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Background: Pathological stage and grade of renal pelvis urothelial carcinoma (RPUC) are difficult to estimate before radical nephroureterectomy (RNU). Objective: To examine tumor size as an independent predictor of muscle-invasive and/or non–organ-confined rates of RPUC at RNU. Design, setting, and participants: Within the Surveillance, Epidemiology and End Results (SEER) database (2004–2016), we identified nonmetastatic RPUC at RNU. Outcome measurements and statistical analysis: First, we examined stage and grade distributions. Second, two separate univariable and subsequent multivariable logistic regression models (LRMs) were fitted to test the association between tumor size and the rate of (1) muscle-invasive or higher (pT2–4N0–2) and (2) non–organ-confined (pT3–4N0–2) RPUC at RNU. Results and limitations: Of 4657 patients, 3052 (65.5%) had pT2–4N0–2 and 2382 (51.2%) pT3–4N0–2 RPUC at RNU. The median tumor size was 3.7 cm (interquartile range 2.5–5.0). The high-grade RPUC rate ranged from 71.1% to 87.2% (p < 0.001) among SEER registries. Conversely, no differences were recorded for stage (p > 0.05) or tumor size (p = 0.1) across all registries. Rates of pT2–4N0–2 and pT3–4N0–2 RPUC increased with tumor size. Specifically, for tumor size intervals from 0.1–1.0 cm to 9.1–10.0 cm, the pT2–4N0–2 rate ranged from 45% to 83% and the pT3–4N0–2 rate ranged from 23% to 75%, respectively (both p < 0.001). In multivariable LRMs, tumor size (in 1-cm units) was an independent predictor of pT2–4N0–2 (odds ratio [OR] 1.25; p < 0.001) and pT3–4N0–2 (OR 1.30; p < 0.001) disease at RNU. Conclusions: Tumor size is a key predictor of muscle-invasive or non–organ-confined RPUC. Greater tumor size directly and virtually linearly predicts a higher rate of invasive or non–organ-confined RPUC at RNU. Patient summary: For patients with cancer in urinary tract cells lining the kidney, larger tumor size predicts worse stage of the disease at surgery.

Background: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations. Methods: Three separate TMA sets were built that differ by purpose and disease state. Results: The intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases. Conclusions: The GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation. Impact: This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment.

Purpose:Our goal was to compare cancer specific mortality (CSM) rates between radical prostatectomy (RP) vs external beam radiotherapy (EBRT) in National Comprehensive Cancer Network© (NCCN©) high ...

Lay abstract Patients with metastatic castration-resistant prostate cancer are often first treated with novel hormonal therapy (NHT) using abiraterone or enzalutamide. To aid decisions about what treatment to use next, we reviewed information about patients who were treated with an alternative NHT (226 patients) or the nuclear medicine radium-223 (120 patients) after the first NHT. Most patients given radium-223 had cancer that had spread to their bones only, whereas many patients given an alternative NHT had cancer in their bones and other parts of their body. Around one in four patients given radium-223 and one in five given an alternative NHT had symptoms related to their bone metastases after starting treatment. Five in every ten patients given radium-223 received further therapy, including chemotherapy in 50% of these patients, while four in every ten patients given an alternative NHT received further therapy, including chemotherapy in 75%. On average, patients lived for almost a year after starting radium-223 or an alternative NHT.

Background Life expectancy (LE) is an important consideration in the clinical decision-making for T1aN0M0 renal cell cancer (RCC) patients. Objective To test the effect of race/ethnicity (Caucasian, African American, Hispanic/Latino, and Asian) on LE predictions from Social Security Administration (SSA) life tables in male and female T1aN0M0 RCC patients. Design, setting, and participants We relied on the Surveillance, Epidemiology, and End Results database. Intervention Radical nephrectomy (RN) and partial nephrectomy (PN). Outcome measurements and statistical analysis Five-year and 10-yr observed overall survival (OS) of pT1aN0M0 RCC patients treated between 2004 and 2006 were compared with the LE predicted from SSA life tables. We repeated the comparison in a more contemporary cohort (2009–2011), with 5-yr follow-up and higher PN rates. Results and limitations In the 2004–2006 cohort, PN rate was 40.7%. OS followed the predicted LE in Caucasians, Hispanics/Latinos, and Asians, but not in African Americans, in whom 5-yr OS rates were 5.0% (male) and 8.7% (female) and 10-yr rates were 4.2% (male) and 11.1% (female) lower than predicted. In the 2009–2011 cohort, PN rate was 59.4%. Same observations were made for OS versus predicted LE in Caucasians, Hispanics/Latinos, and Asians. In African Americans, 5-yr OS rates were 1.5% (male) and 4.9% (female) lower than predicted. Conclusions In RN- or PN-treated pT1aN0M0 RCC patients, LE predictions closely approximated OS of Caucasians, Hispanics/Latinos, and Asians. In African-American patients, SSA life tables overestimated LE, more in females than in males. The limitations of our study are its retrospective nature, its validity for US patients only, and the under-representation of racial/ethnic minorities. Patient summary Social Security Administration life tables can be used to estimate long-term life expectancy in patients who are surgically treated for renal cancer (≤4 cm). However, while for Caucasians, Hispanics/Latinos, and Asians, the prediction performs well, life expectancy of African Americans is generally overestimated by life table predictions. Take Home Message In the clinical decision-making process for T1aN0M0 renal cell cancer patients eligible for radical or partial nephrectomy, the important influence of patient sex and race/ethnicity on life expectancy should be taken into account, when using Social Security Administration life tables.

Background Docetaxel has immunostimulatory effects that may promote an immunoresponsive prostate tumour microenvironment, providing a rationale for combination with nivolumab (programmed death-1 inhibitor) for metastatic castration-resistant prostate cancer (mCRPC). Methods In the non-randomised, multicohort, global phase II CheckMate 9KD trial, 84 patients with chemotherapy-naive mCRPC, ongoing androgen deprivation therapy and ≤2 prior novel hormonal therapies (NHTs) received nivolumab 360 mg and docetaxel 75 mg/m2 every 3 weeks with prednisone 5 mg twice daily (≤10 cycles) and then nivolumab 480 mg every 4 weeks (≤2 years). The co-primary end-points were objective response rate (ORR) and prostate-specific antigen response rate (PSA50-RR; ≥50% decrease from baseline). Results The confirmed ORR (95% confidence interval [CI]) was 40.0% (25.7–55.7), and the confirmed PSA50-RR (95% CI) was 46.9% (35.7–58.3). The median (95% CI) radiographic progression-free survival (rPFS) and overall survival (OS) were 9.0 (8.0–11.6) and 18.2 (14.6–20.7) months, respectively. In subpopulations with versus without prior NHT, the ORR was 38.7% versus 42.9%, the PSA50-RR was 39.6% versus 60.7%, the median rPFS was 8.5 versus 12.0 months and the median OS was 16.2 months versus not reached. Homologous recombination deficiency status or tumour mutational burden did not appear to impact efficacy. The most common any-grade and grade III–IV treatment-related adverse events were fatigue (39.3%) and neutropenia (16.7%), respectively. Three treatment-related deaths occurred (1 pneumonitis related to nivolumab; 2 pneumonias related to docetaxel). Conclusions Nivolumab plus docetaxel has clinical activity in patients with chemotherapy-naive mCRPC. Safety was consistent with the individual components. These results support further investigation in the ongoing phase III CheckMate 7DX trial. ClinicalTrials.gov registration NCT03338790.

Background: For patients with nonmetastatic renal cell carcinoma (nmRCC) treated with nephrectomy, prediction of cancer-specific mortality (CSM) by T stage and substage has not been validated for the separate histological subtypes. Objective: To investigate the ability of pathological T stage and substage to predict CSM for patients with clear-cell, papillary, or chromophobe nmRCC treated with nephrectomy. Design, setting, and participants: Using the SEER database for 2004–2016, we identified 87 149 patients with T1–4 N0/X M0 nmRCC treated with nephrectomy for the clear-cell (65 715; 75.4%), papillary (14 587; 16.7%), or chromophobe (6847; 7.9%) histological subtype. Outcome measurements and statistical analysis: Kaplan-Meier plots and Cox regression models were used to estimate CSM. Results and limitations: For all three histological subtypes, patients with T1a–T3a disease exhibited more favorable CSM than patients with T3b–T4 RCC. For clear-cell RCC, there were clinically meaningful and statistically significant differences for virtually all intergroup comparisons among T1a–T3a stages. For papillary T1a–T3a RCC, clinically meaningful differences disappeared, although the statistical significance remained. For chromophobe T1a–T3a RCC, no clinically meaningful or statistically significant differences were observed. For all three histological subtypes, patients with T3b–T4 RCC exhibited virtually uniformly unfavorable CSM, with no clinically meaningful intergroup CSM differences. Conclusion: The use of T stage and substage for stratification of patients with nmRCC treated with nephrectomy revealed differences in CSM among T1a–T3a cases, but not T3b–T4. The magnitude of the CSM difference was greatest for clear-cell, intermediate for papillary, and marginal for chromophobe RCC. Patient summary: For patients with kidney cancer, the stage of their disease assessed after surgery on the affected kidney can predict how likely they are to die from their cancer. This prediction varies for different subtypes of kidney cancer. Stratification of surgically treated patients with nonmetastatic renal cell carcinoma (RCC) by T stage revealed mortality differences among T1a–T3a cases, but not T3b–T4 cases. The magnitude of the differences was greatest for the clear-cell subtype, intermediate for papillary histology, and marginal for chromophobe RCC.

BACKGROUND: Enzalutamide combined with androgen deprivation therapy (ADT) significantly prolonged metastasis-free survival and overall survival (OS) versus ADT alone in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) with rapidly rising prostate-specific antigen (PSA). The objective of this post hoc analysis of the PROSPER trial is to evaluate OS benefit and safety of enzalutamide in patients across age and regional subgroups. PATIENTS AND METHODS: Eligible men with nmCRPC, PSA doubling time ≤10 months and PSA ≥2 ng/mL with continued ADT use were randomised 2:1 to enzalutamide 160 mg or placebo. OS and safety were examined by age (

OBJECTIVE To determine the prevalence of intra-patient inter-metastatic heterogeneity based on positron emission tomography (PET)/computed tomography (CT) in patients with metastatic castration-resistant prostate cancer (mCRPC) and to determine the prevalence of neuroendocrine disease in these patients and their eligibility for radioligand therapies (RLTs). PATIENTS AND METHODS This multicentre observational prospective clinical study will include 100 patients with mCRPC from five Canadian academic centres. Patients with radiological or biochemical progression and harbouring at least three metastases by conventional imaging will be accrued. Intra-patient inter-metastatic heterogeneity will be determined with triple-tracer imaging using fluorine-18 fluorodeoxyglucose (18 F-FDG), gallium-68-(68 Ga)-prostate-specific membrane antigen (PSMA)-617 and 68 Ga-DOTATATE, which are a glucose analogue, a PSMA receptor ligand and a somatostatin receptor ligand, respectively. The 68 Ga-PSMA-617 and 18 F-FDG PET/CT scans will be performed first. If at least one PSMA-negative/FDG-positive lesion is observed, an additional PET/CT scan with 68 Ga-DOTATATE will be performed. The tracer uptake of individual lesions will be assessed for each PET tracer and patients with lesions presenting discordant uptake profiles will be considered as having inter-metastatic heterogeneous disease and may be offered a biopsy. EXPECTED RESULTS The proposed triple-tracer approach will allow whole-body mCRPC characterisation, investigating the inter-metastatic heterogeneity in order to better understand the phenotypic plasticity of prostate cancer, including the neuroendocrine transdifferentiation that occurs during mCRPC progression. Based on 68 Ga-PSMA-617 or 68 Ga-DOTATATE PET positivity, the potential eligibility of patients for PSMA and DOTATATE-based RLT will be assessed. Non-invasive whole-body determination of mCRPC heterogeneity and transdifferentiation is highly innovative and might establish the basis for new therapeutic strategies. Comparison of molecular imaging findings with biopsies will also link metastasis biology to radiomic features. CONCLUSION This study will add novel, biologically relevant dimensions to molecular imaging: the non-invasive detection of inter-metastatic heterogeneity and transdifferentiation to neuroendocrine prostate cancer by using a multi-tracer PET/CT strategy to further personalise the care of patients with mCRPC.

Purpose To test for differences in cancer-specific mortality (CSM) rates in Hispanic/Latino prostate cancer patients according to treatment type, radical prostatectomy (RP) vs external beam radiotherapy (EBRT). Methods Within the Surveillance, Epidemiology, and End Results database (2010–2016), we identified 2290 NCCN (National Comprehensive Cancer Network) high-risk (HR) Hispanic/Latino prostate cancer patients. Of those, 893 (39.0%) were treated with RP vs 1397 (61.0%) with EBRT. First, cumulative incidence plots and competing risks regression models tested for CSM differences after adjustment for other cause mortality (OCM). Second, cumulative incidence plots and competing risks regression models were refitted after 1:1 propensity score matching (according to age, PSA, biopsy Gleason score, cT-stage, cN-stage). Results In NCCN HR patients, 5-year CSM rates for RP vs EBRT were 2.4 vs 4.7%, yielding a multivariable hazard ratio of 0.37 (95% CI 0.19–0.73, p = 0.004) favoring RP. However, after propensity score matching, the hazard ratio of 0.54 was no longer statistically significant (95% CI 0.21–1.39, p = 0.2). Conclusion Without the use of strictest adjustment for population differences, NCCN high-risk Hispanic/Latino prostate cancer patients appear to benefit more of RP than EBRT. However, after strictest adjustment for baseline patient and tumor characteristics between RP and EBRT cohorts, the apparent CSM benefit of RP is no longer statistically significant. In consequence, in Hispanic/Latino NCCN high-risk patients, either treatment modality results in similar CSM outcome.

Summary Background The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC. Methods ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone–prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone–prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov , number NCT02257736 . Findings 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone–prednisone; 490 to abiraterone–prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0–28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4–27·4) in the apalutamide plus abiraterone–prednisone group versus 16·6 months (13·9–19·3) in the abiraterone–prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58–0·83; p Interpretation Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone–prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC. Funding Janssen Research & Development.

Introduction: Over the last decade, multiple clinical trials demonstrated improved survival after chemotherapy for metastatic prostate cancer (mPCa). However, real-world data validating this effect within large-scale epidemiological data sets are scarce. We addressed this void. Materials and Methods: Men with de novo mPCa were identified and systemic chemotherapy status was ascertained within the Surveillance, Epidemiology, and End Results database (2004–2016). Patients were divided between historical (2004–2013) versus contemporary (2014–2016). Chemotherapy rates were plotted over time. Kaplan–Meier plots and Cox regression models with additional multivariable adjustments addressed overall and cancer-specific mortality. All tests were repeated in propensity-matched analyses. Results: Overall, 19,913 patients had de novo mPCa between 2004 and 2016. Of those, 1838 patients received chemotherapy. Of 1838 chemotherapy-exposed patients, 903 were historical, whereas 905 were contemporary. Chemotherapy rates increased from 5% to 25% over time. Median overall survival was not reached in contemporary patients versus was 24 months in historical patients (hazard ratio [HR]: 0.55, p

Purpose To compare Cancer-specific mortality (CSM) in patients with Squamous cell carcinoma (SCC) vs. non-SCC penile cancer, since survival outcomes may differ between histological subtypes. Methods Within the Surveillance, Epidemiology and End Results database (2004–2016), penile cancer patients of all stages were identified. Temporal trend analyses, cumulative incidence and Kaplan–Meier plots, multivariable Cox regression and Fine and Gray competing-risks regression analyses tested for CSM differences between non-SCC vs. SCC penile cancer patients. Results Of 4,120 eligible penile cancer patients, 123 (3%) harbored non-SCC vs. 4,027 (97%) SCC. Of all non-SCC patients, 51 (41%) harbored melanomas, 42 (34%) basal cell carcinomas, 10 (8%) adenocarcinomas, eight (6.5%) skin appendage malignancies, six (5%) epithelial cell neoplasms, two (1.5%) neuroendocrine tumors, two (1.5%) lymphomas, two (1.5%) sarcomas. Stage at presentation differed between non-SCC vs. SCC. In temporal trend analyses, non-SCC diagnoses neither decreased nor increased over time (p > 0.05). After stratification according to localized, locally advanced, and metastatic stage, no CSM differences were observed between non-SCC vs. SCC, with 5-year survival rates of 11 vs 11% (p = 0.9) for localized, 33 vs. 37% (p = 0.4) for locally advanced, and 1-year survival rates of 37 vs. 53% (p = 0.9) for metastatic penile cancer, respectively. After propensity score matching for patient and tumor characteristics and additional multivariable adjustment, no CSM differences between non-SCC vs. SCC were observed. Conclusion Non-SCC penile cancer is rare. Although exceptions exist, on average, non-SCC penile cancer has comparable CSM as SCC penile cancer patients, after stratification for localized, locally invasive, and metastatic disease.

High mortality of prostate cancer patients is primarily due to metastasis. Understanding the mechanisms controlling metastatic processes remains essential to develop novel therapies designed to prevent the progression from localized disease to metastasis. CdGAP plays important roles in the control of cell adhesion, migration, and proliferation, which are central to cancer progression. Here we show that elevated CdGAP expression is associated with early biochemical recurrence and bone metastasis in prostate cancer patients. Knockdown of CdGAP in metastatic castration-resistant prostate cancer (CRPC) PC-3 and 22Rv1 cells reduces cell motility, invasion, and proliferation while inducing apoptosis in CdGAP-depleted PC-3 cells. Conversely, overexpression of CdGAP in DU-145, 22Rv1, and LNCaP cells increases cell migration and invasion. Using global gene expression approaches, we found that CdGAP regulates the expression of genes involved in epithelial-to-mesenchymal transition, apoptosis and cell cycle progression. Subcutaneous injection of CdGAP-depleted PC-3 cells into mice shows a delayed tumor initiation and attenuated tumor growth. Orthotopic injection of CdGAP-depleted PC-3 cells reduces distant metastasic burden. Collectively, these findings support a pro-oncogenic role of CdGAP in prostate tumorigenesis and unveil CdGAP as a potential biomarker and target for prostate cancer treatments., Mehra et al. investigate the role of CdGAP in early biochemical recurrence and bone metastasis in prostate cancer. The authors find that knocking down CdGAP leads to reduced cell motility, invasion and proliferation in PC-3 and 22Rv1 cells while orthotopic injection of CdGAP-depleted PC-3 cells reduces distant metastatic burden.

Background The efficacy of tyrosine kinase inhibitor (TKI)-based therapy after previous immuno-oncology therapy (IO) failure has been addressed before. However, summary efficacy estimates have never been generated in these reports. We addressed this void. Material and methods We systematically examined TKI efficacy after IO-failure and generated weighted median progression-free survival (PFS) estimates for Pazopanib, Axitinib, Cabozantinib, Sunitinib. A systematic review according to PRISMA was conducted. PubMed and abstracts were queried. Only studies proving median PFS were included. Weighted medians were computed for each TKI alternative. Results Of 245 articles, nine eligible studies were included in the current study with 952 analysed patients. Weighted PFS medians after any previous IO-based therapy were respectively 13.7 (range from 4.6 to 24.4), 8.1 (range from 4.7 to 13.2), 8.5 (range from 4.7 to 15.2) and 6.9 months (range from 2.9 to 11.6) for Pazopanib, Axitinib, Cabozantinib, Sunitinib. Specific second-line weighted PFS median was 14.8 months (range from 5.6 to 24.4), 10.1 months (range from 6.4 to 13.2), 8.7 months (range from 4.7 to 15.2) and 6.0 months (range from 2.9 to 8.0) for Pazopanib, Axitinib, Cabozantinib, Sunitinib, respectively, after first-line IO. Conclusion Pazopanib results in the longest weighted median PFS, after previous IO-failure, regardless of treatment line, as well as in specific second-line, post-first-line IO failure settings. Pending novel studies, Pazopanib appears to represent the most promising treatment option after prior IO.

Race/ethnicity may predispose to less favorable prostate cancer characteristics in intermediate risk prostate cancer (IR PCa) patients. We tested this hypothesis in a subgroup of IR PCa patients treated with radical prostatectomy (RP). We relied on the Surveillance, Epidemiology and End Results 2004–2016. The effect of race/ethnicity was tested in univariable and multivariable logistic regression analyses predicting upstaging (pT3+/pN1) and/or upgrading (Gleason Grade Group [GGG] 4–5) at RP. Of 20,391 IR PCa patients, 15,050 (73.8%) were Caucasian, 2857 (14.0%) African-American, 1632 (8.0%) Hispanic/Latino and 852 (4.2%) Asian. Asian patients exhibited highest age (64 year), highest PSA (6.8 ng/ml) and highest rate of GGG3 (31.9%). African-Americans exhibited the highest percentage of positive cores at biopsy (41.7%) and the highest proportion of NCCN unfavorable risk group membership (54.6%). Conversely, Caucasians exhibited the highest proportion of cT2 stage (35.6%). In univariable analyses, Hispanic/Latinos exhibited the highest rates of upstaging/upgrading among all race/ethnicities, in both favorable and unfavorable groups, followed by Asians, Caucasians and African-Americans in that order. In multivariable analyses, Hispanic/Latino race/ethnicity represented an independent predictor of higher upstaging and/or upgrading in favorable IR PCa (odds ratio [OR] 1.27, p

Background To test the effect of urological primary cancers (bladder, kidney, testis, upper tract, penile, urethral) on overall mortality (OM) after secondary prostate cancer (PCa). Methods Within the Surveillance, Epidemiology and End Results (SEER) database, patients with urological primary cancers and concomitant secondary PCa (diagnosed 2004-2016) were identified and were matched in 1:4 fashion with primary PCa controls. OM was compared between secondary and primary PCa patients and stratified according to primary urological cancer type, as well as to time interval between primary urological cancer versus secondary PCa diagnoses. Results We identified 5,987 patients with primary urological and secondary PCa (bladder, n = 3,287; kidney, n = 2,127; testis, n = 391; upper tract, n = 125; penile, n = 47; urethral, n = 10) versus 531,732 primary PCa patients. Except for small proportions of Gleason grade group and age at diagnosis, PCa characteristics between secondary and primary PCa were comparable. Conversely, proportions of secondary PCa patients which received radical prostatectomy were smaller (29.0 vs. 33.5%), while no local treatment rates were higher (34.2 vs. 26.3%). After 1:4 matching, secondary PCa patients exhibited worse OM than primary PCa patients, except for primary testis cancer. Here, no OM differences were recorded. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis. Conclusions After detailed matching for PCa characteristics, secondary PCa patients exhibit worse survival, except for testis cancer patients. The survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary urological cancer diagnosis.

Background Controversy still exists regarding efficacy of multimodality treatment (MMT) vs. radical cystectomy (RC) for urothelial carcinoma of the urinary bladder (UCUB). Methods Within the SEER database (2004-2016), we retrospectively identified patients with stage T2N0M0 UCUB. Competing risks regression (CRR) tested cancer-specific mortality (CSM) and adjusted for other-cause mortality after MMT vs. RC. Exact matching for age was applied. Subgroup analyses focused on differences in chemotherapy or lymph node dissection rates. In sensitivity analyses, we accounted for 40% understaging rate in patients who underwent MMT. Results Of 9862 patients with T2N0M0 UCUB, 2675 (27.1%) underwent MMT vs. 5751 (58.3%) RC vs. 1436 (14.6%) radiotherapy (RT) without chemotherapy. MMT rate increased (annually +3.0%, P Conclusion In patents with T2N0M0, MMT or even more so RT alone may be associated with higher CSM than RC, even in exact age-matched multivariate CRR analyses, which adjust for other-cause mortality. In consequence, patients with T2 UCUB should be informed of this possible CSM disadvantage outside of highly specialized centers.

We hypothesized that differences in active treatment rates may exist according to race/ethnicity in favorable as well as unfavorable intermediate risk prostate cancer.We relied on the Surveillance, Epidemiology, and End Results 18 database 2010-2015. We stratified according to 3 racial/ethnic groups (White vs Black vs Hispanic) and prostate cancer baseline characteristics (prostate specific antigen, clinical T stage, Gleason group grading, percentage of biopsy cores). We tabulated active treatment rates (radical prostatectomy, external beam radiotherapy) without and with adjustment for baseline age and prostate cancer characteristics.Baseline prostate specific antigen, clinical T stage, Gleason grade and percentage of positive biopsy cores differed according to racial/ethnic groups in both favorable and unfavorable intermediate risk prostate cancer patients (all p0.05). Similarly, radical prostatectomy and external beam radiotherapy rates differed according to race/ethnicity in both favorable and unfavorable intermediate risk prostate cancer patients. Radical prostatectomy and external beam radiotherapy rates respectively ranged from 31.7%-41.8% and 26.3%-31.0% in favorable intermediate risk cases and from 33.4%-43.9% and 30.9%-35.5% in unfavorable intermediate risk prostate cancer, across the 3 race/ethnicity groups (both p0.05). The above heterogeneity in active treatment rates disappeared and marginal differences remained after adjustment for baseline age and prostate cancer characteristics.Interpretation of active treatment rates in favorable and unfavorable intermediate risk prostate cancer may be severely biased, unless detailed and systematic consideration or adjustment for baseline age and prostate cancer characteristic is enforced.

Recently, an increase in the rates of high-risk prostate cancer (PCa) was reported. We tested whether the rates of and low, intermediate, high and very high-risk PCa changed over time. We also tested whether the number of prostate biopsy cores contributed to changes rates over time.Within the Surveillance, Epidemiology and End Results (SEER) database (2010-2015), annual rates of low, intermediate, high-risk according to traditional National Comprehensive Cancer Network (NCCN) and high versus very high-risk PCa according to Johns Hopkins classification were tabulated without and with adjustment for the number of prostate biopsy cores.In 119,574 eligible prostate cancer patients, the rates of NCCN low, intermediate, and high-risk PCa were, respectively, 29.7%, 47.8%, and 22.5%. Of high-risk patients, 39.6% and 60.4% fulfilled high and very high-risk criteria. Without adjustment for number of prostate biopsy cores, the estimated annual percentage changes (EAPC) for low, intermediate, high and very high-risk were respectively -5.5% (32.4%-24.9%, p .01), +0.5% (47.6%-48.4%, p = .09), +4.1% (8.2%-9.9%, p .01), and +8.9% (11.8%-16.9%, p .01), between 2010 and 2015. After adjustment for number of prostate biopsy cores, differences in rates over time disappeared and ranged from 29.8%-29.7% for low risk, 47.9%-47.9% for intermediate risk, 8.9%-9.0% for high-risk, and 13.6%-13.6% for very high-risk PCa (all p .05).The rates of high and very high-risk PCa are strongly associated with the number of prostate biopsy cores, that in turn may be driven by broader use magnetic resonance imaging (MRI).

Introduction Prostate cancer (PC) is the most common cancer in North American men. Advanced PC is incurable. The androgen receptor antagonist enzalutamide is used to manage advanced PC, often over a period of months or years; it is therefore important to evaluate the safety profile of enzalutamide. Areas covered This literature review presents safety data from pivotal trials and real-world data studies of enzalutamide in patients with advanced PC, including metastatic hormone-sensitive prostate cancer (mHSPC), nonmetastatic castration-resistant prostate cancer (nmCRPC), and metastatic castration-resistant prostate cancer (mCRPC). A large body of evidence supports the maintenance or improvement in the health-related quality of life (HRQoL) afforded by enzalutamide treatment in patients with mHSPC, nmCRPC, or chemotherapy-naive mCRPC, as well as improvement in the HRQoL in patients with later-stage symptomatic mCRPC. Efficacy data from clinical trials are also briefly discussed. Expert opinion We aim to provide clinicians with a better understanding of how to properly interpret enzalutamide clinical trial safety data. This knowledge may help clinicians guide their patients with PC to achieve optimal clinical benefit from enzalutamide therapy, and to properly manage their patients to mitigate any potential risk.

To externally validate the STAR-CAP prognostic system for prostate cancer (PCa) and compare it to the CAPRA score to predict for biochemical recurrence (BCR) after radiation therapy (RTx). We included patients treated with RTx between 2002 and 2021 for non-metastatic PCa at our institution. BCR was defined based on Phoenix criteria. The 5-year BCR-free survival was assessed by univariable Kaplan–Meier analyses and log-rank test. Multivariable Cox regression models tested the independent association of each model for BCR. Performance of both models to predict 5-year BCR-free survival was assessed using the area under the curve (AUC). The 2768 patients included were treated with high dose rate brachytherapy (13.3%) as a boost to external beam radiation therapy (EBRT), low dose rate seed brachytherapy (50.4%) or EBRT alone (35.9%). 14.4% of patients received concomitant androgen deprivation therapy (ADT). 222 patients experienced BCR (8%), with a median follow-up of 56 months. The 5-year BCR-free survival ranged from 88 (high risk) to 96% (low risk) in the STAR-CAP classification, and from 87 (high risk) to 97% (low risk) in the CAPRA system (p

Optimal management of metastatic non-clear cell renal cell carcinoma (non-ccmRCC) remains largely unknown.To test the effect of systemic therapy (ST) and/or cytoreductive nephrectomy (CNT) on overall mortality (OM) in patients with non-ccmRCC.Within the Surveillance, Epidemiology and End Results (SEER) registry (2006-2015), we identified patients with papillary, chromophobe, sarcomatoid, and collecting duct metastatic renal cell carcinoma (mRCC).Temporal trends (estimated annual percentage change [EAPC]), Kaplan-Meier plots, and multivariable Cox regression models were used.Of 1573 patients with non-ccmRCC, 22%, 25%, 25%, and 28% underwent no treatment, ST, CNT, and CNT with ST, respectively. Between 2006 and 2015, rates of CNT and the combination of CNT and ST decreased (EAPC: -6.3% and -3.2%, respectively). Conversely, rates of no treatment and ST increased over time (EAPC: 4.6% and 7.5%, respectively). In multivariable Cox regression models, relative to no treatment, ST (hazard ratio [HR]: 0.5; p0.001), CNT (HR: 0.4; p0.001), and CNT with ST (HR: 0.3; p0.001) were associated with lower OM. Histological subtypes were associated with OM, relative to papillary renal cell carcinoma (RCC): chromophobe (HR: 0.7; p0.01), sarcomatoid (HR: 2.1; p0.001), and collecting duct RCC (HR: 1.9; p0.001). Limitations include the impossibility to stratify patients according to mRCC risk groups.Most non-ccmRCC patients are treated with a combination of CNT and ST or CNT alone or ST alone. The rates of ST alone are increasing. Conversely, the rates of combined CNT and ST and CNT alone are decreasing. These observed temporal patterns of treatment rates are counterintuitive with respect to associated OM benefits, where combination of CNT and ST, as well as CNT alone, resulted in the lowest absolute OM, relative to ST alone, or, even worse, no treatment.We investigated the effect of treatment modalities on survival of patients with metastatic non-clear cell renal cell carcinoma. The combination of cytoreductive nephrectomy and systemic therapy confers greater benefit with respect to single treatments alone.

To evaluate stage at presentation and cancer-specific mortality (CSM) in upper urinary tract tumors according to histologic subtype.Within the Surveillance, Epidemiology, and End Results registry (SEER, 2004-2016), we identified patients with upper urinary tract tumors with pure variant histology (UTVH) and pure upper urinary tract urothelial carcinoma (UTUC). Cumulative incidence plots, after propensity score matching for tumor and patient characteristics, addressed CSM. Subgroup analyses addressed efficacy of radical nephroureterectomy (RNU) in stage T1-2 and of chemotherapy in metastatic UTVH patients.Of all 11,809 upper urinary tract tumor patients, 154 (1.3%) harbored squamous cell carcinoma (SCC), 86 (0.7%) adenocarcinoma, 39 (0.3%) neuroendocrine carcinoma, 38 (0.3%) other UTVH, and 11,492 (97.3%) UTUC. UTVH patients were more likely to exhibit metastatic stage disease at diagnosis than UTUC (odds ratio, 1.9; 95% confidence interval, 1.3-2.8; P .01). After detailed matching for performance status, only SCC showed significantly higher CSM than UTUC (multivariate HR = 1.71; P .01). Subgroup analyses in stage T1-2 RNU patients showed, relative to UTUC patients, no CSM differences for SCC or adenocarcinoma patients. No significant survival benefit for chemotherapy administration was identified in patients with metastatic SCC or metastatic adenocarcinoma. This study is limited by its sample size and the missing centralized pathologic review.Disease stage at diagnosis is more advanced in UTVH patients than UTUC. Across all stages, CSM is higher for SCC than for UTUC. However, in T1-2 stage disease, RNU results in similar survival in SCC or adenocarcinoma versus UTUC.

Background Nonmetastatic castration-resistant prostate cancer (nmCRPC) is defined as a rising prostate-specific antigen concentration, despite castrate levels of testosterone with ongoing androgen-deprivation therapy or orchiectomy, and no detectable metastases by conventional imaging. Patients with nmCRPC progress to metastatic disease and are at risk of developing cancer-related symptoms and morbidity, eventually dying of their disease. While patients with nmCRPC are generally asymptomatic from their disease, they are often older and have chronic comorbidities that require long-term concomitant medication. Therefore, careful consideration of the benefit–risk profile of potential treatments is required. Methods In this review, we will discuss the rationale for early treatment of patients with nmCRPC to delay metastatic progression and prolong survival, as well as the factors influencing this treatment decision. We will focus on oral pharmacotherapy with the second-generation androgen receptor inhibitors, apalutamide, enzalutamide, and darolutamide, and the importance of balancing the clinical benefit they offer with potential adverse events and the consequential impact on quality of life, physical capacity, and cognitive function. Results and conclusions While the definition of nmCRPC is well established, the advent of next-generation imaging techniques capable of detecting hitherto undetectable oligometastatic disease in patients with nmCRPC has fostered debate on the criteria that inform the management of these patients. However, despite these developments, published consensus statements have maintained that the absence of metastases on conventional imaging suffices to guide such therapeutic decisions. In addition, the prolonged metastasis-free survival and recently reported positive overall survival outcomes of the three second-generation androgen receptor inhibitors have provided further evidence for the early use of these agents in patients with nmCRPC in order to delay metastases and prolong survival. Here, we discuss the benefit–risk profiles of apalutamide, enzalutamide, and darolutamide based on the data available from their pivotal clinical trials in patients with nmCRPC.

Background Radical cystectomy (RC) is often performed for T1 variant histology bladder cancer (VHBC), based on weak clinical evidence. We tested for cancer specific survival (CSS) differences after RC between T1 VHBC vs. urothelial carcinoma of the urinary bladder (UBC). Methods Within the Surveillance, Epidemiology and End Results registry (SEER, 2001–2016), we retrospectively identified T1N0M0 VHBC (adenocarcinoma, squamous cell carcinoma [SqCC], neuroendocrine carcinoma and other VHBC) and UBC patients. Kaplan-Meier plots, multivariate Cox regression models (CRM) with inverse probability treatment weighting (IPTW) and competing risks regression (CRR) tested CSS rates after RC in stage T1 vs. no-RC according to VHBC type and UBC. Results Of all 37,528 T1N0M0 bladder cancer patients, 1726 (4.6%) harboured VHBC. Of those, 598 (1.6%) had SqCC, 409 (1.1%) adenocarcinoma, 249 (0.7%) neuroendocrine carcinoma and 470 (1.3%) other VHBC. RC was performed in 7.4–11.0% of VHBC vs. 5.1% of high grade UBC patients. In patients with neuroendocrine and SqCC, RC was associated with higher CSS rates than any other surgical treatment modality (both p ≤ 0.01). Sixty-month CSS was 100% vs. 67% in neuroendocrine and 86% vs. 66% in SqCC in unadjusted analyses and remained statistically significantly higher in multivariate, IPTW adjusted analyses and in multivariate CRR. No difference was recorded for adenocarcinoma or other VHBC types. Conclusions RC for stage T1N0M0 VHBC appears to provide a protective effect with respect to CSS in patients with SqCC and neuroendocrine carcinoma, but not in adenocarcinoma or other VHBC.

The initial management of potentially oligometastatic hormone sensitive prostate cancer has been complicated by rapid advances in the field. Clinically, subgroup analyses of two randomized control trials have suggested that a specific synchronous oligometastatic prostate cancer state may be predictive for benefit from radiation to the primary. Further exploration of metastasis-directed therapy has been supported for various prostate cancer populations among three phase II clinical trials. There are numerous caveats in applying this evidence, a dilemma being addressed by present and upcoming clinical trials. Despite existing clinical equipoise and an avenue to address this uncertainty, the temptation to combine this evidence off-trial exists. Matters have become more complex as our ability to evaluate metastatic disease and tumour biology have also matured. This paper synthesizes our understanding of prostate cancer's natural history into a model which rationalizes both the theoretical benefits and limitations of metastasis directed therapy. We postulate that a metastatic prostate cancer's total disease activity is primarily driven by the combination of its burden of disease and underlying biology, namely genomic instability, then highlight the numerous remaining questions that challenge this hypothesis. This review focuses on harmonizing the language used to describe the disease, the current efforts exploring this hypothesis, and the need for clinical trial participation to appropriately advance patient care.

Background: Misclassification rates defined as upgrading, upstaging, and upgrading and/or upstaging have not been tested in contemporary Black patients relative to White patients who fulfilled criteria for very-low-risk, low-risk, or favorable intermediate-risk prostate cancer. This study aimed to address this void. Methods: Within the SEER database (2010–2015), we focused on patients with very low, low, and favorable intermediate risk for prostate cancer who underwent radical prostatectomy and had available stage and grade information. Descriptive analyses, temporal trend analyses, and multivariate logistic regression analyses were used. Results: Overall, 4,704 patients with very low risk (701 Black vs 4,003 White), 17,785 with low risk (2,696 Black vs 15,089 White), and 11,040 with favorable intermediate risk (1,693 Black vs 9,347 White) were identified. Rates of upgrading and/or upstaging in Black versus White patients were respectively 42.1% versus 37.7% (absolute Δ = +4.4%; PPP=.05) in those with favorable intermediate risk. Conclusions: Rates of misclassification were particularly elevated in patients with very low risk and low risk, regardless of race, and ranged from 33.8% to 48.6%. Recalibration of very-low-, low-, and, to a lesser extent, favorable intermediate-risk active surveillance criteria may be required. Finally, our data indicate that Black patients may be given the same consideration as White patients when active surveillance is an option. However, further validations should ideally follow.

Background Prostate cancer (PCa) staging is crucial in clinical decision making and treatment assignment. Objective To develop a predictive tool that is capable of predicting the probability of metastases at initial PCa diagnosis. Design, setting, and participants Within the Surveillance, Epidemiology, and End Results database (2010–2014), we identified patients with newly diagnosed PCa and available clinical tumor stage, prostatic-specific antigen value (PSA), and Gleason grade group (GGG), and with or without metastases. Outcome measurements and statistical analysis We relied on PSA, clinical tumor stages, and GGG to discriminate between M1 and M0 patients. Patients were randomly divided according to the registry of origin between development (n = 102 469) and validation (n = 98 755) cohorts. Logistic regression modeling coefficients were used to devise a lookup table to discriminate between M0 and M1 stages. Receiver operating characteristic-derived area under the curve was tested for model accuracy, within the validation cohort. A total of 2000 bootstrap resamples were applied to 95% confidence intervals (CIs). Decision curve analysis (DCA) and calibration plots were used to test the performance of the lookup table. Results and limitations Of 201 224 patients, 3.5% harbored metastatic PCa (mPCa). PSA >40 ng/ml, GGG5, and GGG4, in that order, represented the strongest predictors of mPCa. Overall, PSA, clinical tumor stage, and GGG were 94.3% (95% CI: 94.2–94.3%) accurate in predicting the probability of mPCa, in the external validation cohort. Up to 39.4% probability of mPCa, the model demonstrated accurate predictions in the calibration plot. In DCA, a net benefit was recorded up to a threshold probability of approximately 54%. Conclusions The proposed lookup table for the prediction of the probability of mPCa may represent a useful clinical tool based on its high accuracy, excellent calibration, and robust nature of predictions. Patient summary Our study provides a highly accurate lookup table for the prediction of the probability of metastatic prostate cancer patients. This clinical tool can be useful in staging decisions.

Background: The NCCN Clinical Practice Guidelines in Oncology for Kidney Cancer recommend active surveillance as an option for initial management of T1a 0- to 2-cm renal lesions, in addition to partial nephrectomy, radical nephrectomy, and focal ablation. However, contemporary data regarding the distribution of patient and renal cell carcinoma characteristics within this special patient group are scarce. Methods: Within the SEER database (2002–2016), 13,364 patients with T1aNanyMany 0- to 2-cm renal lesions treated with nephrectomy were identified. Data were tabulated according to histologic subtype, Fuhrman grade (FG1–2 vs FG3–4), age category, and sex. In addition, rates of synchronous metastases were quantified. Results: Overall, clear-cell (69.3%), papillary (21.4%), chromophobe (6.9%), multilocular cystic (2.0%), sarcomatoid dedifferentiation (0.2%), and collecting-duct histologic subtypes (0.2%) were identified. Advanced age was associated with a lower rate of FG1–2 clear cell histologic subtype (70.8%–50.3%) but higher rates of FG1–2 papillary (11.1%–23.9%) and chromophobe histologic subtypes (6.2%–8.5%). Overall, 14.5% individuals harbored FG3–4 clear cell (9.8%) or FG3–4 papillary histologic subtypes (4.8%), and both were more prevalent in men. FG3–4 clear-cell and FG3–4 papillary histologic subtypes increased with age, more so in women than in men. The overall rate of synchronous metastases was 0.4% and ranged from 0 in the multilocular cystic subtype to 0.9% in the FG3–4 papillary histologic subtype, respectively, except for 13.8% in the sarcomatoid dedifferentiation histologic subtype. Conclusions: Most T1a 0- to 2-cm renal cell carcinoma represents the low-grade clear-cell or low-grade papillary histologic subtype, with an FG3–4 minority. Even in patients with the FG3–4 histologic subtype, rates of synchronous metastases are virtually zero.

Background: We hypothesized that the survival benefit of external beam radiation therapy (EBRT) recorded in European low-volume metastatic prostate cancer (mPCA) patients, will apply to similar North American patients. Methods: Newly diagnosed mPCa patients with M1a/b substages, treated with EBRT or no EBRT were abstracted from the Surveillance, Epidemiology, and End Results database (2004–2016). Kaplan–Meier plots and Cox-regression models targeted overall mortality (OM) and cancer specific-mortality (CSM) according to EBRT administration. M1 substages and PSA stratified analyses were performed. Internal validation relied on 2000 bootstrap resamples. Results: Of 15,494 patients, 1156 (7.5%) were M1a vs 14,338 (92.5%) were M1b. PSA at diagnosis ≤10.0 ng/ml was recorded in 1463 (9.4%) patients. In all 15,494 patients, EBRT did not affect OM (hazard ratio [HR] 1.0; p = 0.5). However, in M1a patients and M1b patients with PSA ≤ 10.0 ng/ml EBRT was associated with lower OM (HR 0.73, CI 0.62–0.86; p < 0.001) but not in M1b patients with PSA > 10.0 ng/ml. The PSA cut-off of ≤ 10.0 ng/ml represented the most statistically significant cut-off for OM prediction in M1b patients. Moreover, internal validation with 2000 bootstrap resamples confirmed these findings. Finally, all results were virtually the same, when CSM represented the endpoint of interest. Conclusions: We validated the OM reduction associated with EBRT in M1a and M1b patients with PSA ≤ 10.0 ng/ml but not in M1b patients with PSA > 10.0 ng/ml. In consequence, it appears that a smaller subset of North American mPCa patients benefit of EBRT than originally reported in European patients. Further North American validation studies are essential.

Androgen deprivation therapy is an established therapy for castration sensitive prostate cancer and recent studies have observed that patients whose testosterone levels are suppressed below 0.7 nmol/l have improved outcomes. Testosterone breakthrough, or a rise in testosterone above a target threshold after the first month of androgen deprivation therapy, is generally associated with treatment deficiency. The purpose of this review is to summarize breakthrough rate data and explore the relationship to clinical outcomes in patients with castration sensitive prostate cancer receiving androgen deprivation therapy.Our systematic search identified 45 studies with a total of 52 cohorts representing 6,047 total patients reporting testosterone breakthrough rates or derivative measures above the thresholds of 1.7 nmol/l (51 cohorts, 6,015 patients) or 0.7 nmol/l (15 cohorts, 2,495 patients).Significantly higher weighted mean breakthrough rates were seen for the 0.7 nmol/l threshold compared to 1.7 nmol/l (41.3% vs 6.9%, p0.0001). A significant association between breakthrough rates and worse clinical outcomes overall was not found, although when larger trials (sample size greater than 100) and higher event rates (greater than 50%) were considered for the lowest threshold, significant associations between breakthrough rates and clinical outcomes were observed. Clinical factors such as administration and monitoring frequency, type of testosterone assay and type of androgen deprivation therapy did not significantly affect breakthrough rates, although nonvalidated assays were associated with a large degree of variability.Results from our analysis indicate that testosterone breakthroughs likely result in worse clinical outcomes and should be avoided. Moreover, there is a need to standardize assessment of testosterone levels both clinically and in the research context to better inform treatment decisions and improve the reliability and comparability of results across studies.

External beam radiotherapy (EBRT) with neoadjuvant/adjuvant androgen deprivation therapy (ADT) is an established treatment option to prolong survival for patients with intermediate- and high-risk prostate cancer (PCa). Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was evaluated in this clinical setting in comparison with degarelix, an injectable GnRH antagonist.To evaluate the safety and efficacy of relugolix to achieve and maintain castration.A phase 2 open-label study was conducted in 103 intermediate-risk PCa patients undergoing primary EBRT and neoadjuvant/adjuvant ADT between June 2014 and December 2015.Patients randomly assigned (3:2) to 24-wk treatment with either daily oral relugolix or 4-wk subcutaneous depot degarelix (reference control).The primary endpoint was the rate of effective castration (testosterone1.73nmol/l) in relugolix patients between 4 and 24 wk of treatment. Secondary endpoints included rate of profound castration (testosterone0.7nmol/l), prostate-specific antigen (PSA) levels, prostate volume, quality of life (QoL) assessed using the Aging Males' Symptoms scale, and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (30-item EORTC core questionnaire [EORTC QLQ-C30] and 25-item EORTC prostate cancer module [EORTC QLQ-PR25]) questionnaires, and safety. No formal statistical comparisons with degarelix were planned.Castration rates during treatment were 95% and 82% with relugolix and 89% and 68% with degarelix for 1.73 and 0.7nmol/l thresholds, respectively. Median time to castration in the relugolix arm was 4 d. During treatment, PSA levels and prostate volumes were reduced in both groups. Three months after discontinuing treatment, 52% of men on relugolix and 16% on degarelix experienced testosterone recovery (statistical significance of differences not tested). Mean and median QoL scores improved following treatment discontinuation. The most common adverse event was hot flush (relugolix 57%; degarelix 61%). Lack of blinding was a potential limitation.Relugolix achieved testosterone suppression to castrate levels within days and maintained it over 24 wk with a safety profile consistent with its mechanism of action.Oral once-daily relugolix may be a novel oral alternative to injectable androgen deprivation therapies.

Background Clinical trials have demonstrated the efficacy of several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC); however, real-world data on their use, survival effect, and safety are limited. Using electronic health record data from the Flatiron Health database, we studied real-world treatment patterns and health outcomes in patients with mCRPC. Patients and Methods We conducted a retrospective, non-interventional cohort analysis of electronic health record data of patients with confirmed mCRPC between January 2013 and September 2017. The primary objective was to describe real-world treatment patterns, including treatment type, duration, and sequencing. Secondary objectives included describing patient characteristics and clinical outcomes. Results Of 2559 patients with mCRPC, 1980 (77%) received at least 1 line of life-prolonging therapy (abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223). Of patients receiving first-line therapy, 49% received second-line therapy, and of these, 43% received third-line therapy. Abiraterone/prednisone and enzalutamide accounted for 65% of first-line therapies and 54% of second-line therapies. Docetaxel was the most common third-line therapy (24%). Back-to-back use of abiraterone/prednisone and enzalutamide was common. Radium-223 monotherapy use was 2% in the first-line setting, 3% in the second-line setting, and 8% in the third-line setting. The median overall survival was longer in patients who received life-prolonging therapies (23.7 months; 95% confidence interval: 22.3-25.1 months) than in those who did not (10.1 months; 95% confidence interval: 9.1-11.5 months). Conclusion These real-world insights on over 2500 patients with mCRPC supplement findings from randomized controlled trials and may help to inform clinical trial design, treatment guidelines, and clinical decision-making.

Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported.In this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O'Brien-Fleming-type alpha-spending function.As of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P = 0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events.Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.).

Background The United States Census Bureau recommends distinguishing between “Asians” vs. “Native Hawaiians or Other Pacific Islanders” (NHOPI). We tested for prognostic differences according to this stratification in patients with prostate cancer (PCa) of all stages. Methods Descriptive statistics, time-trend analyses, Kaplan–Meier plots and multivariate Cox regression models were used to test for differences at diagnosis, as well as for cancer specific mortality (CSM) according to the Census Bureau’s definition in either non-metastatic or metastatic patients vs. 1:4 propensity score (PS)-matched Caucasian controls, identified within the Surveillance, Epidemiology and End Results database (2004–2016). Results Of all 380,705 PCa patients, NHOPI accounted for 1877 (0.5%) vs. 23,343 (6.1%) remaining Asians vs. 93.4% Caucasians. NHOPI invariably harbored worse PCa characteristics at diagnosis. The rates of PSA ≥ 20 ng/ml, Gleason ≥ 8, T3/T4, N1- and M1 stages were highest for NHOPI, followed by Asians, followed by Caucasians (PSA ≥ 20: 18.4 vs. 14.8 vs. 10.2%, Gleason ≥ 8: 24.9 vs. 22.1, vs. 15.9%, T3/T4: 5.5 vs. 4.2 vs. 3.5%, N1: 4.4 vs. 2.8, vs. 2.7%, M1: 8.3 vs. 4.9 vs. 3.9%). Despite the worst PCa characteristics at diagnosis, NHOPI did not exhibit worse CSM than Caucasians. Moreover, despite worse PCa characteristics, Asians exhibited more favorable CSM than Caucasians in comparisons that focussed on non-metastatic and on metastatic patients. Conclusions Our observations corroborate the validity of the distinction between NHOPI and Asian patients according to the Census Bureau’s recommendation, since these two groups show differences in PSA, grade and stage characteristics at diagnosis in addition to exhibiting differences in CSM even after PS matching and multivariate adjustment.

Purpose: To test the effect of perioperative chemotherapy (CHT) on overall mortality (OM) and cancer-specific mortality (CSM) in patients with locally advanced or metastatic squamous cell carcinoma of the urinary bladder (SCC UB). Methods: Within the Surveillance, Epidemiology and End Results database (1988–2016), we identified 1,018 SCC UB patients (664 T3–4aN0M0, 197 TanyN1–3M0 and 156 T4bN0–3 or M1), who underwent radical cystectomy with or without perioperative chemotherapy administration. Inverse probability of treatment-weighting (IPTW), Kaplan–Meier plots and Cox-regression models (CRMs) were used. Results: CHT was administrated in 116 (17.5%) T3–4aN0M0, 77 (39.1%) TanyN1–3M0 and 47 (30.1%) T4bN0–3 or M1 patients. IPTW-adjusted 2-year cancer-specific survival (CSS) was 66.5 vs. 71.5% (p = 0.19), 60.9 vs. 29.5% (p < 0.001) and IPTW-adjusted 1-year CSS was 46.2 vs. 31.1% (p = 0.03) for CHT vs. no CHT administration in T3–4aN0M0, TanyN1–3M0 and T4bN0–3 or M1, respectively. In multivariable IPTW-adjusted CRMs, chemotherapy was an independent predictor of lower CSM in TanyN1–3M0 (HR 0.44) and in T4bN0–3 or M1 (HR 0.60), but not in T3–4aN0M0 (p = 0.6) patients. Virtually the same results were obtained on OM, as well as without IPTW-adjustment and after stratification according to age and gender. Conclusions: The use of perioperative CHT in patients with SCC UB confers survival benefit in the presence of T4b disease, lymph node or distant metastases. Conversely, patients with locally advanced disease but negative lymph node invasion do not benefit from its use. Pending higher quality data from prospective trials, these data should encourage the use of perioperative CHT in those high-risk patient groups.

Objectives: To test the effect of stage and grade migration on cancer specific mortality (CSM) in renal cell carcinoma (RCC) patients, according to clear cell (ccRCC) vs. non-ccRCC histology. Methods and Materials: Within the Surveillance, Epidemiology, and End Results registry (2004–2015), we identified patients with ccRCC and non-ccRCC (papillary [papRCC], chromophobe [chRCC], sarcomatoid [sarcRCC], and collecting duct [cdRCC]). Two consecutive time groups were considered – historical (2004–2009) and contemporary era (2010–2015). Temporal trends of tumor characteristics were evaluated. Cumulative incidence plots and multivariable competing risks regression models tested the effect of year groups on CSM. Results: Overall, 24,746 and 73,228 patients with non-ccRCC and ccRCC were evaluated. Of those, 42% and 58% were recorded in historical and contemporary era. Time trend analyses showed (1) tumor size decreased for non-ccRCC (estimated annual percent changes [EAPC]: −1.1%; P

Background In this study, we evaluated real-world data on radium-223 plus abiraterone/prednisone or enzalutamide. Previously, the ERA 223 trial (NCT02043678) demonstrated increased fracture risk with concurrent treatment with radium-223 and abiraterone plus prednisone/prednisolone in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods We used the Flatiron Health database to perform a retrospective study of patients with mCRPC treated with radium-223. Treatment with radium-223 plus abiraterone/prednisone or enzalutamide was defined as concurrent if both drugs started within 30 days of one another, or layered when the second drug started ≥30 days after the first. The index date was defined as the day of the first radium-223 dose. Outcome measures included symptomatic skeletal events (SSEs), overall survival (OS), and patterns of treatments received. Results Of the 625 patients treated with radium-223, 22% received it together with abiraterone/prednisone and 27% with enzalutamide. When these agents were combined, they were often initiated in a layered fashion (73% layered, 23% concurrent). Prior or concomitant bone health agents (BHAs) were received by 67% and 55% of patients, respectively. Median follow-up was 9 months. Overall, incidence rates for SSEs and pathologic fractures were 0.35 and 0.11 patients per person-year, respectively. Median OS from mCRPC diagnosis was 28.1 months. Conclusions In this real-world setting, combination treatments with radium-223 and abiraterone/prednisone or enzalutamide were common. These agents were more commonly given in a layered than a concurrent fashion. Incidence rates for SSEs were reduced when BHAs were used; however, BHAs were underutilized.

Background Lymph node invasion (LNI) at nephrectomy is one of the most important predictors of mortality in patients with nonmetastatic renal cell carcinoma (RCC). We analyzed the effect of histology on lymph node metastases at nephrectomy and its effect on survival in a contemporary cohort of patients with nonmetastatic RCC. Methods Within the Surveillance, Epidemiology, and End Results database (2004-2015), we identified 100,060 patients with clear-cell, papillary, chromophobe, sarcomatoid, and collecting duct RCC, who underwent nephrectomy with or without lymph node dissection for nonmetastatic RCC. Logistic regression models, cumulative incidence plots, and competing-risks regression models were performed. Results Overall, 10,590 patients underwent lymph node dissection for nonmetastatic RCC. Of these, LNI was recorded in 52 (7.0%), 615 (8.7%), 282 (13.9%), 316 (25.1%), 129 (38.3%), 45 (71.4%) patients with chromophobe, clear-cell, nonotherwise specified RCC, papillary, sarcomatoid, and collecting duct RCC histological subtypes, respectively. In logistic regression models, relative to clear-cell, papillary Odds ratio (OR 3.9), sarcomatoid (OR 6.3), collecting duct (OR 14.6) but not chromophobe RCC (OR 0.9; P = 0.5) independently predicted LNI at surgery. Moreover, in competing-risks regression models, LNI increased the risk of CSM 1.8-fold for sarcomatoid, 3.6-fold for clear-cell, 4.1-fold for papillary, and 6.7-fold for chromophobe histological subtype. Conclusions Histology is an independent predictor of increased risk of LNI at nephrectomy. Moreover, the effect of pathological nodal stage on survival differs according to different histology.

Background: To compare survival outcomes of metastatic patients harbouring either papillary (pRCC) or clear-cell (ccRCC) renal cell carcinoma in overall population and according to treatment modality. Methods: Within the Surveillance, Epidemiology and End Results database (2006–2015), we identified 6800 patients (585 papillary and 6215 clear-cell) with metastatic RCC. Propensity-score (PS) matching, Kaplan–Meier plots and multivariable Cox-regression models (CRMs) were used. Results: Overall, 585 (8.6%) patients harboured pRCC. Rates of nodal metastases were higher in patients with pRCC (49.7 vs. 23.3%; p < 0.001). Median overall survival (OS) was 13 vs. 18months for pRCC vs. ccRCC patients. After multivariable adjustments, no difference in OS was recorded. Furthermore, after propensity-score matching, virtually the same results were recorded. Median OS of pRCC vs. ccRCC was 8 vs. 4months for no treatment (NT), 11 vs. 12months for targeted therapy alone (TT), 17 vs. 35months for cytoreductive nephrectomy alone (CN) and 18 vs. 25months for combination of CN with TT. Conclusions: Metastatic pRCC patients exhibit poor survival, regardless of treatment received. Moreover, pRCC patients are more likely to present nodal metastases, compared to ccRCC patients, as demonstrated by twofold higher rates of lymph node invasion at diagnosis. These observations indicate that papillary variant represents more prognostically unfavorable tumor histology, in the context of metastatic RCC.

Background and Objectives: To investigate other-cause mortality (OCM) rates over time according to several baseline characteristics in bladder cancer (BCa) patients treated with radical cystectomy (RC). Methods: Within the Surveillance, Epidemiology, and End Results database (1988-2011), we identified 7702 T1-2N0M0 urothelial BCa patients treated with RC. Temporal trends and multivariable Cox regression (MCR) analyses assessed 5-year OCM. Data were stratified according to the year of diagnosis (1988-1995 vs 1996-2000 vs 2001-2004 vs 2005-2008 vs 2009-2011), age group (75 years), sex, race, marital status, and socioeconomic status. Results: Overall, OCM rates decreased from 13.9% in 1988-1995 to 8.6% in 2009-2011. The greatest decrease was recorded in elderly (>75) patients (32%-16%, slope: −0.55% per year; P =.01), followed by patients aged 60 to 75 (21%-5%, slope: −0.35% per year; P =.01), unmarried patients (16%-10%, slope: −0.26% per year; P

Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence. Objective: To present the results from the APCCC 2019. Design, setting, and participants: Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naive prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions. Outcome measurements and statistical analysis: The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process. Results and limitations: Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material. Conclusions: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials. Patient summary: The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.

Transrectal ultrasound (TRUS) image guidance is the standard of care for diagnostic and therapeutic interventions in prostate cancer (PCa) patients, but can lead to high false-negative rates, compromising downstream effectiveness of therapeutic choices. A promising approach to improve in-situ detection of PCa lies in using the optical properties of the tissue to discern cancer from healthy tissue. In this work, we present the first in-situ image-guided navigation system for a spatially tracked Raman spectroscopy probe integrated in a PCa workflow, capturing the optical tissue fingerprint. The probe is guided with fused TRUS/MR imaging and tested with both tissue-simulating phantoms and ex-vivo prostates. The workflow was designed to be integrated the clinical workflow for trans-perineal prostate biopsies, as well as for high-dose rate (HDR) brachytherapy. The proposed system developed in 3D Slicer includes an electromagnetically tracked Raman spectroscopy probe, along with tracked TRUS imaging automatically registered to diagnostic MRI. The proposed system is tested on both custom gelatin tissue-simulating optical phantoms and biological tissue phantoms. A random-forest classifier was then trained on optical spectrums from ex-vivo prostates following prostatectomy using our optical probe. Preliminary in-human results are presented with the Raman spectroscopy instrument to detect malignant tissue in-situ with histopathology confirmation. In 5 synthetic gelatin and biological tissue phantoms, we demonstrate the ability of the image-guided Raman system by detecting over 95% of lesions, based on biopsy samples. The included lesion volumes ranged from 0.1 to 0.61 cc. We showed the compatibility of our workflow with the current HDR brachytherapy setup. In ex-vivo prostates of PCa patients, the system showed a 81% detection accuracy in high grade lesions. Pre-clinical experiments demonstrated promising results for in-situ confirmation of lesion locations in prostates using Raman spectroscopy, both in phantoms and human ex-vivo prostate tissue, which is required for integration in HDR brachytherapy procedures.