Prostate cancer associated 3 (PCA3) and TMPRSS2:ERG fusion (T:E) are established urinary RNA biomarkers for detecting clinically significant prostate cancer (csPCa, Grade Group ≥ 2). Large within-subject paired studies directly comparing post-DRE and non-DRE urine collection are lacking. Using a multicenter cohort with samples collected from the same patients, we evaluated the effect of urine collection method on PCA3 and T: E diagnostic performance. In a multicenter prospective study paired post-DRE and non-DRE whole-urine samples were collected before systematic biopsy. PCA3, T:E, and reference PSA RNAs were quantified in 373 post-DRE and 355 non-DRE eligible specimens. Logistic regression models combining PCA3, T:E, PSA density, and age were developed for post-DRE (PD2) and non-DRE (ND2) cohorts and evaluated by cross-validated receiver operating characteristic (ROC) analysis and decision curve analysis. PD2 outperformed ND2 in discrimination (AUC 0.78 versus 0.73) and net benefit. At 95

Small renal masses (SRMs) SRMs are a heterogeneous group of small kidney lesions. Currently, the genomic landscape of SRMs is understudied, and clinically relevant tools for malignancy detection and fast tumor growth prediction are lacking. The aim of the study was to evaluate whether mutations in SRMs are associated with increased risk of renal cell carcinoma (RCC) or aggressive tumors. In this pilot study, 52 patients with SRMs were divided based on tumor histology into RCC and benign tumors, while RCC cases were divided into fast-growing and slow-growing tumor groups. Tissue biopsy samples evaluated for mutations in 51 cancer hotspot genes using next generation sequencing and qPCR. Non-benign mutations were tested for associations with RCC and clinical features. Receiver operating curve analysis used for evaluation of mutation biomarker models prediction of RCC and fast-growing tumors. 75

BACKGROUND:Teverelix drug product (DP) is a novel injectable gonadotropin-releasing hormone antagonist. METHODS:An adaptive phase 2, open-label, multicenter trial was conducted in patients with advanced prostate cancer to evaluate the efficacy and safety of a combined subcutaneous (SC) and intramuscular (IM) loading dose regimen of teverelix DP of 120 mg SC + 120 mg IM (Group 1; N = 9) or 180 mg SC + 180 mg IM (Group 2; N = 41) administered at a single visit, followed by 6-weekly SC maintenance doses of 120 mg (Group 1) or 180 mg (Group 2), up to Day 168. The primary endpoint was the proportion of patients achieving castration levels with serum testosterone <0.5 ng/mL at Day 28 with a target castration rate of 90%. Injection sites were inspected by the investigator at every visit and reactions (ISRs) were proactively recorded. RESULTS:The target castration rate was reached in Group 2 (97.5%) but not in Group 1 (62.5%). The castration rates were not maintained to Day 42 (Group 2: 82.5%; Group 1: 50.0%). Suppression of testosterone to castrate levels occurred rapidly (median time: 2 days for both groups). Suppression of testosterone, prostate-specific antigen, follicle-stimulating hormone, and luteinizing hormone was sustained throughout the treatment period, being more prominent with the higher dose. The adverse event (AE) profile was similar between groups. The most common AEs were injection-site induration (n = 40: 80.0%), injection-site erythema (n = 35: 70.0%), and hot flush (n = 21: 42.0%). Most ISRs were Grade 1. CONCLUSION:Overall, the teverelix DP doses were generally well-tolerated but did not adequately maintain castration levels.

Background/Aim: According to the European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) recommendations, sunitinib is one of the recommended regimens for favorable and intermediate-risk metastatic renal cell carcinoma (mRCC) patients. The objective of this study was to evaluate sunitinib efficacy as a first-line treatment for mRCC patients with favorable/intermediate prognostic risk in a real-world setting. Patients and Methods: Patients diagnosed with mRCC and confirmed as appropriate candidates for the first-line systemic treatment were included in this retrospective study. The prognostic risk was evaluated according to the model of the International Metastatic RCC Database Consortium (IMDC). Results: Patients received sunitinib as a first-line treatment. A total of 94 patients were enrolled from 2019 to the 2020and 67 of them were included in the detailed analysis. Median progression-free survival (PFS) was 23.4 (95%CI=17.3-29.5), and median overall survival (OS) was 66 months (95%CI=44.9-87.1). The age over 60 years was a significant negative predictor for PFS and OS. Regarding the IMDC model for disease risk prediction, the number of two risk factors in the intermediate risk group was a significant predictor for a shorter response to the first-line therapy. Conclusion: Sunitinib is an effective tyrosine kinase inhibitor, which can be used as a first-line treatment in favorable/intermediate-risk groups of patients with mRCC, especially in countries where novel systemic treatment modalities are not yet available.

PURPOSE For patients with metastatic hormone-sensitive prostate cancer (mHSPC), delaying progression to castration-resistant disease is important not only for overall survival (OS) but also for patients' quality of life. Darolutamide plus androgen-deprivation therapy (ADT) with docetaxel improved OS versus ADT and docetaxel in patients with mHSPC. The ARANOTE trial evaluated darolutamide and ADT without chemotherapy in patients with mHSPC. METHODS In this global phase III trial, patients were randomly assigned 2:1 to receive darolutamide 600 mg twice daily or placebo, with concomitant ADT. The primary end point was radiological progression-free survival (rPFS). RESULTS From March 2021 to August 2022, 669 patients were randomly assigned (darolutamide n = 446; placebo n = 223). At the primary cutoff date (June 7, 2024), darolutamide plus ADT significantly improved rPFS, reducing the risk of radiological progression or death by 46% versus placebo plus ADT (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.71]; P < .0001), with consistent benefits across subgroups, including high- and low-volume disease. OS results were suggestive of benefit with darolutamide versus placebo (HR, 0.81 [95% CI, 0.59 to 1.12]), and clinical benefits were seen across all other secondary end points, including delayed time to metastatic castration-resistant prostate cancer (HR, 0.40 [95% CI, 0.32 to 0.51]) and time to pain progression (HR, 0.72 [95% CI, 0.54 to 0.96]). Adverse events were similar in the two groups. Notably, the incidence of fatigue was lower in patients receiving darolutamide (5.6%) versus those receiving placebo (8.1%), and fewer patients receiving darolutamide (6.1%) versus placebo (9.0%) discontinued treatment because of adverse events. CONCLUSION These results confirm the efficacy and tolerability of darolutamide plus ADT in patients with mHSPC, demonstrating clinically and statistically significant improvement in rPFS and a favorable safety profile consistent with prior phase III darolutamide trials.

To evaluate the efficacy and safety of teverelix in treatment naïve patients aged over 50 years with symptomatic benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), and to explore teverelix’ potential in preventing AUR secondary to BPH with the aim to inform a planned Phase 2 trial. This Phase 2, multicenter, randomized, double-blind, placebo-controlled study involved BPH patients with an International Prostate Symptom Score (IPSS) ≥ 13 and uroflow < 13 mL/sec. After a 4-week single-blind placebo run-in, patients were randomized to receive teverelix 60 mg (n = 41) or placebo (n = 40) subcutaneously on day 1 and day 3. The primary endpoint was IPSS reduction at end of treatment period (Week 16); secondary endpoints included uroflow, prostate volume (PV), pharmacokinetics, pharmacodynamics, quality of life (QoL), and safety. Data were analyzed using analysis of covariance with α set at 0.05. At Week 16, teverelix significantly reduced IPSS by a mean of 6.3 (SD: ± 3.9) versus 1.1 (SD: ± 2.9) for placebo. By Week 2, teverelix showed a mean IPSS reduction of 13.0

Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer, accounting for over 75% of cases. The asymptomatic nature of the disease contributes to late-stage diagnoses and poor survival. Highly vascularized and immune infiltrated microenvironment are prominent features of ccRCC, yet the interplay between vasculature and immune cells, disease progression and response to therapy remains poorly understood. Using droplet-based single-cell RNA sequencing we profile 50,236 transcriptomes from paired tumor and healthy adjacent kidney tissues. Our analysis reveals significant heterogeneity and inter-patient variability of the tumor microenvironment. Notably, we discover a previously uncharacterized vasculature subpopulation associated with epithelial-mesenchymal transition. The cell-cell communication analysis reveals multiple modes of immunosuppressive interactions within the tumor microenvironment, including clinically relevant interactions between tumor vasculature and stromal cells with immune cells. The upregulation of the genes involved in these interactions is associated with worse survival in the TCGA KIRC cohort. Our findings demonstrate the role of tumor vasculature and stromal cell populations in shaping the ccRCC microenvironment and uncover a subpopulation of cells within the tumor vasculature that is associated with an angiogenic phenotype.

You have accessJournal of UrologyCME1 Apr 2023MP11-14 TREATMENT DURATION AND LONG-TERM SAFETY AND TOLERABILITY WITH DAROLUTAMIDE IN NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (nmCRPC): ARAMIS ROLLOVER STUDY Neal D. Shore, Murilo Luz, Albertas Ulys, Jorge Ortiz, Shankar Srinivasan, Etah Kurland, and Karim Fizazi Neal D. ShoreNeal D. Shore More articles by this author , Murilo LuzMurilo Luz More articles by this author , Albertas UlysAlbertas Ulys More articles by this author , Jorge OrtizJorge Ortiz More articles by this author , Shankar SrinivasanShankar Srinivasan More articles by this author , Etah KurlandEtah Kurland More articles by this author , and Karim FizaziKarim Fizazi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003226.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In patients (pts) with nmCRPC, darolutamide (DARO) significantly improved metastasis-free survival by ∼2 years and reduced the risk of death by 31% vs placebo, with a favorable safety profile (ARAMIS study; NCT02200614). We report the long-term safety and tolerability of DARO in the ARAMIS Rollover Study (ROS; NCT04464226). METHODS: In ARAMIS, 954 pts received double-blind (DB) DARO 600 mg orally twice daily, of whom 591 pts continued on open-label (OL) DARO following the primary analysis. On completion of ARAMIS, 294 pts with no evidence of metastases and benefitting clinically from DARO entered the ROS. DARO treatment duration and safety are described for the 954 pts over the DB, DB+OL, and DB+OL+ROS periods. RESULTS: At data cut-off of Jan 31, 2022, the median (range) duration of DARO treatment was DB 1.5 years (0.0–4.0), DB+OL 2.1 years (0.0–4.9), and DB+OL+ROS 2.8 years (0.0–6.8). Of the 954 randomized pts, 32.3% received DARO treatment for ≥2–<4 years, 17.3% for ≥4–<5 years, and 12.8% for ≥5 years. As expected, cumulative incidences of treatment-emergent adverse events (TEAEs) increased slightly with longer observation time. For the DB, DB+OL, and DB+OL+ROS periods, respectively, TEAE incidences were: any grade 85.7%, 89.8%, 91.5%; grade 3/4 26.3%, 31.8%, 35.5%; serious 26.1%, 32.1%, 38.5%; and leading to treatment discontinuation 8.9%, 10.5%, 12.9%. Increases in incidences of TEAEs commonly associated with androgen receptor inhibition across the DB, DB+OL, and DB+OL+ROS periods were mostly minimal (Figure 1). During the first 24 months of DARO treatment, incidences of most of these TEAEs were low and ≤2% different vs placebo, except for fatigue. Onset of these TEAEs by time intervals across all study phases (DB, DB+OL, DB+OL+ROS) will be presented. CONCLUSIONS: Approximately 30% of pts with nmCRPC remained on DARO for ≥4 years, suggesting long-term clinical benefit. Most adverse events (AEs) occurred in the first 2 years of treatment, with small increments over time. The favorable safety profile of DARO was maintained with long-term exposure. No new safety concerns were observed in the ROS. Source of Funding: Bayer AG and Orion Pharma © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e129 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal D. Shore More articles by this author Murilo Luz More articles by this author Albertas Ulys More articles by this author Jorge Ortiz More articles by this author Shankar Srinivasan More articles by this author Etah Kurland More articles by this author Karim Fizazi More articles by this author Expand All Advertisement PDF downloadLoading ...

Background and Objectives: Germline DNA damage response (DDR) gene mutations correlate with increased prostate cancer (PCa) risk and a more aggressive form of the disease. DDR mutation testing is recommended for metastatic PCa cases, while eligible information about the mutations’ burden in the early-stage localized PCa is still limited. This study is aimed at the prospective detection of DDR pathway mutations in cases with localized PCa and correlation with clinical, histopathological, and radiological data. A comparison to the previously assessed cohort of the advanced PCa was performed. Materials and Methods: Germline DDR gene mutations were assessed prospectively in DNA samples from 139 patients, using a five-gene panel (BRCA1, BRCA2, ATM, CHEK2, and NBN) targeted next-generation sequencing. Results: This study revealed an almost three-fold higher risk of localized PCa among mutation carriers as compared to non-carriers (OR 2.84 and 95% CI: 0.75–20.23, p = 0.16). The prevalence of germline DDR gene mutations in PCa cases was 16.8% (18/107) and they were detected only in cases with PI-RADS 4/5 lesions. BRCA1/BRCA2/ATM mutation carriers were 2.6 times more likely to have a higher (>1) cISUP grade group compared to those with a CHEK2 mutation (p = 0.27). However, the number of cISUP > 1-grade patients with a CHEK2 mutation was significantly higher in advanced PCa than in localized PCa: 66.67% vs. 23.08% (p = 0.047). Conclusions: The results of our study suggest the potential of genetic screening for selected DDR gene mutations for early identification of cases at risk of aggressive PCa.

(1) Background: DNA damage response (DDR) pathway gene mutations are detectable in a significant number of patients with metastatic castration-resistant prostate cancer (mCRPC). The study aimed at identification of germline and/or somatic DDR mutations in blood and urine samples from patients with mCRPC for correlation with responses to entire sequence of systemic treatment and survival outcomes. (2) Methods: DDR gene mutations were assessed prospectively in DNA samples from leukocytes and urine sediments from 149 mCRPC patients using five-gene panel targeted sequencing. The impact of DDR status on progression-free survival, as well as treatment-specific and overall survival, was evaluated using Kaplan–Meier curves and Cox regression. (3) Results: DDR mutations were detected in 16.6% of urine and 15.4% of blood samples. BRCA1, BRCA2, CHEK2, ATM and NBN mutations were associated with significantly shorter PFS in response to conventional androgen deprivation therapy and first-line mCRPC therapy with abiraterone acetate. Additionally, BRCA1 and BRCA2 mutation-bearing patients had a significantly worse response to radium-223. However, DDR mutation status was predictive for the favourable effect of second-line abiraterone acetate after previous taxane-based chemotherapy. (4) Conclusions: Our data confirm the benefit of non-invasive urine-based genetic testing for timely identification of high-risk prostate cancer cases for treatment personalization.

This study aimed to investigate the extent of field cancerization adjacent to index lesions in prostate cancer (PCa) by measuring DNA methylation of selected tumor suppressor genes in the perifocal tissue of PCa not visible on multiparametric magnetic resonanse imaging (mpMRI) for the safe zone of focal therapy identification.

147 Background: Darolutamide (DARO) significantly improved metastasis-free survival by ~2 y and reduced the risk of death by 31% vs placebo, with a favorable safety profile in patients (pts) with nmCRPC (ARAMIS study; NCT02200614). We report long-term safety and tolerability with continued DARO treatment in the ARAMIS Rollover Study (ROS; NCT04464226). Methods: Following the primary analysis of double-blind (DB) treatment, the ARAMIS study was unblinded, and all pts were permitted to continue on open-label (OL) DARO. After study completion, pts could continue DARO in the ROS if they had no evidence of metastases and were benefitting clinically. Of 955 pts initially randomized to DARO, 954 pts started DB DARO, 466 continued to OL DARO, and 294 entered the ROS. Pts received DARO 600 mg orally twice daily. DARO safety and treatment duration are described for the 954 pts over the DB, DB+OL, and DB+OL+ROS periods, with a data cutoff of Jan 31, 2022. Results: The median (range) treatment duration was 1.5 y (0.0–4.0) for DB DARO, 2.1 y (0.0–4.9) for DB+OL DARO, and 2.8 y (0.0–6.8) for DB+OL+ROS DARO. By the data cutoff date, 62.4% of the 954 pts had received DARO for ≥2 years, 30.1% for ≥4 years, and 12.8% for ≥5 yrs; 24.0% were still receiving DARO at data cutoff. Incidences of treatment-emergent adverse events (TEAEs) increased slightly as expected with longer observation time: any grade (DB 85.7%; DB+OL 89.8%; DB+OL+ROS 91.5%), grade 3/4 (26.3%; 31.8%; 35.5%), serious (26.1%; 32.1%; 38.5%), and leading to treatment discontinuation (8.9%; 10.5%; 12.9%). Increases in incidences of TEAEs of special interest across the DB, DB+OL, and DB+OL+ROS periods were mostly minimal. Conclusions: Approximately 30% of pts with nmCRPC remained on DARO for ≥4 y, suggesting long-term clinical benefit. The favorable safety profile of DARO was maintained with long-term exposure. No new safety concerns were observed with longer DARO treatment in the ROS. Clinical trial information: NCT04464226 . [Table: see text]

Background and objectives: Teverelix drug product (DP) is a gonadotropin-releasing hormone antagonist in development for the treatment of patients with prostate cancer in whom androgen deprivation therapy is indicated. The aim of this paper is to present the results of five Phase 2 studies that assessed the pharmacokinetics, pharmacodynamics, efficacy and safety of different loading dose regimens of teverelix DP. Methods: Five single-arm, uncontrolled clinical trials were conducted in patients with advanced prostate cancer. The five different loading dose regimens of teverelix DP tested were (a) a single 90 mg subcutaneous (SC) injection of teverelix DP given on 3 consecutive days (Days 0, 1 and 2); (b) a single 90 mg intramuscular (IM) injection of teverelix DP given 7 days apart (Days 0 and 7); (c) a single 120 mg SC injection of teverelix DP given on 2 consecutive days (Days 0 and 1); (d) 2 × 60 mg SC injections of teverelix DP given on 3 consecutive days (Days 0, 1 and 2), and (e) 2 × 90 mg SC injections of teverelix DP given on 3 consecutive days (Days 0, 1 and 2). The primary efficacy parameter was the duration of action of an initial loading dose regimen in terms of suppression of testosterone to below the castration level (0.5 ng/mL). Results: Eighty-two patients were treated with teverelix DP. Two regimens (90 mg and 180 mg SC on 3 consecutive days) had a mean duration of castration of 55.32 days and 68.95 days with >90% of patients having testosterone levels < 0.5 ng/mL at Day 28. The mean onset of castration for the SC regimens ranged from 1.10 to 1.77 days, while it was slower (2.4 days) with IM administration. The most common adverse event (AE) was injection site reaction. No AEs of severe intensity were reported. Conclusions: Teverelix DP is safe and well tolerated. Castrate levels of testosterone can be rapidly achieved following the subcutaneous injection of teverelix DP on 3 consecutive days. Streamlining of the administration of the loading dose and identifying a suitable maintenance dose will be investigated in future trials.

Background: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have a high risk of progression to metastatic disease, particularly if their prostate-specific antigen doubling time (PSADT) is <6 mo. However, patients remain at a high risk with a PSADT of >6 mo. Objective: To evaluate the efficacy and safety of darolutamide versus placebo in patients stratified by PSADT >6 or <6 mo. Design, setting, and participants: A planned subgroup analysis of a global multicenter, double-blind, randomized, phase 3 trial in men with nmCRPC and PSADT <10 mo was conducted. Intervention: Patients were randomized 2:1 to oral darolutamide 600 mg twice daily or placebo, while continuing androgen-deprivation therapy. Outcome measurements and statistical analysis: The primary endpoint was metastasis-free survival (MFS). Secondary endpoints were overall survival (OS) and times to pain progression, first cytotoxic chemotherapy, and symptomatic skeletal events. Quality of life (QoL) was measured using validated prostate-relevant tools. Safety was recorded throughout the study. Results and limitations: Of 1509 patients enrolled, 469 had PSADT >6 mo (darolutamide n = 286; placebo n = 183) and 1040 had PSADT <6 mo (darolutamide n = 669; placebo n = 371). Baseline characteristics were balanced between subgroups. Darolutamide sig-nificantly prolonged MFS versus placebo in both subgroups (unstratified hazard ratio [95% confidence interval]: PSADT >6 mo, 0.38 [0.26-0.55]; PSADT <6 mo, 0.41 [0.33- 0.52]). OS and other efficacy and QoL endpoints favored darolutamide with significant improvement over placebo in both subgroups. The incidence of adverse events, including events commonly associated with androgen receptor inhibitors (fractures, falls, hyper-tension, and mental impairment), and discontinuations due to adverse events were low and similar to placebo. Limitations include small subgroup populations. Conclusions: In patients with nmCRPC and PSADT >6 mo (maximum 10 mo), darolu-tamide provided a favorable benefit/risk ratio, characterized by significant improve-ments in MFS, OS, and other clinically relevant endpoints; maintenance of QoL; and favorable tolerability. Patient summary: In patients with prostate cancer that has stopped responding to stan-dard hormonal therapy (indicated by an increase in prostate-specific antigen [PSA] levels), there is a risk that the cancer will spread to other parts of the body. This risk is highest when the time it takes for the PSA level to double (ie, "PSA doubling time"[PSADT]) is less than 6 mo. However, there is still a risk that the cancer will spread even if the PSADT is longer than 6 mo. In a group of patients whose PSADT was more than 6 mo but no more than 10 mo, treatment with darolutamide slowed the cancer spread and allowed them to live longer than patients who received placebo (inactive drug). Darolutamide treatment did not cause many side effects and helped maintain patients' quality of life without disruptions. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY-NC-ND license (http://creative-commons.org/licenses/by-nc-nd/4.0/).