A Phase 2 Randomized Open-label Study of Oral Darolutamide Monotherapy Versus Androgen Deprivation Therapy in Men with Hormone-sensitive Prostate Cancer (EORTC-GUCG 1532).

BACKGROUND AND OBJECTIVE: Darolutamide is an androgen receptor inhibitor that increases overall survival in combination with androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive and nonmetastatic castration-resistant prostate cancer (PCa). This phase 2 study assessed the efficacy and safety of darolutamide as monotherapy without ADT in patients with eugonadal testosterone levels. METHODS: This was a 24-wk, open-label, randomized study of patients with hormone-sensitive, histologically confirmed PCa requiring gonadotropin-releasing hormone (GnRH); an Eastern Cooperative Oncology Group performance status score of 0/1; and life expectancy >1 yr. All patients received darolutamide 600 mg bid or a commercially available GnRH analog. The primary endpoint is a prostate-specific antigen (PSA) response, defined as a ≥80% decline at week 24 relative to baseline in the darolutamide study arm. The GnRH arm is used as an internal control. The secondary endpoints included changes in T levels, safety/tolerability, and quality of life. KEY FINDINGS AND LIMITATIONS: Among 61 men enrolled, the median (range) age was 72 yr (53-86 yr); 42.6% of them had metastases. In the darolutamide arm, the evaluable population with available PSA values at baseline and week 24 consisted of 23 patients. Twenty-three (100%) evaluable darolutamide patients achieved a PSA decline of >80% at week 24 (primary endpoint), with a median (range) decrease of -99.1% (-91.9%, -100%). Serum T levels increased by a median (range) of 44.3 (5.7-144.0) at week 24, compared with baseline. In the darolutamide arm, 48.4% of men reported drug-related adverse events (AEs; mostly grade 1 or 2). The most frequent treatment-emergent AEs included gynecomastia (35.5%), fatigue (12.9%), hot flush (12.9%), and hypertension (12.9%). Health-related quality of life measures are descriptive, and GnRH arm results will be presented as an internal reference. CONCLUSIONS AND CLINICAL IMPLICATIONS: Darolutamide monotherapy was associated with a significant PSA response in nearly all men with hormone-naïve PCa. Testosterone-level changes and most common AEs (gynecomastia, fatigue, hypertension, and hot flush) were consistent with potent androgen receptor inhibition. PATIENT SUMMARY: In this study, we report the first use of darolutamide, a novel antiandrogen, as monotherapy without androgen deprivation therapy (ADT). The study shows that darolutamide induce a profound suppression of prostate-specific antigen in all patients, with a safety profile different from that of ADT.

Clinical Outcomes of Enzalutamide in Metastatic Hormone-sensitive Prostate Cancer in Patients Aged <75 and ≥75 Years: ARCHES Post Hoc Analysis.

BACKGROUND: In ARCHES, treatment intensification of androgen deprivation therapy (ADT) with enzalutamide versus placebo improved clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC). Understanding the benefits and tolerability of enzalutamide for men aged ≥75 yr may inform disease management. OBJECTIVE: To determine whether age is associated with clinical outcomes in mHSPC. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of the multinational, double-blind, randomized, placebo-controlled, phase 3 ARCHES trial in 1150 men with mHSPC (median follow-up [mo]: <75 yr, 44.6; ≥75 yr, 44.3) was performed. INTERVENTION: Randomization 1:1 to enzalutamide (160 mg/d) plus ADT or placebo plus ADT; stratification by disease volume and prior docetaxel use. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS), radiographic progression-free survival (rPFS), safety, and other secondary endpoints were compared between age groups (<75 and ≥75 yr) and treatment arms (Cox proportional hazard models). RESULTS AND LIMITATIONS: Men aged <75 versus ≥75 yr had longer OS (enzalutamide plus ADT: hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.47-0.91; p = 0.02; placebo plus ADT: HR 0.81; 95% CI 0.60-1.09; p = 0.13) and rPFS (enzalutamide plus ADT: HR 0.78; 95% CI 0.58-1.04; p = 0.12; placebo plus ADT: HR 0.98; 95% CI 0.74-1.30; p = 0.007). Enzalutamide improved OS (<75 yr: HR 0.61; 95% CI 0.47-0.79; ≥75 yr: HR 0.76; 95% CI 0.54-1.09) and secondary efficacy endpoints without evidence of statistical heterogeneity, and was generally well tolerated in both age groups, with minimal quality-of-life impact. Older versus younger patients experienced more frequent dose interruptions (20.2% vs 10.9%) and treatment-emergent adverse events (95.2% vs 89.1%). Post hoc examination and small sample size preclude definitive conclusions. CONCLUSIONS: Enzalutamide plus ADT improved efficacy outcomes and was generally well tolerated despite shorter treatment exposure in older patients, indicating enzalutamide's utility in patients with mHSPC aged <75 and ≥75 yr. PATIENT SUMMARY: Enzalutamide is a drug approved to treat men with prostate cancer. In this report, we compared patients aged <75 and ≥75 yr treated with enzalutamide plus androgen deprivation therapy to determine whether age affected how long they lived without the cancer spreading to other parts of their body. We found that, although younger patients had more favorable survival outcomes, enzalutamide was associated with longer survival and reduced disease spread in both age groups.

The Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Oligometastatic Hormone-sensitive Prostate Cancer: A Post Hoc Analysis of ARCHES.

BACKGROUND: Few phase 3 studies have evaluated optimal systemic treatment strategies for patients with oligometastatic hormone-sensitive prostate cancer (HSPC), who may be at risk of undertreatment. OBJECTIVE: To evaluate outcomes for patients with oligometastatic and polymetastatic HSPC treated with enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of data for 927 patients with nonvisceral metastatic HSPC in the ARCHES trial (NCT02677896). INTERVENTION: Patients were randomized 1:1 to enzalutamide (160 mg/d orally) plus ADT or placebo plus ADT with HSPC categorized as oligometastatic (1-5 metastases) or polymetastatic (≥6 metastases). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The treatment effect on radiographic progression-free survival (rPFS), overall survival (OS), and secondary efficacy endpoints was evaluated in terms of the number of metastases. Safety was assessed. Cox proportional hazards models were used to generate hazard ratios (HRs). The Brookmeyer and Crowley method was used to generate 95% confidence intervals (CIs) for Kaplan-Meier median values. RESULTS AND LIMITATIONS: Enzalutamide plus ADT improved rPFS (HR 0.27, 95% CI 0.16-0.46; p < 0.001), OS (HR 0.59, 95% CI 0.40-0.87; p < 0.005), and secondary endpoints in patients with oligometastatic or polymetastatic disease (rPFS: HR 0.33, 95% CI 0.23-0.46; p < 0.001; OS: HR 0.55, 95% CI 0.41-0.74; p < 0.001). Safety profiles were generally similar across subgroups. Limitations include the small numbers of patients with fewer than three metastases. CONCLUSIONS: This post hoc analysis demonstrated the utility of enzalutamide, irrespective of metastatic burden or type of oligometastatic disease, and suggests that earlier treatment intensification with systemic potent androgen receptor inhibition is advantageous. PATIENT SUMMARY: This study considered two treatment options for metastatic hormone-sensitive prostate cancer in patients with one to five metastases or six or more metastases. Treatment with enzalutamide plus ADT improved survival and other outcomes over ADT alone, whether patients had few or many metastases.

Hyperthermic Mitomycin C in Intermediate-risk Non-muscle-invasive Bladder Cancer: Results of the HIVEC-1 Trial.

BACKGROUND: Optimising therapeutic strategies of intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) is needed. OBJECTIVE: To compare recurrence-free survival (RFS) with adjuvant intravesical mitomycin C (MMC) at normothermia or hyperthermia using the COMBAT bladder recirculation system at 43 °C for 30 and 60 min. DESIGN, SETTING, AND PARTICIPANTS: A prospective open-label, phase 3 randomised controlled trial (HIVEC-1) accrued across 13 centres between 2014 and 2020 in Spain. After complete transurethral resection of the bladder and immediate postoperative MMC instillation, patients with IR-NMIBC were randomised (1:1:1) to four weekly followed by three monthly 40-mg MMC instillations at normothermia (control; n = 106), 43 °C for 30 min (n = 107), or 43 °C for 60 min (n = 106) were investigated. Therapeutic compliance was defined as four or more instillations. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was RFS at 24 mo in the intention-to-treat (ITT) and per-protocol (PP) populations. The secondary outcomes included progression-free survival at 24 mo, safety outcome measures, and changes in health-related quality of life. Log-rank, Fisher, χ2, and analysis of variance tests were used. RESULTS AND LIMITATIONS: The ITT 24-mo RFS was 77% for control, 82% for 43 °C-30 min, and 80% for 43 °C-60 min (p = 0.6). The PP 24-mo RFS was 77% for control, 83% for 43 °C-30 min, and 80% for 43 °C-60 min (p = 0.59). Six patients progressed to muscle-invasive disease in the ITT population (four in the control, 43 °C-30 min, and 43 °C-60 min groups each) and four in the PP population (all controls). Serious adverse events occurred in 26 patients (8.1%), and we were unable to demonstrate a difference between groups (p = 0.5). Adverse events, mainly dysuria and spasms, occurred in 124 patients (33% in control, 35% in 43 °C-30 min, and 48% in 43 °C-60 min; p = 0.05). The total International Prostate Symptom Score worsened by 1.2 ±â€¯7.3 points, similarly across groups (p = 0.29). The Functional Assessment of Cancer Therapy-Bladder domains and indexes showed no significant change. CONCLUSIONS: Four-month adjuvant hyperthermic MMC using the COMBAT system for 30 and 60 min in IR-NMIBC is well tolerated, but we did not find it to be superior to normothermic MMC at 24 mo. PATIENT SUMMARY: We were unable to demonstrate the effectiveness of hyperthermia using the COMBAT system in intermediate-risk non-muscle-invasive bladder cancer. Further evaluation of long-term recurrence and progression, and maintenance regimens appears mandatory.

Effect of LHRH analogs on lower urinary tract symptoms associated with advanced prostate cancer in real clinical practice: ANALUTS study.

AIMS: To estimate the prevalence of lower urinary tract symptoms (LUTS) in patients with prostate cancer scheduled to receive LHRH analogs, and to assess the effectiveness of LHRH analogs on LUTS in patients presenting moderate/severe symptoms. METHODS: Prospective, noninterventional, multicenter study conducted at 28 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 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, antiandrogens, or alpha-blockers).

The impact of enzalutamide on quality of life in men with metastatic hormone-sensitive prostate cancer based on prior therapy, risk, and symptom subgroups.

BACKGROUND: Enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival versus ADT alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in ARCHES (NCT02677896). While health-related quality of life (HRQoL) was generally maintained in the intent-to-treat population, we further analyzed patient-reported outcomes (PROs) in defined subgroups. METHODS: ARCHES was a randomized, double-blind, placebo-controlled, phase 3 study. Patients with mHSPC received enzalutamide (160 mg/day) plus ADT (n = 574) or placebo plus ADT (n = 576). Questionnaires, including the Functional Assessment of Cancer Therapy-Prostate, Brief Pain Inventory-Short Form, and EuroQol 5-Dimension, 5-Level (EQ-5D-5L), were completed at baseline, Week 13, and every 12 weeks until disease progression. PRO endpoints were time to first confirmed clinically meaningful deterioration (TTFCD) in HRQoL or pain. Subgroups included prognostic risk, pain/HRQoL, prior docetaxel, and local therapy (radical prostatectomy [RP] and/or radiotherapy [RT]). RESULTS: There were several between-treatment differences in TTFCD for pain and functioning/HRQoL PROs. Enzalutamide plus ADT delayed TTFCD for worst pain in the prior RT group (not reached vs. 14.06 months; hazard ratio [HR]: 0.56 [95% confidence interval: 0.34-0.94]) and pain interference in low-baseline-HRQoL group (19.32 vs. 11.20 months; HR: 0.64 [0.44-0.94]) versus placebo plus ADT. In prior/no prior RP, prior RT, prior local therapy, no prior docetaxel, mild baseline pain, and low-risk subgroups, TTFCD was delayed for the EQ-5D-5L visual analog scale. CONCLUSION: Enzalutamide plus ADT provides clinical benefits in defined patient subgroups versus ADT alone, while maintaining lack of pain and high HRQoL, with delayed deterioration in several HRQoL measures.

Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In primary analysis, enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC); however, overall survival data were immature. In the phase III, double-blind, global ARCHES trial (ClinicalTrials.gov identifier: NCT02677896), 1,150 patients with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg once daily) plus ADT or placebo plus ADT, stratified by disease volume and prior docetaxel use. Here, we report the final prespecified analysis of overall survival (key secondary end point) and an update on rPFS, other secondary end points, and safety. After unblinding, 180 (31.3%) progression-free patients randomly assigned to placebo plus ADT crossed over to open-label enzalutamide plus ADT. As of May 28, 2021 (median follow-up, 44.6 months), 154 of 574 patients randomly assigned to enzalutamide plus ADT and 202 of 576 patients randomly assigned to placebo plus ADT had died. Enzalutamide plus ADT reduced risk of death by 34% versus placebo plus ADT (median not reached in either group; hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P < .001). Enzalutamide plus ADT continued to improve rPFS and other secondary end points. Adverse events were generally consistent with previous reports of long-term enzalutamide use. In conclusion, enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in patients with mHSPC.

Efficacy of enzalutamide in subgroups of men with metastatic hormone-sensitive prostate cancer based on prior therapy, disease volume, and risk.

BACKGROUND: While enzalutamide plus androgen deprivation therapy (ADT) significantly reduces the risk of radiographic progression-free survival (rPFS) and improves overall survival in metastatic hormone-sensitive prostate cancer (mHSPC), the efficacy in clinically relevant subgroups of patients based on prior local and systemic therapy, disease volume, and risk has not been analyzed to date. These post hoc analyses of the phase 3 ARCHES trial (NCT02677896) evaluated the efficacy of enzalutamide plus ADT according to prior local and systemic treatment, disease volume, and risk, assessed at trial baseline. METHODS: In ARCHES, a global, double-blind, placebo-controlled, phase 3 study, 1150 patients with mHSPC were randomized 1:1 to receive enzalutamide (160 mg/day) plus ADT or placebo plus ADT, stratified by prior docetaxel therapy and disease volume. Primary endpoint was rPFS. Secondary endpoints included time to prostate-specific antigen progression, symptomatic skeletal events, and prostate-specific antigen and radiographic responses. Analyses of clinical endpoints were completed by prior local therapy, prior docetaxel exposure, CHAARTED (NCT00309985)-defined disease volume, and LATITUDE (NCT01715285)-defined risk groups. RESULTS: Patients were randomized to enzalutamide plus ADT (n = 574) and placebo plus ADT (n = 576). Enzalutamide plus ADT significantly improved rPFS (hazard ratio: 0.39; p < 0.0001), with similar improvements reported in all subgroups based on prior local and docetaxel treatment, disease volume, and risk. Treatment benefits were observed with enzalutamide plus ADT in multiple secondary clinical endpoints in the overall population and all subgroups. CONCLUSIONS: Enzalutamide plus ADT demonstrated clinical benefit across all patients with mHSPC, irrespective of prior local and systemic treatment, disease volume, and risk.

Mapping the Patient-Oriented Prostate Utility Scale From the Expanded Prostate Cancer Index Composite and the Short-Form Health Surveys.

OBJECTIVES: This study aimed to develop mapping algorithms from the Expanded Prostate Cancer Index Composite (EPIC) and the Short-Form (SF) Health Surveys to the Patient-Oriented Prostate Utility Scale (PORPUS), an econometric instrument specifically developed for patients with prostate cancer. METHODS: Data were drawn from 2 cohorts concurrently administering PORPUS, EPIC-50, and SF-36v2. The development cohort included patients who had received a diagnosis of localized or locally advanced prostate cancer from 2017 to 2019. The validation cohort included men who had received a diagnosis of localized prostate cancer from 2014 to 2016. Linear regression models were constructed with ln(1 - PORPUS utility) as the dependent variable and scores from the original and brief versions of the EPIC and SF as independent variables. The predictive capacity of mapping models constructed with all possible combinations of these 2 instruments was assessed through the proportion of variance explained (R2) and the agreement between predicted and observed values. Validation was based on the comparison between estimated and observed utility values in the validation cohort. RESULTS: Models constructed with EPIC-50 with and without SF yielded the highest predictive capacity (R2 = 0.884, 0.871, and 0.842) in comparison with models constructed with EPIC-26 (R2 = 0.844, 0.827, and 0.776). The intraclass correlation coefficient was excellent in the 4 models (>0.9) with EPIC and SF. In the validation cohort, predicted PORPUS utilities were slightly higher than those observed, but differences were not statistically significant. CONCLUSIONS: Mapping algorithms from both the original and the abbreviated versions of the EPIC and the SF Health Surveys allow estimating PORPUS utilities for economic evaluations with cost-utility analyses in patients with prostate cancer.

[Active surveillance for patients with localized prostate cáncer. Adherence and protocol drop analysis.] / La vigilancia activa en pacientes con cáncer de próstata localizado. Análisis de adherencia y salida del protocolo.

OBJECTIVE: VA is currently considered the treatment of choice for patients with low and very low risk prostate cancer. We analyzed the evolution of this treatment strategy in our series and adherence to the protocol. MATERIAL AND METHODS: Ambispective study of patients in VA in our center between 2014- 2019. 237 meet inclusion criteria, of which 142 (60%) have a minimum of 12 months of follow- up. Mean age: 68.5 (4678), median PSA 6.37 ng / ml (1-33). 229 (96.6%) are ISUP 1 and 8 (3.4%) ISUP 2. Objectives are proposed to assess our adherence to the protocol. Descriptive statistics are used to communicate the results. RESULTS: According to the classification by risk groups of the NCCN, 145 (61.2%), 49 (20.7%) and 42 (17.7%) were very low risk, low risk and favorable intermediate risk patients, respectively. The median of follow-up is 14 months (0-66). Of the patients with a minimum follow-up of 12 months, 107 (75.4%) were re-biopsied. 80 (33.8%) leave the protocol in these 5 years, 31.3% (25) by their own decision, 55% (44) due to medical criteria, and 11.3% (9) go to WW. After 5 years of follow-up, 99.2% of patients are still alive, 0.8% died of specific non-cancer causes. Of the objectives to assess adherence, 8 are achieved, 1 partially and 1 is not evaluable. CONCLUSIONS: VA in our center is already the treatment of choice for very low-risk patients, with a constant increase from year to year. Adherence to the protocol has been favorable during the period of time studied.

OBJETIVO: La VA se ha convertido en uno de los tratamientos de elección del CP localizado de bajo y muy bajo riesgo. Analizamos la evolución de esta estrategia de tratamiento en nuestra serie, así como la adherencia al protocolo.MATERIAL Y MÉTODOS: Estudio ambispectivo de los pacientes incluidos en VA en nuestro centro entre los años 2014-2019. 237 pacientes cumplen los criterios de inclusión en VA, de los cuales 142 (60%) tienen un seguimiento mínimo de 12 meses. Edad media: 68,5(46-78), mediana PSA 6,37 ng/ml (1-33). 229 pacientes (96,6%) son ISUP 1 y 8 (3,4%) ISUP 2. Se proponen unos objetivos para valorar nuestra adherencia al protocolo. Se utiliza estadística descriptiva y contraste de hipótesis para comunicar los resultados.RESULTADOS Y DISCUSIÓN: Atendiendo a la clasificación por grupos de riesgo de la NCCN, 145 (61,2%), 49 (20,7%) y 42 (17,7%) eran pacientes muy bajo riesgo, bajo riesgo y riesgo intermedio favorable respectivamente. El tiempo (mediana) de permanencia en el programa es de 14 meses (0-66). De los pacientes con un seguimiento mínimo de 12 meses, 107 (75,4%) son re ­ biopsiados. 80 pacientes (33,8%) salen del protocolo en estos 5 años, 31,3% (25) por decisión propia, 55% (44) por criterios médicos, y 11,3% (9) pasan a WW. Tras 5 años de seguimiento, el 99,2% de los pacientes continúan vivos, el 0,8% falleció por causas no cáncer específicas. De los objetivos para evaluar la adherencia, 8 de ellos se alcanzan, 1 parcialmente y 1 no es evaluable. CONCLUSIONES: La VA en nuestro centro constituye actualmente el tratamiento de elección para los pacientes con muy bajo riesgo. La adherencia al protocolo ha sido favorable durante el periodo de tiempo estudiado.

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.

BACKGROUND: Despite standard-of-care androgen-deprivation therapy and an increasing number of treatment options, the mortality 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 characteristics, 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.

Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer by Pattern of Metastatic Spread: ARCHES Post Hoc Analyses.

PURPOSE: Enzalutamide plus androgen deprivation therapy has previously been shown to improve clinical outcomes in men with metastatic hormone-sensitive prostate cancer (ARCHES; NCT02677896). Here, we assessed if and how the pattern of metastatic spread impacts efficacy of enzalutamide plus androgen deprivation therapy in men enrolled in ARCHES. MATERIALS AND METHODS: Men with metastatic hormone-sensitive prostate cancer were randomized 1:1 to enzalutamide (160 mg/day) plus androgen deprivation therapy or placebo plus androgen deprivation therapy, stratified by disease volume and prior docetaxel treatment. The primary end point was radiographic progression-free survival. Secondary end points included time to prostate specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event and castration resistance. Post hoc analyses were performed by pattern of metastatic spread based on study entry imaging. RESULTS: Of the overall population with metastases identified at enrollment (1,146), the largest patient subgroups were those with bone metastases only (513) and those with bone plus lymph node metastases (351); there were fewer men with lymph node metastases only (154) and men with visceral±bone or lymph node metastases (128). Enzalutamide plus androgen deprivation therapy reduced the risk of radiographic progression vs placebo plus androgen deprivation therapy in men with bone metastases only (HR 0.33) and bone plus lymph node metastases (HR 0.31). Similar improvements in secondary end points were also observed in these subgroups. CONCLUSIONS: These findings indicate that treatment with enzalutamide plus androgen deprivation therapy provides improvements in men with bone and/or lymph node metastases but may be less effective in men with visceral patterns of spread.

Real-World Outcomes in First-Line Treatment of Metastatic Castration-Resistant Prostate Cancer: The Prostate Cancer Registry.

BACKGROUND: Metastatic prostate cancer has a 30% 5-year survival rate despite recent therapeutic advances. There is a need to improve the clinical understanding and treatment of this disease, particularly in the real-world setting and among patients who are under-represented in clinical trials. OBJECTIVE: We aimed to evaluate the characteristics and clinical outcomes of patients who received their first treatment for metastatic castration-resistant prostate cancer (mCRPC) in routine clinical practice, independent of treatment used, including subgroups with baseline cardiac disease, diabetes mellitus, or visceral metastases. PATIENTS AND METHODS: Prospective, noninterventional analysis of patient record data in the multicenter Prostate Cancer Registry (PCR) of men with mCRPC. The data were collected in 16 countries with the aim of recruiting more than 3000 patients between 2013 and 2016. The study end date was 9 July 2018. Data evaluated included baseline characteristics, treatment exposure, and efficacy outcomes [overall survival (OS) and time to progression (TTP)] of patients treated with abiraterone acetate plus prednisone or prednisolone (collectively, "abiraterone"), enzalutamide, or docetaxel. Descriptive outcomes are reported from the overall patient population and subgroups of patients with baseline cardiovascular disease, diabetes mellitus, or visceral metastases. The treatment effects for time to progression were compared for the overall patient population. RESULTS: The study enrollment period lasted 2.5 years, and each patient was followed for a maximum of 3 years. A total of 1874 patients in the PCR had not received previous mCRPC treatment at baseline, although they had received androgen-deprivation therapy. Prevalent co-morbidities included cardiovascular disease in 65.4% and diabetes mellitus in 17.4% of patients. Baseline characteristics suggested that patients with more advanced disease received docetaxel treatment. In the overall patient population, the median time to progression with abiraterone, enzalutamide, and docetaxel as first-line mCRPC therapy was 9.6, 10.3, and 7.6 months, respectively, and median OS was 27.1, 27.1, and 27.9 months, respectively. Outcomes in the subgroups of patients with cardiovascular disease or diabetes mellitus were similar to those of the whole population in the analysis. As expected, patients with visceral metastases had shorter TTP and OS than patients in the overall population. CONCLUSIONS: This analysis shows, for the first time, the effectiveness in parallel of first-line abiraterone, enzalutamide, and docetaxel in mCRPC, including in patients with co-morbidities such as cardiovascular disease or diabetes mellitus or in patients with visceral metastases. These real-world findings from the PCR provide meaningful information to help manage mCRPC, particularly in patients under-represented in clinical studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02236637; registered September 2014.

[Diagnostic and therapeutic management in a series of 1156 patients with the diagnosis of prostate cancer in Castilla y Leon during 2014.] / Manejo diagnóstico y actitud terapeútica de 1156 pacientes diagnosticados de cáncer de próstata en la comunidad de Castilla y León durante el año 2014.

OBJECTIVES: To evaluate the current clinical practice for patients with Prostate Cancer (CP) in the Health Areas of Castilla y León (CyL) in 2014. METHODS: A retrospective multicenter study was designed to provide data on the diagnosis and treatment of PC in CyL: 87.8% of patients were screened. Descriptive statistics on variables related to characteristics of the patient, the tumor and the treatment modality of the first line to which it was submitted are provided. RESULTS: A total of 1156 new cases of PC were analyzed with a mean age of 68.2 years and a mean PSA of 8.40 ng/ml. The Gleason score (GS) showed 538 (46.2%), 418 (35.9 %) and 200 (17.1%) patients for GS ≤ 6, 7 and  ≥ 8 respectively. 91% of patients (1053 patients) are diagnosed at a localized stage. 56 (4.8%) patients received treatment with active surveillance/ watchful waiting, 423 (36.6%) radical prostatectomy (PR), 348 (30.1%) radiotherapy (RT), 98 (8.4%) brachytherapy (BT) and 170 (14.7%) hormone therapy (HT) respectively. CONCLUSIONS: Differed strategies still accounted for a small percentage of treatments. PR and RT/BT were of choice in patients with localized stages of the disease and younger than 70 years. More advanced stages and older patients were treated with HT mainly. Age is postulated as the main factor involved in therapeutic decision making.

OBJETIVO: Conocer la práctica clínica real en pacientes con Cáncer de Próstata (CP) en las Áreas Sanitarias de Castilla y León (CyL) en el año 2014. MATERIAL Y MÉTODOS: Se diseña un estudio multicéntrico con carácter retrospectivo para disponer de datos sobre el diagnóstico y tratamiento del CP en CyL: se logra una cobertura del 87,8% de los pacientes comunitarios. Se aporta estadística descriptiva sobre las variables referentes a características del paciente, del tumor y de la modalidad de tratamiento de primera línea a la que fue sometido. RESULTADOS: Se analizan 1.156 nuevos casos de CP con una edad media de 68,2 años y una mediana de PSA de 8,4 ng/ml. La puntuación de Gleason (PG) muestra 538 (46,2%), 418 (35,9%) y 200 (17,1%) pacientes para PG ≤  6, 7 y  ≥ 8 respectivamente. El 91,0% de los pacientes (1.053 pacientes) son diagnosticados en estadio localizado. 56 pacientes (4,8%) son tratados con estrategias diferidas (EDs), vigilancia activa/ observación, 423 (36,6%) con prostatectomia radical (PR), 348 (30,1%) con radioterapia, 98 (8,4%) con braquiterapia (BT) y 170 (14,7%) con hormonoterapia (HT). CONCLUSIONES: Las EDs aún supusieron un porcentaje pequeño de los tratamientos. PR y RT/BT fueron de elección en pacientes con estadios localizados de la enfermedad y menores de 70 años. Estadios más avanzados y pacientes mayores fueron tratados con HT principalmente. La edad se postula como el principal factor implicado en la toma de decisiones terapéuticas.

Manejo diagnóstico y actitud terapeútica de 1156 pacientes diagnosticados de cáncer de próstata en la comunidad de Castilla y León durante el año 2014 / Diagnostic and therapeutic management in a series of 1156 patients with the diagnosis of prostate cancer in Castilla y Leon during 2014

Objetivo: Conocer la práctica clínica real en pacientes con Cáncer de Próstata (CP) en las Áreas Sanitarias de Castilla y León (CyL) en el año 2014. Material y métodos: Se diseña un estudio multicéntrico con carácter retrospectivo para disponer de datos sobre el diagnóstico y tratamiento del CP en CyL: se logra una cobertura del 87,8% de los pacientes comunitarios. Se aporta estadística descriptiva sobre las variables referentes a características del paciente, del tumor y de la modalidad de tratamiento de primera línea a la que fue sometido. Resultados: Se analizan 1.156 nuevos casos de CP con una edad media de 68,2 años y una mediana de PSA de 8,4 ng/ml. La puntuación de Gleason (PG) muestra 538 (46,2%), 418 (35,9%) y 200 (17,1%) pacientes para PG ≤ 6, 7 y ≥ 8 respectivamente. El 91,0% de los pacientes (1.053 pacientes) son diagnosticados en estadio localizado. 56 pacientes (4,8%) son tratados con estrategias diferidas (EDs), vigilancia activa/ observación, 423 (36,6%) con prostatectomia radical (PR), 348 (30,1%) con radioterapia, 98 (8,4%) con braquiterapia (BT) y 170 (14,7%) con hormonoterapia (HT). Conclusiones: Las EDs aún supusieron un porcentaje pequeño de los tratamientos. PR y RT/BT fueron de elección en pacientes con estadios localizados de la enfermedad y menores de 70 años. Estadios más avanzados y pacientes mayores fueron tratados con HT principalmente. La edad se postula como el principal factor implicado en la toma de decisiones terapéuticas

Objectives: To evaluate the current clinical practice for patients with Prostate Cancer (CP) in the Health Areas of Castilla y León (CyL) in 2014. Methods: A retrospective multicenter study was designed to provide data on the diagnosis and treatment of PC in CyL: 87.8% of patients were screened. Descriptive statistics on variables related to characteristics of the patient, the tumor and the treatment modality of the first line to which it was submitted are provided. Results: A total of 1156 new cases of PC were analyzed with a mean age of 68.2 years and a mean PSA of 8.40 ng/ml. The Gleason score (GS) showed 538 (46.2%), 418 (35.9 %) and 200 (17.1%) patients for GS ≤6, 7 and ≥8 respectively. 91% of patients (1053 patients) are diagnosed at a localized stage. 56 (4.8%) patients received treatment with active surveillance/ watchful waiting, 423 (36.6%) radical prostatectomy (PR), 348 (30.1%) radiotherapy (RT), 98 (8.4%) brachytherapy (BT) and 170 (14.7%) hormone therapy (HT) respectively. Conclusions: Differed strategies still accounted for a small percentage of treatments. PR and RT/BT were of choice in patients with localized stages of the disease and younger than 70 years. More advanced stages and older patients were treated with HT mainly. Age is postulated as the main factor involved in therapeutic decision making

[Advanced prostate cancer and quality of life.] / Cáncer de próstata avanzado y calidad de vida.

OBJECTIVES: The therapeutic range in advanced and castration resistant prostate cancer is widening. Therapies must offer real clinical efficacy, and they also should be acceptable and desirable for patients, specially in advanced disease. We analyze the value of quality of life analysis in patients with advanced prostate cancer. METHODS: We performed a bibliographic review (Pubmed) with the various health related quality of life scales available and different clinical trials on advanced prostate cancer. RESULTS: There are numerous therapeutic options but, due to variations in study design, a different evaluation of adverse events and different therapeutic regimens, comparisons are difficult. A common method to interpret results is not available, so most of the times that interpretation is left to statistical significance, which is not always well correlated with clinical significance. CONCLUSIONS: To propose the most adequate treatment in patient`s interest, we need results focused on patients that combine not only quantity or overall survival but also quality of life. Parameters such as QALY should be included in clinical trials as evaluation objectives in order to favor decision taking.

Cáncer de próstata avanzado y calidad de vida / Advanced prostate cancer and quality of life

OBJETIVOS: El abanico terapéutico en cáncer de próstata avanzado y resistente a castración es cada vez mayor. Los tratamientos deben ofrecer una eficacia clínica real, pero también, especialmente en enfermedades avanzadas deben ser aceptables deseables para los pacientes. En el presente trabajo analizamos el valor del análisis de calidad de vida en paciente con cáncer de próstata avanzado. MÉTODOS: Realizamos una revisión de la literatura disponible -pubmed- con las distintas escalas de calidad de vida relacionada con la salud y los distintitos ensayos clínicos en cáncer de próstata avanzado. RESULTADOS: Existen numerosas opciones terapéuticas pero debido a la variación en los diseños de los estudios, distinta valoración de los efectos adversos y distintos régimenes de tratamiento la comparación entre ellos es difícil, no se dispone de un método común para interpretar resultados, por lo que la mayor parte de la veces esa interpretación se deja a la significación estadística, no siempre bien correlacionada con la significación clínica. CONCLUSIONES: Necesitamos resultados centrados en el paciente que combinen no sólo cantidad o supervivencia global sino también calidad de vida para proponer el tratamiento más adecuado en interés del paciente. Los parámetros como los AVACS deberían ser incluidos como objetivos de valoración en los ensayos clínicos para favorecer la toma de decisiones

OBJECTIVES: The therapeutic range in advanced and castration resistant prostate cancer is widening. Therapies must offer real clinical efficacy, and they also should be acceptable and desirable for patients, specially in advanced disease. We analyze the value of quality of life analysis in patients with advanced prostate cancer. METHODS: We performed a bibliographic review (Pubmed) with the various health related quality of life scales available and different clinical trials on advanced prostate cáncer. RESULTS: There are numerous therapeutic options but, due to variations in study design, a different evaluation of adverse events and different therapeutic regimens, comparisons are difficult. A common method to interpret results is not available, so most of the times that interpretation is left to statistical significance, which is not always well correlated with clinical significance. CONCLUSIONS: To propose the most adequate treatment in patient's interest, we need results focused on patients that combine not only quantity or overall survival but also quality of life. Parameters such as QALY should be included in clinical trials as evaluation objectives in order to favor decision taking

[Consensus on castration-resistant prostate cancer management in Spain.] / Consenso sobre el manejo del cáncer de próstata resistente a la castración avanzado en España.

OBJECTIVES: To move towards a more standardized approach in clinical practice to manage patients with castration-resistant prostate cancer (CRPC) in Spain. METHODS: A panel of 18 Spanish experts in Urology with expertise managing CRPC followed a modified Delphi process with two rounds and a final face-to-face consensus meeting. The panel considered a total of 106 clinical questions divided into the following 6 sections: definition of CRPC, diagnosis of metastases by imaging techniques, symptoms of CRPC, progression of CRPC, M0 and M1 management and therapeutic sequencing. RESULTS: A bone scan (BS) is recommended at diagnosis, at the onset of bone pain, and depending on PSA levels, but it is not sensitive enough to confirm or exclude bone metastases if there is bone pain. Whole-body MRI and axial MRI are more sensitive than BS and plain X-rays, but more expensive, so they have to be used in certain situations. There is CRPC progression when there is radiologic, clinical or confirmed PSA progression. Flare phenomenon appears in treatment with taxanes and abiraterone. It was agreed that in M0 CRPC patients no drug treatment is currently recommended, although in M1 CRPC patients the first-line therapy would be mainly enzalutamide/abiraterone and/or docetaxel, depending on the symptom burden. CONCLUSION: After the consensus, we provide a series of recommendations for Spanish physicians treating CRPC to address the disease characteristics,how to tailor patient management decisions, the use of imaging techniques, and how to handle disease progression appropriately to improve patients' quality of life.

Consenso sobre el manejo del cáncer de próstata resistente a la castración avanzado en España / Consensus on castration-resistant prostate cancer management in Spain

OBJETIVOS: Establecer recomendaciones sobre la práctica clínica habitual del manejo del cáncer de próstata resistente a la castración (CPRC) en España. MÉTODOS: Un panel de 18 expertos en Urología con experiencia en el manejo del CPRC participaron en un proceso Delphi modificado a dos rondas con una reunión final presencial. El panel consideró un total de 106 cuestiones clínicas divididas en las siguientes secciones: definición del CPRC, diagnóstico de metástasis por técnicas de imagen, síntomatología, progresión, manejo de M0 y M1 y secuenciación terapéutica. RESULTADOS: Se recomienda realizar una gammagrafía ósea (GO) en el diagnóstico, al comienzo del dolor óseo y dependiendo de los niveles de PSA. La resonancia magnética de cuerpo entero y la axial son más sensibles que la GO y la radiografía, pero más caras, por lo que se reservan para ciertas situaciones. Existe progresión del CPRC cuando se confirma la progresión radiológica, clínica o por PSA. El fenómeno "flare" aparece en el tratamiento con taxanos y abiraterona. En pacientes M0 no se recomienda tratamiento farmacológico actualmente, y el tratamiento en primera línea para los pacientes M1 incluiría principalmente enzalutamida/ abiraterona y/o docetaxel, según los síntomas. CONCLUSIÓN: Se proponen recomendaciones para personalizar la toma de decisiones ante cada paciente, el uso de técnicas de imagen y cómo abordar la progresión de la enfermedad para mejorar la calidad de vida de los pacientes

OBJECTIVES: To move towards a more standardized approach in clinical practice to manage patients with castration-resistant prostate cancer (CRPC) in Spain. METHODS: A panel of 18 Spanish experts in Urology with expertise managing CRPC followed a modified Delphi process with two rounds and a final face-to-face consensus meeting. The panel considered a total of 106 clinical questions divided into the following 6 sections: definition of CRPC, diagnosis of metastases by imaging techniques, symptoms of CRPC, progression of CRPC, M0 and M1 management and therapeutic sequencing. RESULTS: A bone scan (BS) is recommended at diagnosis, at the onset of bone pain, and depending on PSA levels, but it is not sensitive enough to confirm or exclude bone metastases if there is bone pain. Whole-body MRI and axial MRI are more sensitive than BS and plain X-rays, but more expensive, so they have to be used in certain situations. There is CRPC progression when there is radiologic, clinical or confirmed PSA progression. Flare phenomenon appears in treatment with taxanes and abiraterone. It was agreed that in M0 CRPC patients no drug treatment is currently recommended, although in M1 CRPC patients the first-line therapy would be mainly enzalutamide/abiraterone and/or docetaxel, depending on the symptom burden. CONCLUSION: After the consensus, we provide a series of recommendations for Spanish physicians treating CRPC to address the disease characteristics how to tailor patient management decisions, the use of imaging techniques, and how to handle disease progression appropriately to improve patients' quality of life