Impact of time to metastatic disease onset and extent of disease volume across metastatic hormone-sensitive and castration-resistant prostate cancer.

OBJECTIVE: In recently published phase III trials, overall survival (OS) differences were demonstrated in patients with secondary vs. De Novo and low vs. high volume metastatic hormone-sensitive prostate cancer (mHSPC). We hypothesized that these factors may also be attributable in real-world setting of new intensified combination therapies and in metastatic castration resistant prostate cancer (mCRPC) patients. MATERIALS AND METHODS: We relied on an institutional tertiary-care database to identify mHSPC and subsequent mCRPC patients. The main outcome consisted of time to mCRPC and OS. Patients were stratified according to De Novo vs. secondary and low vs. high volume mHSPC and mCRPC, respectively. RESULTS: Of 504 mHSPC patients, 371 (73.6%) were De Novo vs. 133 (26.4%) secondary mHSPC. Patients with De Novo and high volume mHSPC harbored shorter time to mCRPC and OS than secondary and low volume mHSPC patients (both P < 0.01). After stratification regarding disease volume, median time to mCRPC differed significantly between De Novo high volume (DNHV) vs. De Novo low volume (DNLV) vs. secondary high volume (SecHV) vs. secondary low volume mHSPC patients (SecLV, P < 0.001). Similarly in OS analyses, median OS was 44 vs. 53 vs. 88 vs. 120 months for respectively DNHV vs. SecHV vs. SecLV vs. DNLV mHSPC (P < 0.001). After progression to mCRPC, the effect of onset of metastatic disease and metastatic volume was still observed (all P < 0.01). CONCLUSION: Patients with DNHV mHSPC harbor worse prognosis in a real world setting and in the light of combination therapies. This effect is also discernible in the context of mCRPC.

Histopathological, Molecular and Clinical Profiling of Lymphoepithelioma-Like Carcinoma of the Bladder (LELC-B).

Lymphoepithelioma-like urothelial carcinoma of the urinary bladder (LELC-B) is a rare histologic subtype characterized by strong immune cell infiltrates. A better prognosis and favorable response rates to immune-checkpoint inhibitors (ICI) have been described. We aimed to characterize the molecular profiles and immune cell infiltration of LELC-B for a better understanding and its therapeutic implications. We identified eleven muscle-invasive bladder cancer cases with pure and mixed LELC-B. PD-L1 expression and mismatch-repair (MMR) proteins were evaluated using immunohistochemistry. We calculated the tumor-mutational burden (TMB) and characterized mutational profiles using whole exome DNA-sequencing data. Transcriptomic signatures were detected using the NanoString nCounter PanCancer IO360 panel. Multiplex immunofluorescence of tumor microenvironment (PD-L1, PanCK, aSMA, Vimentin, CD45, Ki67) and T-cells (CD4, CD3, PD-1, CD163, CD8, FoxP3) was used to quantify cell populations. All LELC-B cases were highly positive for PD-L1 (median TPS/TC 70%; range 20-100; median CPS 100; range 50-100), MMR-proficient and negative for Epstein-Barr virus infection. Immune cell infiltrates were characterized by high CD8+ T-cell count and high PD-1/PD-L1 expression on immune and tumor cells. LELC-B showed upregulation of signaling pathways involved in immune cell response. Most common mutations were found in chromatin remodeling genes causing epigenetic dysregulation. All LELC-B cases showed high TMB of 39 Mut/Mb (IQR 29-66). In conclusion, LELC-B is a highly immunogenic tumor, showing strong upregulation of PD1/PD-L1 and making ICI a promising treatment option.

Regional Differences in Stage III Nonseminoma Germ Cell Tumor Patients Across SEER Registries.

PURPOSE: We investigated regional differences in patients with stage III nonseminoma germ cell tumor (NSGCT). Specifically, we investigated differences in baseline patient, tumor characteristics and treatment characteristics, as well as cancer-specific mortality (CSM) across different regions of the United States. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database (2004-2018), patient (age, race/ethnicity), tumor (International Germ Cell Cancer Collaborative Group [IGCCCG] prognostic groups) and treatment (systemic therapy and retroperitoneal lymph dissection [RPLND] status) characteristics were tabulated for stage III NSGCT patients, according to 12 SEER registries representing different geographic regions. Multinomial regression models and multivariable Cox regression models testing for cancer-specific mortality (CSM) were used. RESULTS: In 3,174 stage III NSGCT patients, registry-specific patient counts ranged from 51 (1.5%) to 1630 (51.3%). Differences across registries existed for age (12%-31% for age 40+), race/ethnicity (5%-73% for others than non-Hispanic whites), IGCCCG prognostic groups (24%-43% vs. 14-24% vs. 3%-20%, in respectively poor vs. intermediate vs. good prognosis), systemic therapy (87%-96%) and RPLND status (12%-35%). After adjustment, clinically meaningful inter-registry differences remained for systemic therapy (84%-97%) and RPLND (11%-32%). Unadjusted 5-year CSM rates ranged from 7.1% to 23.3%. Finally in multivariable analyses addressing CSM, 2 registries exhibited more favorable outcomes than SEER registry of reference (SEER Registry 12): SEER Registry 4 (Hazard Ratio (HR): 0.36) and SEER Registry 9 (HR: 0.64; both P = .004). CONCLUSION: We identified important regional differences in patient, tumor and treatment characteristics, as well as CSM which may be indicative of regional differences in quality of care or expertise in stage III NGSCT management.

[Contemporary treatment standards and trends of systemic therapy in metastatic hormone-sensitive prostate cancer-implementing study data in clinical practice]. / Aktueller Behandlungsstandard und Trends der Systemtherapie beim metastasierten hormonsensiblen Prostatakarzinom ­ Anwendung der Studiendaten in der Praxis.

BACKGROUND: The treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC) has undergone fundamental changes in recent decades, moving away from the sole use of androgen deprivation therapy (ADT) and towards intensified combination therapies. PURPOSE: To what extent have the data from prospective phase III studies influenced clinical practice in the management of mHSPC over the past 5 or 10 years? RESULTS: A total of 1098 mHSPC patients with a median age at metastasis of 70 years and a median prostate-specific antigen (PSA) level of 43 ng/ml were included in the present study. Significant differences were observed in terms of PSA nadirs in mHSPC after stratification by year of metastatic onset. Significant differences were also observed regarding systemic therapies applied in mHSPC and metastatic castration-resistant prostate cancer (mCRPC; p < 0.001). Regarding the annual estimated percentage change (EAPC) over the past 10 years, a significant decrease in ADT monotherapy from 85% (2013) to 29% (2023; EAPC: -12%, p < 0.001) was observed. Conversely, there was a significant increase in androgen receptor signaling inhibitor (ARSI) use from 6% in 2013 to 55% in 2023 (EAPC: +21.7%, p < 0.001). Regarding docetaxel chemotherapy, a bell-shaped pattern was apparent over the past 10 years, with rates increasing from 8% in 2013 to 25% in 2019 and decreasing to 0% in 2023. The proportion of triplet therapies was 16% in 2023. CONCLUSION: Over the past 10 years there has been an adaptation of intensified combination therapies for mHSPC in clinical reality, with the most frequent use of ARSI and triplet therapies.

Influence of Tumor Characteristics and Time to Metastatic Disease on Oncological Outcomes in Metachronous Metastatic Prostate Cancer Patients.

INTRODUCTION: Metachronous metastatic prostate cancer (mmPCa) patients harbor different characteristics and outcomes, relative to DeNovo metastatic PCa patients. Onset of metastatic disease might be influenced by primary PCa characteristics such as Gleason score (GS) or cancer stage, as well as overall survival (OS) by timing of metastatic onset. PATIENTS AND METHODS: We relied on an institutional tertiary-care database to identify mmPCa patients. Kaplan Meier and Cox Regression models tested for onset of metastases and OS, stratified according to GS, pathological stage and time to mmPCa. RESULTS: Of 341 mmPCa patients, 8% harbored GS6 versus 41% versus 51% GS7 and GS8-10. Median time to onset of metastatic disease was 79 versus 54 versus 41 months for GS6 versus GS7 versus GS8-10 (P = .01). Moreover, median time to onset of metastases was 64 versus 44 months for pT1-2 versus pT3-4 mmPCa patients undergoing radical prostatectomy (P = .027). In multivariable Cox regression models, higher GS and pT-stage was associated with earlier onset of metastases. Additionally, significant OS differences could be observed for time interval of < 24 versus 24-60 versus 60-120 versus ≥ 120 months between primary PCa diagnosis and onset of mmPCa. Specifically, median OS was 56 versus 69 versus 97 months versus not reached (P < .01) for these categories. In multivariable Cox regression, shorter time to metastatic onset was associated with shorter OS. CONCLUSION: Timing of mmPCa is strongly influenced by grading and pT-stage in real-life setting. OS benefits can be observed with longer time interval between primary PCa diagnosis and onset of mmPCa.

Contemporary Treatment Patterns and Oncological Outcomes of Metastatic Hormone-sensitive Prostate Cancer and First- to Sixth- line Metastatic Castration-resistant Prostate Cancer Patients.

Background and objective: With approval of novel systemic therapies within the past decade for metastatic hormone-sensitive (mHSPC) and castration-resistant (mCRPC) prostate cancer, patients may receive several therapy lines. However, the use of these treatments is under an ongoing change. We investigated contemporary treatment trends and progression-free (PFS) and overall (OS) survival of different therapy lines. Methods: Relying on our institutional tertiary-care database, we identified mHSPC and mCRPC patients. The main outcome consisted of treatment changes (estimated annual percentage change [EAPC]) within the past decade, as well as PFS and OS for different mHSPC and mCRPC treatment lines. Key findings and limitations: In 1098 metastatic patients, the median age was 70 yr with a median of two systemic therapy lines. For first-line mCRPC between 2013 and 2023, androgen deprivation monotherapy (ADT) monotherapy usage decreased significantly from 31% to 0% (EAPC -38.3%, p < 0.001), while the administration of chemotherapy increased from 16.7% to 33.3% (EAPC: +10.1%, p < 0.001). The PFS/OS rates of mHSPC patients was 21/67 mo, and those for first-, second-, third-, fourth-, fifth-, and sixth-line mCRPC patients were 11/47, eight of 30, seven of 24, six of 19, seven of 17, and seven of 13 mo, respectively. With an increased number of new combination therapy lines received, the median OS in mCRPC improved from 26 mo (one systemic treatment) to 52 mo (two or more lines of systemic treatment). Conclusions and clinical implications: Significant changes in treatment patterns could be observed for mHSPC and mCRPC patients within the past decade, and usage of ADT monotherapy has decreased rapidly in real-world practice. Moreover, PFS decreases significantly with every therapy line, and OS increases with the implementation of new therapies. Patient summary: Improvements in the real-world setting regarding the usage of combination therapies for metastatic hormone-sensitive and castration-resistant prostate cancer were made, which is reflected in contemporary survival outcomes.

Survival of patients with lymph node versus bone versus visceral metastases according to CHAARTED/LATITUDE criteria in the era of intensified combination therapies for metastatic hormone-sensitive prostate cancer.

BACKGROUND: The first approvals of novel systemic therapies within recent years for metastatic hormone-sensitive (mHSPC) were mainly based on improved overall survival (OS) and time to castration resistance (ttCRPC) in mHSPC patients stratified according to CHAARTED low (LV) versus high volume (HV) and LATITUDE low (LR) versus high-risk (HR) disease. METHODS: Relying on our institutional tertiary-care database we identified all mHSPC stratified according to CHAARTED LV versus HV, LATITUDE LR versus HR and the location of the metastatic spread (lymph nodes (M1a) versus bone (M1b) versus visceral/others (M1c) metastases. OS and ttCRPC analyses, as well as Cox regression models were performed according to different metastatic categories. RESULTS: Of 451 mHSPC, 14% versus 27% versus 48% versus 12% were classified as M1a LV versus M1b LV versus M1b HV versus M1c HV with significant differences in median OS: 95 versus 64 versus 50 versus 46 months (p < 0.001). In multivariable Cox regression models HV M1b (Hazard Ratio: 2.4, p = 0.03) and HV M1c (Hazard Ratio: 3.3, p < 0.01) harbored significant worse than M1a LV mHSPC. After stratification according to LATITUDE criteria, also significant differences between M1a LR versus M1b LR versus M1b HR versus M1c HR mHSPC patients were observed (p < 0.01) with M1b HR (Hazard Ratio: 2.7, p = 0.03) and M1c HR (Hazard Ratio: 3.5, p < 0.01), as predictor for worse OS. In comparison between HV M1b and HV M1c, as well as HR M1b versus HR M1c no differences in ttCRPC or OS were observed. CONCLUSIONS: Significant differences exist between different metastatic patterns of HV and LV and HR and LR criteria. Best prognosis is observed within M1a LV and LR mHSPC patients.

Impact of homologous recombination repair/BReast CAncer (BRCA) gene alterations on survival in a real-world setting of metastatic prostate cancer.

OBJECTIVE: To investigate alterations of homologous recombination repair (HRR) and especially BReast CAncer 1/2 (BRCA1/2) gene on overall survival (OS). Moreover, to explore the effect of inhibition of poly(ADP-ribose)-polymerase (PARPi) as systemic therapy for metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Of all HRR-screened patients with metastatic prostate cancer, baseline characteristics were sampled. Kaplan-Meier estimates and multivariable Cox regression models predicted the effect of HRR/BRCA1/2 alterations on OS. RESULTS: Of 196 eligible patients, 61 (31%) harboured any HRR and 40 (20%) BRCA1/2 alterations. Of HRR alterations, 40 (66%) vs six (10%) vs five (8.2%) vs four (6.6%) vs two (3.3%) vs four (6.6%) were BRCA1/2 vs Ataxia-telangiectasia mutated kinase (ATM) vs checkpoint kinase 2 (CHEK2) vs cyclin-dependent kinase 12 (CDK12) vs Fanconi anaemia complementation Group A (FANCA) vs positive for other mutations. Of these, 30% received a PARPi. OS differed significantly between HRR-positive vs -negative patients. Specifically in hormone-sensitive prostate cancer, the median OS was 63 (HRR positive) vs 57 (BRCA1/2 positive) vs 113 months (HRR negative) (P ≤ 0.01). In mCRPC, OS was 42 (HRR positive) vs 41 (BRCA1/2 positive) vs 70 months (HRR negative) (P ≤ 0.01). HRR and BRCA1/2 alterations were associated with worse OS after multivariable adjustment. Finally, patients with mCRPC with BRCA1/2 mutation treated without PARPi harboured worse OS than patients with BRCA1/2 mutation and PARPi therapy (median OS: 33 vs 48 months, P < 0.03). CONCLUSION: Incidence of HRR alteration in a clinical real-world setting is high when using blood- and tissue-based tests. Patients with HRR/BRCA alterations have worse outcomes resulting in significant OS differences between HRR/BRCA-positive patients with mCRPC with and without PARPi usage vs HRR/BRCA-negative patients.

First-Line Immune Combination Therapies for Nonclear Cell Versus Clear Cell Metastatic Renal Cell Carcinoma: Real-World Multicenter Data From Germany.

INTRODUCTION: The aim was to compare treatment outcomes of clear cell metastatic renal cell carcinoma (ccmRCC) versus non-ccmRCC (nccmRCC) patients who received first-line immune combination therapies. MATERIALS AND METHODS: Within our retrospective multi-institutional consecutive database of eight tertiary-care centers, we identified mRCC patients treated with first-line immune combination therapies between 11/2017 and 12/2022. Using log-rank analysis and multivariable Cox regression, we tested for differences in overall survival (OS) and progression-free survival (PFS) of nccmRCC versus ccmRCC patients. Covariables consisted of age at diagnosis, sex, International Metastatic Renal Cell Carcinoma Database Consortium risk groups, Eastern Cooperative Oncology Group status, and sarcomatoid feature. RESULTS: Of 289 study patients, 39 (13%) patients harbored nccmRCC. Median OS was 37 months versus not reached for ccmRCC versus nccmRCC patients (P = .6). Median PFS was 13 versus 15 months (P = .9). Multivariable Cox regression models did not identify nccmRCC as an independent predictor of higher overall mortality in mRCC patients (hazard ratio [HR]: 1.23; P = .6) or a higher progression rate (HR: 1.0; P = 1.0). CONCLUSION: In our real-world multi-institutional study, no differences in OS and PFS between ccmRCC and nccmRCC patients receiving first-line immune combination treatment were observed, even after adjustment for important patient and tumor characteristics. More prospective trials in nccmRCC patients are needed.

Treatment patterns and oncological outcomes of older adults with metastatic prostate cancer in real-world setting.

BACKGROUND: The landscape of systemic therapies for metastatic hormone-sensitive (mHSPC) and castration resistant prostate cancer (mCRPC) extensively improved within the last decades resulting in a significantly prolonged overall survival. However, subgroup analyses of phase III trials suggest potentially different overall survival outcomes for older adults. METHODS: We relied on our institutional metastatic prostate cancer database to identify mHSPC and subsequently mCRPC patients. Older adults were stratified according to age groups 70-74 versus ≥75-79 versus ≥80 years at metastatic occurrence. Subsequently, uni- and multivariable time to mCRPC and overall survival analyses were performed. RESULTS: Of 494 older adults, 217 (44%) were 70-74 versus 180 (36%) 75-79 versus 97 (20%) ≥80 years old. Rates of local prostate cancer treatment differed significantly between all three groups (p < 0.01). Regarding mHSPC treatment, androgen receptor signaling inhibitors (ARSI) were administered in 30-39% of patients and docetaxel with 9% in age group 70-74 years and 6% and 3% in age groups 75-79 years and ≥80 years. Regarding mCRPC treatment, significant differences between treatment proportions were observed (p < 0.01). Most common treatment was ARSI for all three groups. Conversely, chemotherapy was more frequently administered in patients aged 70-74 (16%), relative to 4% and 3% in 75-79 year and ≥80 year aged patients. In univariable and multivariable time to mCRPC analyses, overall survival in mHSPC and OS in mCRPC analyses, no significant differences between all three age groups were observed (all p ≥ 0.3). CONCLUSIONS: Treatment patterns differ significantly between older adults with metastatic prostate cancer. However, these differences may not result in differences of overall life expectancy.

Impact of PSA nadir, PSA response and time to PSA nadir on overall survival in real-world setting of metastatic hormone-sensitive prostate cancer patients.

BACKGROUND: To evaluate the impact of prostate-specific antigen (PSA) nadir, PSA response and time to PSA nadir (TTN) in metastatic hormone-sensitive prostate cancer (mHSPC) patients on overall survival (OS) in the era of combination therapies. METHODS: Different PSA nadir cut-offs (including ultra-low PSA) were tested for OS analyses. Additionally, PSA response ≥99% was evaluated, as well as TTN categorized as <3 versus 3-6 versus 6-12 versus >12 months. Multivariable Cox regression models predicted the value of PSA nadir cut-offs, PSA response and TTN on OS. Sensitivity analyses were performed in de novo and high volume mHSPC patients. RESULTS: Of 238 eligible patients, PSA cut-offs of <0.2 versus 0.2-4.0 versus >4.0 ng/mL differed significantly regarding median OS (96 vs. 56 vs. 44 months, p < 0.01), as well as in subgroup analyses of de novo mHSPC patients and multivariable Cox regression models. A more stringent PSA cut-off of <0.02 versus 0.02-0.2 versus >0.2 ng/mL also yielded significant median OS differences (not reached vs. 96 vs. 50 months, p < 0.01), even after additional multivariable adjustment. A PSA response ≥99% was also significantly associated with better OS than counterparty with <99% response, even after multivariable adjustment (both p < 0.02). When TTN groups were compared, patients with longer TTN harbored more extended OS than those with short TTN (<3 vs. 3-6 vs. 6-12 vs. >12 months: 34 vs. 50 vs. 67 vs. 96 months, p < 0.01). Virtually similar results were observed in sensitivity analyses for high volume mHSPC patients. CONCLUSIONS: In times of combination therapies for mHSPC, a PSA nadir of respectively, <0.2 and <0.02 ng/mL are associated with best OS rates. Moreover, a relative PSA response ≥99% and a longer TTN are clinical important proxies for favorable OS estimates.

Use of inpatient palliative care in metastatic urethral cancer.

BACKGROUND: In metastatic urethral cancer, temporal trends, and patterns of inpatient palliative care (IPC) use are unknown. METHODS: Relying on the National Inpatient Sample (2006-2019), metastatic urethral cancer patients were stratified according to IPC use. Estimated annual percentage changes (EAPC) analyses and multivariable logistic regression models (LRM) for the prediction of IPC use were fitted. RESULTS: Of 1,106 metastatic urethral cancer patients, 199 (18%) received IPC. IPC use increased from 5.8 to 28.0% over time in the overall cohort (EAPC +9.8%; P < 0.001), from <12.5 to 35.1% (EAPC +11.2%; P < 0.001), and from <12.5 to 24.7% (EAPC +9.4%; P = 0.01) in respectively females and males. Lowest IPC rates were recorded in the Midwest (13.5%) vs. highest in the South (22.5%). IPC patients were more frequently female (44 vs. 37%), and more frequently exhibited bone metastases (45 vs. 34%). In multivariable LRM, female sex (multivariable odds ratio [OR] 1.46, 95% confidence interval [CI] 1.05-2.02; P = 0.02), and bone metastases (OR 1.46, 95%CI 1.02-2.10; P = 0.04) independently predicted higher IPC rates. Conversely, hospitalization in the Midwest (OR 0.53, 95%CI 0.31-0.91; P = 0.02), and in the Northeast (OR 0.48, 95%CI 0.28-0.82; P = 0.01) were both associated with lower IPC use than hospitalization in the West. CONCLUSION: IPC use in metastatic urethral cancer increased from a marginal rate of 5.8% to as high as 28%. Ideally, differences according to sex, metastatic site, and region should be addressed to improve IPC use rates.

Real-World Evidence of Tumor and Patient Characteristics and Survival with Avelumab Maintenance after Chemotherapy for Advanced and Metastatic Urothelial Carcinoma.

INTRODUCTION: Despite the prospective randomized controlled JAVELIN Bladder 100 trial, no real-world evidence exists regarding tumor characteristics, adverse events (AEs), and survival of avelumab maintenance (AVM)-treated patients with partial/complete response or stable disease after previous platinum-based chemotherapy for advanced/metastatic urothelial carcinoma (mUC). METHODS: We relied on our institutional database to identify mUC patients who received AVM between January, 2021 and December, 2023. The main outcomes consisted of overall survival (OS) and progression-free survival (PFS) and were computed by Kaplan-Meier estimates. Stratification was performed according to programmed death ligand 1 (PD-L1) status. RESULTS: Overall, 24 AVM patients were identified at a median age of 71 (interquartile range [IQR]: 67-76) years, of which 67% were males. Of these, 63%, 21%, and 17% received AVM therapy for bladder cancer and upper tract urothelial carcinoma or both, respectively. PD-L1 status was positive in 45% of patients. During AVM treatment, AEs were observed in 33% of patients; however, they were limited to ≤2 grade AEs. At a median follow-up of eight (IQR 4-20) months, 71% of patients had progressed under AVM with median PFS of 6.2 months (confidence interval [CI]: 3.2-18.2). Median OS was 13.4 (CI: 6.9 - not reached [NR]) months. One-year OS after AVM was 52%. In PD-L1-positive patients, median PFS and OS were 6.4 (CI: 2.7 - NR) months and 13.4 (CI: 7.7 months - NR), respectively. CONCLUSION: AVM is associated with moderate AE rates. Despite similarities in baseline characteristics compared to trial-selected JAVELIN Bladder 100 mUC patients, AVM resulted in longer/similar PFS but significantly shorter OS in real-world setting.

Metastatic Squamous Cell Carcinoma of the Urinary Bladder: Urgent Call for New Therapies.

BACKGROUND: Squamous cell carcinoma (SCC) of the urinary bladder is the most common non-urothelial variant histology. Currently, upfront radical cystectomy is the gold standard for non-metastatic SCC of the bladder. However, several studies have shown that SCC of the bladder is associated with higher aggressiveness and worse survival outcomes, such as progression-free and cancer-specific survival, relative to the urothelial histological subtype. Moreover, metastatic SCC seems to poorly respond to systemic treatments and/or radiotherapy. SUMMARY: This review summarizes the current knowledge and medical evidence regarding local and systematic treatment of mSCC of the bladder, including a case series of four initially locally advanced and later metastatic SCC patients of our tertiary care hospital. KEY MESSAGES: Despite being the second most common variant histology of bladder cancer, current therapies for SCC do not provide satisfactory therapeutic responses.

[First clinical and oncological experiences with triplet therapy for high-volume metastatic hormone-sensitive prostate cancer]. / Erste klinische und onkologische Erfahrungen mit der Triplet-Therapie beim "high-volume" metastasierten hormonsensiblen Prostatakarzinom.

BACKGROUND: Treatment with androgen deprivation therapy (ADT) plus extended hormone therapy (ARTA) is the standard of care for metastatic hormone-sensitive prostate cancer (mHSPC). Recent data of triplet combination therapies of ADT + ARTA (abiraterone/darolutamide) + docetaxel chemotherapy showed a survival advantage for specific mHSPC patient subgroups. PURPOSE: What treatment response is observed in real-world mHSPC setting using triplet combination therapy and what are the expected side effects? RESULTS: All patients receiving triplet combination therapy of ADT + ARTA (abiraterone/darolutamide) + docetaxel were included in the current study. A total of 14 patients with a median age of 62 years and 10/14 abiraterone or 4/14 darolutamide therapy could be included. The median PSA before initiation of therapy was 77 ng/ml (IQR 44-150). Overall, 86% of patients had a PSA response > 90% and the median PSA nadir was 0.3 ng/ml. Severe adverse events (grade III) during triplet therapy occurred in two patients (35,7%) with respectively febrile neutropenia 7.1% (1/14) and diarrhea with infection 7.1%. Other low grade adverse events (grade I/II) consisted of polyneuropathy (1/14), mucositis (1/14), xerostomia (1/14), weight loss (1/14) and fatigue (3/14) were detected. Chemotherapy was interrupted in one patient due to adverse events. After a median follow-up of ten months (IQR: 7-17), two patients (14.2%) showed progression to castration resistance. CONCLUSION: Triplet therapy shows a very good PSA response in clinical practice. Adverse events during therapy are mainly triggered by classical chemotherapy-known side effects.

Comparison of survival outcomes between laparoscopic versus open radical nephroureterectomy in upper tract urothelial cancer patients: Experiences of a tertiary care single center.

Objectives: To test for differences in overall and recurrence-free survival between laparoscopic and open surgical approaches in patients undergoing radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Materials and methods: We retrospectively identified patients treated for UTUC from 2010 to 2020 from our institutional database. Patients undergoing laparoscopic or open RNU with no suspicion of metastasis (cM0) were for the current study population. Patients with suspected metastases at diagnosis (cM1) or those undergoing other surgical treatments were excluded. Tabulation was performed according to the laparoscopic versus open surgical approach. Kaplan-Meier plots were used to test for differences in overall and recurrence-free survival with regard to the surgical approach. Furthermore, separate Kaplan-Meier plots were used to test the effect of preoperative ureterorenoscopy on overall and recurrence-free survival within the overall study cohort. Results: Of the 59 patients who underwent nephroureterectomy, 29% (n = 17) underwent laparoscopic nephroureterectomy, whereas 71% (n = 42) underwent open nephroureterectomy. Patient and tumor characteristics were comparable between groups (p ≥ 0.2). The median overall survival was 93 and 73 months in the laparoscopic nephroureterectomy group compared to the open nephroureterectomy group (p = 0.5), respectively. The median recurrence-free survival did not differ between open and laparoscopic nephroureterectomies (73 months for both groups; p = 0.9). Furthermore, the median overall and recurrence-free survival rates did not differ between patients treated with and without preoperative ureterorenoscopy. Conclusions: The results of this retrospective, single-center institution showed that overall and recurrence-free survival rates did not differ between patients with UTUC treated with laparoscopic and open RNU. Furthermore, preoperative ureterorenoscopy before RNU was not associated with higher overall or recurrence-free survival rates.

Impact of consensus molecular subtypes on survival with and without adjuvant chemotherapy in muscle-invasive urothelial bladder cancer.

AIMS: Adjuvant chemotherapy after radical cystectomy can reduce the risk of recurrence and death in advanced muscle-invasive urothelial bladder cancer (MIBC). Molecular subtypes have been shown to be associated with survival. However, their predictive value to guide treatment decisions is controversial and data to use subtypes as guidance for adjuvant chemotherapy is sparse. We aimed to assess survival rates based on MIBC consensus molecular subtypes with and without adjuvant chemotherapy. METHODS: Gene expression profiles of 143 patients with MIBC undergoing radical cystectomy were determined from formalin-fixed, paraffin-embedded specimen to assign consensus molecular subtypes. Expression of programmed cell death ligand-1 (PD-L1) and immune cell infiltration were determined using multiplex immunofluorescence. Matched-pair analysis was performed to evaluate the effect of adjuvant chemotherapy on overall survival (OS) for molecular subtypes applying Kaplan-Meier and Cox regression survival analyses. RESULTS: Samples were luminal papillary: 9.1% (n=13), luminal non-specified: 6.3% (n=9), luminal unstable: 4.9% (n=7), stroma-rich: 27.9% (n=40), basal/squamous (Ba/Sq): 48.9% (n=70) and neuroendocrine-like (NE-like): 2.8% (n=4). Ba/Sq tumours had the highest concentration of PD-L1+ tumour and immune cells. Patients with luminal subtypes had better OS than those with NE-like (HR 0.2, 95% CI 0.1 to 0.7, p<0.05) and Ba/Sq (HR 0.5, 95% CI 0.2 to 0.9, p<0.05). No survival benefit with adjuvant chemotherapy was observed for luminal tumours, whereas Ba/Sq had significantly improved survival rates with adjuvant chemotherapy. Retrospective design and sample size are the main limitations. CONCLUSION: Consensus molecular subtypes can be used to stratify patients with MIBC. Luminal tumours have the best prognosis and less benefit when receiving adjuvant chemotherapy compared with Ba/Sq tumours.

Early CRP kinetics to predict long-term efficacy of first-line immune-checkpoint inhibition combination therapies in metastatic renal cell carcinoma: an updated multicentre real-world experience applying different CRP kinetics definitions.

Objectives: Although biomarkers predicting therapy response in first-line metastatic renal carcinoma (mRCC) therapy remain to be defined, C-reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. Here, we aimed to assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real-world first-line mRCC cohort. Methods: Metastatic renal carcinoma patients treated with IO-based first-line therapy within 5 years were retrospectively included in this multicentre study. According to Fukuda et al., patients were defined as 'CRP flare-responder', 'CRP responder' and 'non-CRP responder'; according to Ishihara et al., patients were defined as 'normal', 'normalised' and 'non-normalised' based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression-free survival (PFS), including multivariable Cox regression analyses. Results: Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare- (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non-CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalised patients had a significantly longer PFS and OS, compared with non-normalised group. Conclusion: Different early CRP kinetics may predict therapy response in first-line mRCC therapy in a large real-world cohort. However, further research regarding the optimal timing and frequency of measurement is needed.

Regional differences in metastatic urothelial carcinoma of the urinary bladder patients across the United States SEER registries.

INTRODUCTION: Despite advances in treatment, metastatic urothelial carcinoma of the urinary bladder (mUCUB) is associated with high mortality and treatment risk. We tested for regional differences in mUCUB within a large-scale, population-based database. METHODS: Using the Surveillance, Epidemiology and End Results (SEER) database (2010-2018), patient (age, sex, race/ethnicity), tumor (T-stage, N-stage, number of metastatic sites), and treatment (systemic therapy, radical cystectomy) characteristics were tabulated for mUCUB patients according to 11 SEER registries. Multinomial regression models and multivariable Cox regression models tested overall mortality (OM), adjusting for patient, tumor and treatment characteristics. RESULTS: In 4817 mUCUB patients, registry-specific patient counts ranged from 1855 (38.5%) to 105 (2.2%). Important inter-regional differences existed for race/ethnicity (3-36% for others than non-Hispanic Whites), N-stage (28-39% for N1-3, 44-58% in N0, 8-22% for unknown N-stage), systemic therapy (38-54%) and radical cystectomy (3-11%). In multivariable analyses adjusting for these patient, tumor, and treatment characteristics, one registry exhibited significantly lower OM (SEER registry 10: hazard ratio [HR] 0.83) and two other registries exhibited significantly higher OM (SEER registries 9: HR 1.13; SEER registry 8: HR 1.24) relative to the largest reference registry (n=1855). CONCLUSIONS: We identified important regional differences that included patient, tumor, and treatment characteristics. Even after adjustment for these characteristics, important OM differences persisted, which may warrant more detailed investigation.

Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND: Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2 alterations who have progression after platinum-containing chemotherapy. The effects of erdafitinib in patients with FGFR-altered metastatic urothelial carcinoma who have progression during or after treatment with checkpoint inhibitors (anti-programmed cell death protein 1 [PD-1] or anti-programmed death ligand 1 [PD-L1] agents) are unclear. METHODS: We conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible FGFR3/2 alterations who had progression after one or two previous treatments that included an anti-PD-1 or anti-PD-L1. Patients were randomly assigned in a 1:1 ratio to receive erdafitinib or the investigator's choice of chemotherapy (docetaxel or vinflunine). The primary end point was overall survival. RESULTS: A total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P = 0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients). CONCLUSIONS: Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and FGFR alterations after previous anti-PD-1 or anti-PD-L1 treatment. (Funded by Janssen Research and Development; THOR ClinicalTrials.gov number, NCT03390504.).