Impact of darolutamide on local symptoms: pre-planned and post hoc analyses of the ARAMIS trial.

OBJECTIVE: To assess, the effect of darolutamide (a structurally distinct androgen receptor inhibitor) on urinary and bowel symptoms, using data from the phase III ARAMIS trial (NCT02200614) that showed darolutamide significantly reduced the risk of metastasis and death versus placebo. PATIENTS AND METHODS: Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) were randomised 2:1 to darolutamide (n = 955) or placebo (n = 554). Local symptom control was assessed by first prostate cancer-related invasive procedures and post hoc analyses of time to deterioration in quality of life (QoL) using total urinary and bowel symptoms, and individual questions for these symptoms from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer Module subscales and Functional Assessment of Cancer Therapy-Prostate prostate cancer subscale. Prostate-specific antigen (PSA) responses were correlated with urinary and bowel adverse events (AEs). RESULTS: Fewer patients receiving darolutamide (4.7%) versus placebo (9.6%) underwent invasive procedures, and time to first procedure was prolonged with darolutamide (hazard ratio 0.42, 95% confidence interval 0.28-0.62). Darolutamide significantly (P < 0.01) delayed worsening of QoL for total urinary and bowel symptoms versus placebo, mostly attributed by individual symptoms of urinary frequency, associated pain, and interference with daily activities. AEs of urinary retention and dysuria were less frequent with darolutamide, and greater PSA response (≥90%, ≥50% and <90%, <50%) among darolutamide-treated patients was associated with lower incidences of urinary retention (2.2%, 4.2%, 5.1%) and dysuria (0.5%, 3.2%, 5.1%), respectively. CONCLUSIONS: Darolutamide demonstrated a positive impact on local disease recurrence and symptom control in patients with nmCRPC, delayed time to deterioration in QoL related to urinary and bowel symptoms, and a favourable safety profile showing similar incidence of urinary- and bowel-related AEs compared with placebo.

Development of castration resistance in prostate cancer patients treated with luteinizing hormone-releasing hormone analogues (LHRHa): results of the ANARESISTANCE study.

PURPOSE: Evaluate the percentage of patients with prostate cancer treated with luteinizing hormone-releasing hormone analogues (LHRHa) that develop castration resistance after a follow-up period of 3 years. The secondary objective is to evaluate the variables potentially related to the progression to castration resistant prostate cancer (CRPC). METHODS: A post-authorization, nation-wide, multicenter, prospective, observational, and longitudinal study that included 416 patients treated with LHRHa between 2012 and 2017 is presented. Patients were followed for 3 years or until development of CRPC, thus completing a per-protocol population of 350 patients. A Cox regression analysis was carried out to evaluate factors involved in progression to CRPC. RESULTS: After 3 years of treatment with LHRHa 18.2% of patients developed CRPC. In contrast, in the subgroup analysis, 39.6% of the metastatic patients developed CRPC, compared with 8.8% of the non-metastatic patients. The patients with the highest risk of developing CRPC were those with a nadir prostate-specific antigen (PSA) > 2 ng/ml (HR 21.6; 95% CI 11.7-39.8; p < 0.001) and those receiving concomitant medication, most commonly bicalutamide (HR 1.8; 95% CI 1-3.1, p = 0.0431). CONCLUSIONS: The proportion of metastatic patients developing CRPC after 3 years of treatment with LHRHa is consistent with what has been previously described in the literature. In addition, this study provides new findings on CRPC in non-metastatic patients. Concomitant medication and nadir PSA are statistically significant predictive factors for the time to diagnosis of CRPC, the nadir PSA being the strongest predictor.

Efficacy and safety of darolutamide in Black/African-American patients from the phase III ARAMIS study.

Aim: Darolutamide significantly improved metastasis-free survival (MFS) and overall survival (OS) versus placebo in the phase III ARAMIS study. We evaluated outcomes in Black/African-American patients in ARAMIS. Materials & methods: Patients with nonmetastatic castration-resistant prostate cancer were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554) plus androgen-deprivation therapy. The primary end point was MFS. Secondary end points included OS and safety. Results: In 52 (3.4%) Black/African-American patients, darolutamide improved MFS (median: not reached vs 12.4 months) and OS (3-year survival rates: 100 vs 71%) versus placebo. The safety profile of darolutamide in Black/African-American patients was consistent with that of all ARAMIS patients. Conclusion: In Black/African-American patients, darolutamide improved MFS and OS and was well tolerated, consistent with the overall ARAMIS population.

In patients with prostate cancer that has stopped responding to androgen-deprivation therapy, or 'ADT,' and has not spread to other parts of the body (known as nonmetastatic castration-resistant prostate cancer, or 'nmCRPC'), darolutamide is an oral treatment option. Darolutamide added to ADT was tested in patients with nmCRPC in a large international study called ARAMIS and was found to prolong the time that patients were free from their cancer spreading compared with patients who received ADT alone. This report provides information on the effect of darolutamide in the 52 Black/African­American patients who took part in ARAMIS. In these patients, darolutamide showed similar effects on lowering the risk of their cancer spreading and was well tolerated.

Is computed tomography a necessary part of a metastatic evaluation for castration-resistant prostate cancer? Results from the Shared Equal Access Regional Cancer Hospital Database.

BACKGROUND: Metastatic lesions in prostate cancer beyond the bone have prognostic importance and affect clinical therapeutic decisions. Few data exist regarding the prevalence of soft-tissue metastases at the initial diagnosis of metastatic castration-resistant prostate cancer (mCRPC). METHODS: This study analyzed 232 men with nonmetastatic (M0) castration-resistant prostate cancer (CRPC) who developed metastases detected by a bone scan or computed tomography (CT). All bone scans and CT scans within the 30 days before or after the mCRPC diagnosis were reviewed. The rate of soft-tissue metastases among those undergoing CT was determined. Then, predictors of soft-tissue metastases and visceral and lymph node metastases were identified. RESULTS: Compared with men undergoing CT (n = 118), men undergoing only bone scans (n = 114) were more likely to have received primary treatment (P = .048), were older (P = .013), and less recently developed metastases (P = .018). Among those undergoing CT, 52 (44%) had soft-tissue metastases, including 20 visceral metastases (17%) and 41 lymph node metastases (35%), whereas 30% had no bone involvement. In a univariable analysis, only prostate-specific antigen (PSA) predicted soft-tissue metastases (odds ratio [OR], 1.27; P = .047), and no statistically significant predictors of visceral metastases were found. A higher PSA level was associated with an increased risk of lymph node metastases (OR, 1.38; P = .014), whereas receiving primary treatment was associated with decreased risk (OR, 0.36; P = .015). CONCLUSIONS: The data suggest that there is a relatively high rate of soft-tissue metastasis (44%) among CRPC patients undergoing CT at the initial diagnosis of metastases, including some men with no bone involvement. Therefore, forgoing CT during a metastatic evaluation may lead to an underdiagnosis of soft-tissue metastases and an underdiagnosis of metastases in general. Cancer 2015. © 2015 American Cancer Society. Cancer 2016;122:222-229. © 2015 American Cancer Society.

[Advanced prostate cancer: sequence of androgen receptor-targeted substances and chemotherapy determines long-term survival]. / Fortgeschrittenes Prostatakarzinom: Sequenz aus androgenrezeptorgerichteten Substanzen und Chemotherapie entscheidet über das Langzeitüberleben.

The treatment of advanced prostate cancer is changing. New study data and the resulting new therapeutic options have led to increasingly differentiated treatment decisions. Despite the changing therapy landscape, taxane-based chemotherapy-being a life-prolonging treatment-remains an indispensable therapeutic component for chemotherapy-fit patients in the metastatic setting. The current results of the randomized study CARD show that cabazitaxel has a higher oncological effectiveness, including a significant survival benefit and no negative impact on quality of life parameters, compared to a second androgen receptor targeted agent (ARTA) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after treatment with docetaxel and an androgen receptor-targeted agent (ARTA). In mCNPC the combination therapies of ADT (androgen deprivation therapy) plus docetaxel or of ADT plus ARTA have been established. In addition, three ARTAs tested in recent phase III studies in a clinical setting for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) showed that their use significantly prolongs metastasis-free survival and overall survival. The potential early use of ARTAs also has implications for the treatment of mCNPC. The aim of this publication is to provide guidance for clinical routine and to develop criteria for individual therapy decisions with a special focus on the use of chemotherapy.

The PREVAIL trial of enzalutamide in men with chemotherapy-naïve, metastatic castration-resistant prostate cancer: Post hoc analysis of Korean patients.

PURPOSE: This post hoc analysis evaluated treatment effects, safety, and pharmacokinetics of enzalutamide in Korean patients in the phase 3, double-blind, placebo-controlled PREVAIL trial. MATERIALS AND METHODS: Asymptomatic or mildly symptomatic chemotherapy-naive men with metastatic castration-resistant prostate cancer that progressed on androgen deprivation therapy received 160 mg/d oral enzalutamide or placebo (1:1) until death or discontinuation due to radiographic progression or skeletal-related event and initiation of subsequent therapy. Coprimary end points were centrally assessed radiographic progression-free survival (rPFS) and overall survival (OS). Secondary end points included investigator-assessed rPFS, time to initiation of chemotherapy, time to prostate-specific antigen (PSA) progression, PSA response (≥50% decline), and time to skeletal-related event. RESULTS: Of 1,717 total patients, 78 patients were enrolled in Korea (enzalutamide, n=40; placebo, n=38). Hazard ratios (95% confidence interval) for enzalutamide versus placebo were 0.23 (0.02-2.24) for centrally assessed rPFS, 0.77 (0.28-2.15) for OS, 0.21 (0.08-0.51) for time to chemotherapy, and 0.31 (0.17-0.56) for time to PSA progression. A PSA response was observed in 70.0% of enzalutamide-treated and 10.5% of placebo-treated Korean patients. Adverse events of grade ≥3 occurred in 33% of enzalutamide-treated and 11% of placebo-treated Korean patients, with median treatment durations of 13.0 and 5.1 months, respectively. At 13 weeks, the plasma concentration of enzalutamide plus N-desmethyl enzalutamide was similar in Korean and non-Korean patients (geometric mean ratio, 1.04; 90% confidence interval, 0.97-1.10). CONCLUSIONS: In Korean patients, treatment effects and safety of enzalutamide were consistent with those observed in the overall PREVAIL study population (ClinicalTrials.gov Identifier: NCT01212991).

The effect of continuous androgen deprivation treatment on prostate cancer patients as compared with intermittent androgen deprivation treatment.

PURPOSE: To investigate the efficacy of androgen deprivation treatment (ADT) between continuous and intermittent ADT. MATERIALS AND METHODS: Between January 2006 and May 2015, 603 patients were selected and divided into continuous ADT (CADT) (n=175) and intermittent ADT (IADT) (n=428) groups. The median follow-up in this study was 48.19 (1.0-114.0) months. The primary end point was time to castration resistant prostate cancer (CRPC). The types of ADT were monotherapy and maximal androgen blockade (i.e., luteinizing hormone-releasing hormone agonist and antiandrogen). RESULTS: The characteristics of patients showed no significant differences between the CADT and IADT groups, except for the Gleason score (p<0.001). The median time to CRPC of all enrolled patients with ADT was 20.60±1.60 months. The median time to CRPC was 11.20±1.31 months in the CADT group as compared with 22.60±2.08 months in the IADT group. In multivariate analysis, percentage of positive core (p=0.047; hazard ratio [HR], 0.976; 95% confidence interval [CI], 0.953-1.000), Gleason score (p=0.007; HR, 1.977; 95% CI, 1.206-3.240), lymph node metastasis (p=0.030; HR, 0.498; 95% CI, 0.265-0.936), bone metastasis (p=0.028; HR, 1.921; 95% CI, 1.072-3.445), and CADT vs. IADT (p=0.003; HR, 0.254; 95% CI. 0.102-0.633) were correlated with the duration of progression to CRPC. The IADT group presented a significantly longer median time to CRPC compared with the CADT group. Additionally, patients in the IADT group showed a longer duration in median time to CRPC in subgroup analysis according to the Gleason score. CONCLUSIONS: This study found that IADT produces a longer duration in median time to CRPC than does CADT.

Effects of statin use on the response duration to androgen deprivation therapy in metastatic prostate cancer.

PURPOSE: To determine whether statin use delays the development of castration-resistant prostate cancer (CRPC) in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT). MATERIALS AND METHODS: A total of 171 patients with metastatic prostate cancer at the time of diagnosis who were treated with ADT between January 1997 and December 2013 were retrospectively analyzed. The patients were classified into two groups: the nonstatin use group (A group) and the statin use group (B group). Multivariate analysis was performed on statin use and other factors considered likely to have an effect on the time to progression to CRPC. RESULTS: The mean patient age was 67.1±9.1 years, and the mean follow-up period was 52 months. The mean initial prostate-specific antigen (PSA) level was 537 ng/mL. Of the 171 patients, 125 (73%) were in group A and 46 (27%) were in group B. The time to progression to CRPC was 22.7 months in group A and 30.5 months in group B, and this difference was significant (p=0.032). Blood cholesterol and initial PSA levels did not differ significantly according to the time to progression to CRPC (p=0.288, p=0.198). Multivariate analysis using the Cox regression method showed that not having diabetes (p=0.037) and using a statin (p=0.045) significantly increased the odds ratio of a longer progression to CRPC. CONCLUSIONS: Statin use in metastatic prostate cancer patients appears to delay the progression to CRPC. Large-scale, long-term follow-up studies are needed to validate this finding.

Intratumoral steroidogenesis in castration-resistant prostate cancer: a target for therapy.

Development of castration-resistant prostate cancer (CRPC) in a low androgen environment, arising from androgen deprivation therapy (ADT), is a major problem in patients with advanced prostate cancer (PCa). Several mechanisms have been hypothesized to explain the progression of PCa to CRPC during ADT, one of them is so called persistent intratumoral steroidogenesis. The existence of intratumoral steroidogenesis was hinted based on the residual levels of intraprostatic testosterone (T) and dihydrotestosterone (DHT) after ADT. Accumulating evidence has shown that the intraprostatic androgen levels after ADT are sufficient to induce cancer progression. Several studies now have demonstrated that PCa cells are able to produce T and DHT from different androgen precursors, such as cholesterol and the adrenal androgen, dehydroepiandrosterone (DHEA). Furthermore, up-regulation of genes encoding key steroidogenic enzymes in PCa cells seems to be an indicator for active intratumoral steroidogenesis in CRPC cells. Currently, several drugs are being developed targeting those steroidogenic enzymes, some of which are now in clinical trials or are being used as standard care for CRPC patients. In the future, novel agents that target steroidogenesis may add to the arsenal of drugs for CRPC therapy.