamaño, Raúl Poza de version to be published. Francisco Gómez‐Veiga: Data Celis, Francisco Gómez‐Veiga, Juan Pablo Ciria, Jesús collection, critical revision of the article and final Calleja, Javier Extramiana and Javier C. Angulo have no approval of the version to be published. Juan Pablo disclosure. Maria Pérez‐Sampietro and Valerie Perrot are Ciria: Data collection, critical revision of the article and employees of Ipsen Pharma. final approval of the version to be published. Jesús Calleja: Data collection, critical revision of the article DATA AVAILABILITY STATEMENT and final approval of the version to be published. Javier Where patient data can be anonymized, Ipsen will Extramiana: Data collection, critical revision of the share all individual participant data that underlie the article and final approval of the version to be published. results reported in this article with qualified research- Maria Pérez‐Sampietro: Conception and design of the ers who provide a valid research question. Study study, data analysis and interpretation, critical revision of documents, such as the study protocol and clinical the article, and final approval of the version to be study report, are not always available. Proposals published. Valerie Perrot: Conception and design of the should be submitted to DataSharing@Ipsen.com and study, data analysis and interpretation, critical revision of will be assessed by a scientific review board. Data are the article, and final approval of the version to be available beginning 6 months and ending 5 years published. after publication; after this time, only raw data may be available. ACKNOWLEDGMENTS In addition, authors would like to thank the following ETHICS STATEMENT researchers and participating sites: Juan José Areal This study has been approved by the Clinical Research (Hospital Germans Trias i Pujol, Badalona); Victor Ethics Committee of all participating centers. The Ethics Barrondo (Hospital Universitario de Basurto, Bilbao); Committee of reference was that of Vall d'Hebron Luis Calahorra (Hospital General Universitario de Hospital (Barcelona, Spain). MOROTE ET AL. | 1833 PATIENT CONSENT STATEMENT 14. Bosch JL, Hop WC, Kirkels WJ, Schroder FH. 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