bluuebunny/crossref_metadata_2025 huggingface dataset:
Overall survival between veterans with metastatic castration-resistant prostate cancer treated with enzalutamide or abiraterone with kidney disease.
Authors: Wilson Robert , Doherty Jason M , Luo Suhong , Candelieri-Surette Danielle , Eaton Daniel B. , Schoen Martin W.
Published: February 2025

76

Background:
Enzalutamide and abiraterone are androgen receptor pathway inhibitors (ARPIs) used in metastatic castration-resistant prostate cancer (mCRPC). However, little research has compared their efficacy in this population with co-morbid chronic kidney disease (CKD). Since these medications alter androgen signaling differently and abiraterone is co-administered with prednisone, median overall survival (OS) may differ in patients with decreased renal function.
Methods:
Veterans within the Veterans Health Administration initially treated with abiraterone or enzalutamide for mCRPC between September 8, 2014, and October 9, 2023 were included. Age at treatment initiation, PSA at diagnosis, race, Charlson comorbidity index, and baseline serum creatinine values were acquired for each patient. Patients with an estimated glomerular filtration rate (eGFR) less than 60 mL/min were included in the CKD group. Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards modeling was used to adjust for differences in baseline characteristics between study groups.
Results:
We analyzed 10,356 veterans with mCRPC. 1944 (18.8%) had an eGFR less than 60 mL/min and 8412 (81.2%) had an eGFR greater than or equal to 60 mL/min. Of the CKD group, 1093 (56.2%) were treated first with abiraterone and 851 (43.8%) with enzalutamide. The enzalutamide group contained a larger percentage of patients with both cardiovascular disease and diabetes mellitus (47.7% vs. 40.4%, p = 0.06). The abiraterone group had a higher median PSA at diagnosis (7.2 vs 3.9 ng/mL, p < 0.001) and lower median eGFR at treatment initiation (48.82 vs. 49.32 mL/min, p = 0.03). There was no significant difference in median OS between patients treated with abiraterone (n = 4752) or enzalutamide (n = 3660) in the group of patients without CKD (42.9 vs. 44.0 months, p = 0.29). However, in the group of patients with CKD, enzalutamide revealed a longer median OS (35.2 vs 30.5 months, p < 0.001) and decreased mortality when adjusting for differences in baseline characteristics (Adjusted HR 0.80, 95% CI 0.77-0.94). Additionally, patients with CKD were able to take enzalutamide for a longer duration than abiraterone (11 vs. 7 months, p < 0.001).
Conclusions:
In Veterans with CKD, enzalutamide exhibited longer median OS and decreased risk of death relative to abiraterone. Further research into treatment selection based on comorbid disease could generate revised clinical guidelines that optimize survival in patients with mCRPC.

Survival Time
Hazard Ratio with 95% CI
Adjusted Hazard Ratio with 95% CI

CKD Group (n=1944)
Enzalutamide (n=851): 35.2 monthsAbiraterone (n=1093): 30.5 monthsp < 0.001
0.835 (0.754 - 0.926)
0.849 (0.766 - 0.941)

Non-CKD Group (n=8412)
Enzalutamide (n=3660): 44.0 monthsAbiraterone (n=4752): 42.9 monthsp = 0.29
0.944 (0.899 - 0.998)
0.947 (0.899 - 0.998)
Impact of tumor burden on treatment patterns and outcomes in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) treated with avelumab first-line maintenance (1LM).
Authors: Moon Helen , Kearney Mairead , Mahmoudpour Seyed Hamidreza , Ike Chiemeka , Morris Valerie A. , Rava Andrew , Kim Sonia , Sun Haiyan , Dillon Allison , Masek Marty , Sun Jocelyn
Published: February 2025

764

Background:
With the evolving treatment (tx) landscape in la/mUC, patient (pt) clinical characteristics are increasingly important when selecting systemic anticancer tx. This study describes pt characteristics, tx patterns, and clinical outcomes by tumor burden in pts with la/mUC treated with avelumab 1LM following 1L platinum-based chemotherapy (PBC) with no progressive disease (PD).
Methods:
In this noninterventional retrospective study, pts with la/mUC were identified using Flatiron Health’s electronic health record database. Inclusion criteria were pts aged ≥18 years diagnosed with la/mUC between Jan 1, 2019, and Jul 31, 2023, treated with 1L PBC with no PD, followed by avelumab 1LM on/after Jul 1, 2020. Pt characteristics at 1LM initiation, tx patterns, and real-world overall response rate (rwORR) were reported using descriptive statistics. Real-world overall survival (rwOS), progression-free survival (rwPFS), time to next tx (TTNT), and time to tx discontinuation (TTD) were assessed using Kaplan-Meier methods. Subgroup analyses by disease burden were conducted reported: visceral (bone and other visceral) vs nonvisceral metastases (bone only) and lymph node only (includes distant lymph node) vs distant metastases.
Results:
Of 290 pts included, 156 (53.8%) were still receiving avelumab 1LM at data cutoff (Jul 31, 2023). Median age was 71 years; most pts were male (75.9%), White (70.7%), and had ECOG performance status 0/1 (78.3%). Median follow-up from 1LM initiation was 8.7 months. Among 266 pts with metastases, these were visceral in 142 (53.4%), nonvisceral in 124 (46.6%), distant in 183 (68.8%) and lymph node only in 83 (31.2%). 1L PBC was cisplatin-based in 52.4% and carboplatin-based in 47.6%. Median rwPFS and rwOS from avelumab 1LM initiation were 5.0 (95% CI, 3.9-5.8) and 22.0 (95% CI, 18.2-24.8) months, respectively. In pts with tumor assessment during avelumab 1LM (n=236), rwORR was 34.7%. Outcomes by disease burden are shown in the table.
Conclusions:
These results provide insights into clinical outcomes by tumor burden in pts with la/mUC treated with avelumab 1LM. Pts with nonvisceral and/or lymph node-only metastases had more favorable outcomes, consistent with the JAVELIN Bladder 100 trial.

Outcome from 1LM start, median (95% CI), months
Pts with metastases (n=266)

Nonvisceral (n=124)

Visceral (n=142)

rwPFS
5.6 (4.1-7.8)
3.6 (3.1-5.0)

rwOS
23.8 (15.4-NE)
19.1 (12.5-23.8)

TTNT
6.6 (6.6-9.8)
6.0 (4.3-7.4)

TTD
5.3 (4.2-10.1)
4.4 (3.5-5.7)

Lymph node only (n=83)

Distant (n=183)

rwPFS
8.7 (5.0-NE)
3.6 (3.1-4.6)

rwOS
24.3 (20.7-NE)
16.5 (12.5-22.6)

TTNT
8.1 (6.2-23.8)
5.2 (4.3-6.7)

TTD
10.1 (4.9-NE)
4.2 (3.3-5.5)

NE, not estimable.
Patient perceptions about their treatment for muscle-invasive bladder cancer (MIBC) over the last decade.
Authors: Chowdhury Deepro , Apolo Andrea B , Jiang Di Maria , Skinner Eila C. , Chisolm Stephanie , Bangs Rick , Maganti Manjula , Steinberg Gary D. , Kaag Matthew , Efstathiou Jason A. , Sridhar Srikala S.
Published: February 2025

765

Background:
The Bladder Cancer Advocacy Network (BCAN) is a national patient advocacy organization that has promoted awareness about the signs, symptoms, diagnosis, treatment and need for a multidisciplinary approach to the care of patients with MIBC. To better understand the impact of these efforts, and patients’ perceptions of their care, we surveyed bladder cancer patients initially in 2013 and again in 2023 through the BCAN website.
Methods:
We developed a 32-question survey with input from physicians, nurses, patients and caregivers. The survey was posted on the BCAN website 06/13-10/14 (Cohort A) and again from 06/23-04/24 (Cohort B). Questions focused on time from initial symptoms to diagnosis and treatment; proportion seeing a medical oncologist (MO) or radiation oncologist (RO); and treatments offered/received.
Results:
Overall, 337 (243 and 94) patients completed the survey. Respondents were self-selected and most were from the US/Canada, male, white, and had at least an undergraduate education. Median age was 61 (cohort A; range 31-93) and 63 (cohort B; range 38-87), respectively, at the time of diagnosis. The most common presenting symptom was hematuria (88% vs 78%, p=0.05). Overall, 35% vs 30% (p=0.56) waited > 3 months to seek medical attention; in 38% and 43% it took > 3 months to obtain a pathologic diagnosis (p=0.76). Men were more likely than women to be diagnosed within 1-2 months of seeking medical attention: Cohort A (68% vs 47% p=0.03) and Cohort B (70% vs 37%, p=0.03). In both cohorts, prior to surgery, approximately 50% saw a medical oncologist and were offered neoadjuvant chemotherapy; however, less than 10% saw a radiation oncologist and were offered bladder sparing approaches. Most patients reported having all the necessary information, knowing the right questions to ask, and were satisfied with their choices. A higher proportion in Cohort A vs Cohort B felt they had enough time to make their decisions (77% vs 67%, p=0.004).
Conclusions:
Despite nearly two decades of advocacy, there are ongoing areas of unmet need in MIBC. These include reducing time to definitive diagnosis and treatment, especially in women, and increasing multidisciplinary assessments prior to definitive surgery. Respondents were self-selected, had access to the BCAN website, and were highly educated, potentially limiting the generalizability of these results.
Additivity and the efficacy of immune checkpoint blockade-based combination regimens in urothelial cancer.
Authors: Schlachter Noah , Miller Eric James , Anker Jonathan Forrest , Galsky Matthew D. , Palmer Adam C
Published: February 2025

779

Background:
Immune checkpoint blockade (ICB)-based combination regimens have transformed the treatment landscape of advanced solid tumors including urothelial cancer. Understanding whether such combinations are synergistic, additive, or less than additive is crucial for (a) refining combination therapy in urothelial cancer, (b) dissecting the role of concurrent versus sequential treatment, and (c) identifying which cytotoxic agents combine most favorably with ICB. Here we analyzed phase III trials in advanced urothelial cancer to determine if the efficacy of combination therapies were predictable by additivity or exhibited non-additive effects.
Methods:
We analyzed progression-free survival (PFS) from phase III trials of ICB-containing regimens for advanced urothelial cancer (Table). PFS distributions of constituent drugs were used to calculate the predicted PFS of combination therapy under the null hypothesis of additive PFS times (Hwangbo et al, Nature Cancer, 2023). For KEYNOTE-361 and IMvigor130, which allowed investigator’s choice of cisplatin or carboplatin, separate predictions were made for cisplatin- and carboplatin-treated cohorts. The Cox Proportional Hazards model tested whether observed PFS significantly differed from additivity.
Results:
PFS of combination therapies in EV-302, CheckMate901, and DANUBE were statistically indistinguishable from additivity (Table). Trials using choice of cisplatin or carboplatin (KEYNOTE-361, IMvigor130) showed that ICB with cisplatin produced additive PFS, but ICB with carboplatin was significantly antagonistic (inferior to additive PFS;
P
= 0.00004).
Conclusions:
Recently approved regimens enfortumab vedotin + pembrolizumab, and nivolumab + gemcitabine-cisplatin, were as effective as predicted by additivity, demonstrating that combining individually effective agents without synergy can make effective regimens. In advanced urothelial cancer, PD-1 or PD-L1 inhibitors are antagonistic with carboplatin, but confer additive PFS benefits with cisplatin. Modeling the PFS of combination regimens from single agent data could have predicted the success of most contemporary phase III trials in advanced urothelial cancer.

Trial
Combination
Predicted HR for PFS (95% CI)
Observed HR for PFS (95% CI)
P value

EV-302
Enfortumab vedotin + Pembrolizumab
0.49 (0.44 - 0.55)
0.45 (0.38 - 0.54)
0.93

CheckMate901
Nivolumab + Gemcitabine-Cisplatin
0.69 (0.60 - 0.79)
0.72 (0.59 - 0.88)
0.78

DANUBE
Durvalumab + Tremelimumab
0.87 (0.78 - 0.98)
0.88 (0.75 - 1.03)
0.92

KEYNOTE-361
Pembrolizumab + Chemotherapy
0.67 (0.59 - 0.77)
0.78 (0.65 - 0.93)
0.02

IMvigor130
Atezolizumab + Chemotherapy
0.61 (0.55 - 0.68)
0.82 (0.70 - 0.96)
0.0006

Pooled ICB + Gemcitabine-Cisplatin
0.65 (0.56 - 0.74)
0.71 (0.58 - 0.86)
0.78

Pooled ICB + Gemcitabine-Carboplatin
0.63 (0.57 - 0.70)
0.84 (0.73 - 0.97)
0.00004
The prognostic significance of prostate-specific antigen dynamics during abiraterone therapy in patients with high-risk metastatic hormone-sensitive prostate cancer.
Authors: Wang Qian , Zeng Hong , Dai Jindong , Zhu Qiyu , Zhao Jinge , Zhang Xingming , Zeng Hao , Shen Pengfei
Published: February 2025

78

Background:
The depth reduction in prostate-specific antigen (PSA) levels serves as a prognostic indicator for patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC) undergoing treatment with abiraterone. However, the potential impact of the duration of PSA level depth reduction on prognosis remains uncertain.
Methods:
We conducted a comprehensive review of data from 153 high-risk mHSPC patients undergoing first-line abiraterone therapy. The group analysis was conducted based on the alterations in PSA levels during abiraterone therapy. Kaplan-Meier survival curves and Cox proportional hazards regression analysis were used to evaluate the association between the trend and duration of PSA decline and treatment outcomes, which include PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS).
Results:
Among the 153 patients treated, 85 exhibited a minimum PSA level of less than 0.2 ng/ml, 48 had a minimum PSA level ranging from 0.2 to 0.4 ng/ml, and 20 presented with a minimum PSA level exceeding 4 ng/ml.During abiraterone treatment, the lowest PSA level of <0.2 ng/ml was significantly associated with improved mPSA-PFS (51.0 vs. 18.5 vs. 6.9 months, P < 0.0001), mrPFS (52.0 vs. 24.3 vs. 10.3 months, P < 0.0001), and mOS (NR vs. 48.5 vs. 28.1 months, P < 0.0001). A reduction in PSA levels exceeding 90% was correlated with enhanced patient survival outcomes; additionally, a baseline PSA level of <80 ng/ml at the initiation of abiraterone therapy significantly improved patients' mPSA-PFS (43 .1 vs .26 .0 months, P=0 .01), mrPFS (46 .8 vs .27 .5 months, P=0 .01), and mOS (NR vs .43 .8 months, P=0.03).In the cohort with the lowest PSA levels (PSA < 0.2 ng/ml), achieving a PSA level of less than 0.2 ng/ml within six months and maintaining this level for over ten months significantly enhanced clinical outcomes, as evidenced by mPSA-PFS (NR vs. 26.9 months, P < 0.0001), mrPFS (NR vs. 27.5 months, P < 0.0001), and mOS (NR vs. 44.4 months, P < 0.0001). Cox regression analysis indicated that achieving a PSA level of less than 0.2 ng/ml within six months, sustaining this level for more than ten months, along with age and initial PSA at diagnosis were independent prognostic factors.
Conclusions:
In mHSPC patients undergoing first-line abiraterone treatment, a sustained improvement in PSA levels serves as an indicator of therapeutic response, while the rate and depth of PSA decline, along with its duration, are critical prognostic determinants.
Safety and efficacy of FGFR inhibitors in urothelial carcinoma: A systematic review and meta-analysis.
Authors: Sahin Oguz Kagan , Ayesha Ayesha , Łajczak Paweł , Koduru Sriharsha , Khan Rafae Ali , Almirón Giulia , Akram Hussam
Published: February 2025

782

Background:
Urothelial carcinoma is the most frequently occurring bladder cancer and originates from urothelial cells lining the bladder and the urinary tract. Fibroblast growth factor receptor (FGFR) inhibitors are the emerging treatment option, due to their ability to alter FGFR signaling which plays a role in tumor proliferation, survival, and angiogenesis. This study aims to assess the efficacy of FGFR inhibitors for urothelial carcinoma.
Methods:
We conducted a systematic review and single-arm meta-analysis by systematically searching PubMed, Cochrane, and Embase for studies evaluating the efficacy and/or safety of FGFR inhibitors for urothelial carcinoma. The primary measures of effect were hazard ratios (HRs) and the proportion of events per 100 observations, both with 95% confidence intervals (CIs), pooled using a random-effects model with a generalized linear mixed model (GLMM). Heterogeneity was assessed using the I² statistic and Cochran’s Q test. Statistical analyses were performed using RStudio v4.3.3.
Results:
We included 19 studies, comprising two cohort studies and 17 clinical trials, five of which were randomized controlled trials (RCTs), with a combined total of 1,187 patients. The pooled median overall survival (mOS) was 8.77 months (95% CI, 7.28; 10.56), the pooled median progression-free survival (mPFS) was 3.46 months (95% CI, 2.73; 4.40), and the median duration of response (mDOR) was 5.38 months (95% CI, 4.72; 6.14). The grade ≥ 3 adverse effects rate was 49.43% (95% CI, 35.44; 63.51%). The overall objective response rate (ORR) was 24.16% (95% CI, 17.65; 32.14%), in the subgroup analysis of 218 patients using Erdafitinib ORR was 42.25%. The progressive disease and stable disease rates were 48.64% (95% CI, 38.88; 58.50%) and 26.07% (95% CI, 20.01; 33.21%), respectively.
Conclusions:
Our meta-analysis suggests that FGFR-targeted treatment regimens show promising clinical activity in urothelial carcinoma with a comparable safety profile to conventional treatment modalities.
Checkpoint blockade as neoadjuvant strategy: A single-arm meta-analysis of dual PD-1/PD-L1 and CTLA-4 inhibition in urothelial cancer.
Authors: Gazzoni Gabriela , Mamede Isadora , Lopes Guilherme Melchior Maia , Stecca Carlos
Published: February 2025

783

Background:
Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is the standard treatment for muscle-invasive urothelial cancer (MIUC). In patients who are ineligible or deny chemotherapy, upfront surgery is typically preferred. Immune checkpoint inhibitors, such as anti-PD-1/PD-L1 and anti-CTLA-4 antibodies, have emerged as potential neoadjuvant alternatives for these patients. This single-arm meta-analysis evaluates the efficacy and safety of combining anti-PD-1/PD-L1 with anti-CTLA-4 in MIUC.
Methods:
A systematic review of PubMed, Cochrane, ClinicalTrials.gov, and EMBASE identified clinical trials assessing neoadjuvant anti-PD-1/PD-L1 plus anti-CTLA-4 therapy in resectable, non-metastatic high-risk or muscle-invasive urothelial cancer. Outcomes included pathological complete response (pCR), pathological downstaging (<ypT2N0), recurrence-free survival (RFS), mortality, progressive disease (PD), and treatment-related adverse events (TRAEs). Pooled proportions and 95% confidence intervals (CI) were calculated using a random-effects model. Heterogeneity was assessed using I² statistics.
Results:
137 patients were included from 4 clinical trials, encompassing 6 cohorts. Two cohorts received Durvalumab plus Tremelimumab (D+T), and four cohorts received Nivolumab plus Ipilimumab (N+I). Of these, 73.7% were cisplatin-ineligible, and 15.3% had upper tract urothelial carcinoma (UTUC). The overall pooled pCR rate was 35% (CI: 27–44%, I² = 11%), with no significant subgroup difference between in muscle-invasive bladder cancer (MIBC)-only studies compared to studies that included patients with UTUC (p-interaction = 0.33). The downstaging rate was 47% (CI: 36–58%, I² = 41%). One-year RFS was 81% (CI: 64–92%, I² = 44%), while PD occurred in 19% of patients (CI: 9–36%, I² = 44%). The mortality rate was 16% (CI: 10–26%, I² = 11%). Grade ≥3 TRAEs were reported in 29% of patients (CI: 18–44%, I² = 61%). Additionally, TRAEs grade ≥ 3 were numerically less common in the D+T group (22%, 95% CI: 12–35%, I² = 0%) compared to the N+I group (33%, 95% CI: 16–56%, I² = 68%), although this difference was not statistically significant (p-interaction = 0.33).
Conclusions:
Neoadjuvant anti-PD-1/PD-L1 combined with anti-CTLA-4 therapy demonstrates promising pCR, pathological downstaging rates and 1-year RFS in patients with MIUC. Despite Grade ≥3 TRAEs occurring in nearly one-third of patients, the majority were manageable. While these results highlight the potential of this combination for patients who are ineligible or deny NAC, randomized controlled trials are needed to refine patient selection and validate these findings.
Safety and efficacy of intravesical bacillus Calmette-Guerin instillation for superficial recurrence following bladder-sparing therapy of muscle invasive bladder cancer.
Authors: Du Gan , Xie Rui-Yang , Cui Honglei , Bi Xingang , Shi Hongzhe , Zhou Aiping , Guan Youyan , Shou Jianzhong
Published: February 2025

787

Background:
Patients treated with bladder-preserving therapy for muscle-invasive bladder cancer are at risk of developing recurrent non-muscle-invasive bladder cancer. This study aims to evaluate the efficacy and adverse events of postoperative Bacillus Calmette-Guerin (BCG) instillation in patients with superficial recurrence following bladder-preserving therapy for muscle-invasive bladder cancer.
Methods:
We retrospectively analyzed 120 patients diagnosed with non-muscle-invasive bladder cancer who underwent transurethral resection followed by BCG instillation. The 19 patients with prior muscle-invasive bladder cancer were categorized as the NMIBC-M group, while the remaining 101 patients formed the NMIBC group. All patients completed a six-cycle BCG course.
Results:
Both groups showed no significant differences in baseline characteristics, except for the number of BCG instillations (15.5 vs. 9, p = 0.010). Overall survival, recurrence-free survival, metastasis, bladder preservation, and adverse event profiles were comparable between groups. However, patients in the group with prior muscle-invasive bladder cancer reported lower rates of urinary retention (28.7% vs. 0.0%, p = 0.017) and fever (30.7% vs. 5.3%, p = 0.044).
Conclusions:
Postoperative BCG instillation in patients with superficial recurrence following bladder-preserving therapy for muscle-invasive bladder cancer showed comparable efficacy and side effects to those without muscle-invasive bladder cancer history.
Kidney-sparing approach for selected localized high-risk upper tract urothelial carcinoma: A pilot study combining endoscopic thulium laser ablation with perioperative disitamab vedotin and immune checkpoint inhibitors.
Authors: Ye Jianjun , Chen Zeyu , Liao Xinyang , Tu Xiang , Wang Qihao , Zheng Lei , Chen Kai , Wei Qiang , Bao Yige
Published: February 2025

791

Background:
Radical nephroureterectomy (RNU) is the standard treatment for localized high-risk upper tract urothelial carcinoma (UTUC). However, the predominance of UTUC in elderly populations with significant comorbidities necessitates alternative treatment strategies that prioritize functional nephron preservation. This pilot study aims to assess the efficacy and safety of a comprehensive modality of kidney-sparing approach, comprising endoscopic Thulium laser ablation and perioperative systemic therapy (Disitamab vedotin [DV] and immune checkpoint inhibitors [ICIs]), in a carefully selected cohort of localized high-risk UTUC.
Methods:
This ongoing study, initiated in November 2021 at West China Hospital of Sichuan University, included selected patients with localized UTUC patients (cT≤2N0M0) characterized by conditions such as solitary kidney, bilateral tumors, impending/already renal insufficiency and individual refusal/ineligibility for RNU. The treatment protocol consisted of endoscopic biopsy and initial laser ablation, followed by 3-4 cycles of DV and ICIs administered every three weeks as induction therapy. Subsequently, patients underwent maximal endoscopic laser ablation. Those exhibiting efficient response received a 6-month course of DV and a 12-month course of ICIs as maintenance therapy. Co-primary endpoints were 1-yr disease-free survival (DFS) and conversion-free survival (CFS). Secondary endpoints included clinical complete response (cCR) rate, renal function benefits, and treatment safety.
Results:
Thirty-two patients were enrolled, with a median follow-up of 15 months. The majority of patients (26/32, 81.25%) were diagnosed with HER2-positive in biopsy-related IHC, including 3 cases of HER2 3+ and 23 cases of HER2 2+. During the follow-up, 17 local recurrences were observed in 10 patients and the 1-yr DFS rate was 68.75%. HER2 status was a significant predictive factor for local recurrence (OR, 0.15; 95% CI, 0.03, 0.91). Salvage RNU was performed in 2 patients, yielding a 1-yr CFS rate was 93.75%. The cCR rate is 78.13% (25/32). Postoperative renal function impairment was noted in 6 patients (18.75%). Mean eGFR improvements (ml/min/1.73m2) were observed with 3.15 at 1 month, 5.07 at 3 months, 2.41 at 6 months, and 3.97 at 12 months. Notably, no grade 3 or higher systemic toxicities were observed.
Conclusions:
Preliminary findings indicate that the combination of endoscopic Thulium laser ablation with perioperative systemic therapy (DV and ICIs) demonstrated promising efficacy and manageable safety in selected patients with localized high-risk UTUC. These results provide a solid foundation for the ongoing phase 2 trial (WUTSUP-03) and suggest a potential paradigm shift in the management of this challenging patient population.
Efficacy of neoadjuvant/induction (NAC) chemotherapy in nonmetastatic muscle-invasive bladder cancer treated with chemoradiotherapy (CRT): A systematic review and meta-analysis.
Authors: Fauth Seibel Mariana , Dal Ri Letícia , Souza Bruno , Lopes Julia Belone , Liutti Vitor Teixeira , Araujo Daniel Vilarim
Published: February 2025

814

Background:
Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the established standard for nonmetastatic muscle-invasive bladder cancer (MIBC). However, bladder-sparing approaches using chemoradiotherapy (CRT) offer comparable outcomes. While NAC has proven beneficial before RC, its value prior to CRT remains uncertain. This systematic review and meta-analysis aimed to evaluate the impact of NAC on outcomes in patients undergoing CRT for bladder preservation.
Methods:
A comprehensive search of PubMed, Embase, and Cochrane databases was conducted to identify studies comparing NAC plus CRT versus CRT alone in MIBC. Both randomized controlled trials (RCTs) and observational studies were eligible. Studies with overlapping populations or non-English publications were excluded. Heterogeneity was assessed with I² statistics, and all analyses were performed using random-effects models in Review Manager 5.4.1. The study was registered in PROSPERO (CRD42024590258).
Results:
Four observational studies, encompassing 3,354 patients, were included as no RCTs met the inclusion criteria. NAC was administered to 656 patients (19.5%). Median follow-up ranged from 15.9 to 74.4 months. All patients in the NAC group received platinum-based chemotherapy (MVAC, ddMVAC, GC, or CMV). Concurrent CRT regimens included cisplatin, gemcitabine, or mitomycin with radiotherapy. No significant difference in overall survival was observed between NAC + CRT and CRT alone (HR = 0.99, 95% CI 0.87–1.13, p = 0.89, I² = 0%). Disease-free survival data were available from two studies, showing no significant difference (HR = 1.07, 95% CI 0.57–2.01, p = 0.82, I² = 39%). All included studies had a serious risk of bias, mainly due to confounding and selection bias, as assessed by the ROBINS-I tool. The overall certainty of the evidence was rated as very low using the GRADE framework.
Conclusions:
Our analysis found no survival benefit from adding NAC to CRT in patients with MIBC. However, the quality of the evidence is very low, largely due to the retrospective nature of the data. Further randomized clinical trials are needed to clarify the role of NAC in bladder preservation strategies.
Evaluation of systemic therapy and surgical consolidation in patients with node positive upper tract urothelial carcinoma.
Authors: Kim Joon Kyung , Spencer Katelyn , Cranford Will , Fleisch Justus , Myint Zin , Allison Derek B. , Martin Frances Marian , Strup Stephen , McLouth Christopher , Hensley Patrick J.
Published: February 2025

816

Background:
The recommended treatment for high-grade upper tract urothelial carcinoma (UTUC) includes radical nephroureterectomy with regional lymph node dissection for clinically organ-confined disease. The timing of peri-operative systemic therapy is multifactorial, with extrapolation of data from muscle-invasive bladder cancer in the neoadjuvant setting, and level 1 data for UTUC in the adjuvant setting. The timing of peri-operative systemic therapy and need for surgical consolidation in the clinically node positive setting is even more unclear. The goal of this study is to compare survival in cN+ patients managed with neoadjuvant, adjuvant, and systemic therapy alone approaches.
Methods:
Patients with cT0-4 N1-3 M0 UTUC who received chemotherapy with or without nephroureterectomy (NU) between 2018 and 2021 in the National Cancer Database (NCDB) were included. Patients were stratified into three treatment groups: chemotherapy only (CO), neoadjuvant chemotherapy followed by nephroureterectomy (NAC-NU), and nephroureterectomy followed by adjuvant chemotherapy (NU-AC). OS was analyzed using Kaplan-Meier analysis and log rank tests. Cox proportional hazard models were employed to adjust for potential confounders.
Results:
A total of 1193 patients were included (CO, NAC-NU, and NU-AC treatment groups consisted of 495, 287, and 411 patients, respectively). Patients in the CO group were older (P<0.001), more commonly males (P<0.001) compared with NAC-NU and NU-AC cohorts. There was no significant difference in Charlson comorbidity index between the three groups. The pathologic complete response rate (ypT0N0) in the NAC-NU was 6.5%. Patients managed with NAC-NU exhibited the most favorable OS compared to NU-AC and CO (P<0.0001), with 3-year OS 65.4% (95% CI 58.4%-73.3%), 53.5% (47.9%-59.6%), and 20.8% (15.7%-27.6%) in these groups, respectively. On multivariate analysis controlling for age, sex, and clinical stage using NAC-NU as a referent, NU-AC and CO exhibited inferior OS (HR 1.48, 95% CI 1.06-2.06, P=0.021 and HR 2.92, 2.14-4.00, P<0.001, respectively).
Conclusions:
The use of neoadjuvant chemotherapy followed by nephroureterectomy provides optimal survival outcomes in patients with cN+ high-grade UTUC. These data suggest that, when feasible, surgical consolidation is an important treatment component in patients with cN+ disease, likely owing to low rates of pathologic complete response.

Estimated overall survival at 1- and 3-year endpoints.

Treatment
Sample Size
1 Year Survival (95% CI)
3 Year Survival (95% CI)

Chemo Alone
348
57.6% (52.5% - 63.2%)
20.8% (15.7% - 27.6%)

Chemo before Surgery
202
80.8% (75.4% - 86.6%)
65.4% (58.4% - 73.3%)

Surgery before Chemo
329
72.8% (68.1% - 77.8%)
53.5% (47.9% - 59.6
Survival outcomes of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) receiving lutetium-177-PSMA-617 (Lu) based on line of therapy.
Authors: Sayegh Nicolas , Jo Yeonjung , Ozay Zeynep Irem , Hage Chehade Chadi , Gebrael Georges , Ostrowski Micah , Campbell Patrick , Tripathi Nishita , HU Siqi , Chigarira Beverly , Anderson Ethan , Ji Richard , Fortuna Gliceida Galarza , Mathew Thomas Vinay , Li Haoran , Gupta Sumati , Maughan Benjamin L. , Agarwal Neeraj , Swami Umang
Published: February 2025

82

Background:
Lu is a prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical that delivers beta radiation to PSMA-positive cells. It is approved for pts with mCRPC who had prior progression on an androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy. However, there are limited real-world data on the efficacy of Lu based on the line of therapy. Herein, we aimed to assess the survival outcomes of pts with mCRPC receiving Lu in a real-world setting.
Methods:
This retrospective study utilized the nationwide Flatiron Health electronic health record (EHR) derived de-identified database. Eligibility: pts diagnosed with mCRPC who received Lu for the first time. Survival was calculated from the date pts received their first treatment with Lu. Time to next treatment (TTNT) and overall survival (OS) were summarized using Kaplan Meier survival estimates and its 95% confidence intervals (CI).
Results:
Of the overall cohort of 24,105 pts with metastatic prostate cancer in the dataset, 303 diagnosed between 1/1/2013 and 7/11/2023 received treatment with Lu. The median age of these pts was 75 years (IQR 69 – 80). The majority were White non-Hispanic (69%), treated in a community practice (82%), covered by a commercial health plan (86%), and received Lu in the third line or later (91.4%). For pts treated with Lu, the median TTNT was 8.5 months (95% CI, 7.3 – 9.8), and the median OS was 12 months (95% CI, 11 – 15). Median TTNT and OS by line of therapy are summarized (Table).
Conclusions:
Lu retains clinical activity in pts with mCRPC regardless of line of therapy. These data may aid with patient counseling, prognostication, and selection of therapy in the clinic.

Median TTNT and OS by line of therapy in pts with mCRPC receiving Lu.

Line of therapy
Number of pts, n (%)
Median TTNT (mo) (95% CI)
Median OS (mo) (95% CI)

2
26 (8.6)
8.5 (5.6, -)
12 (8.5, -)

3
77 (25.4)
8.0 (6.4, 11)
17 (8.9, -)

4
82 (27)
8.2 (6, 10)
10 (7.2, 22)

5
64 (21)
9.8 (6, 13)
13 (11, -)

6
28 (9.2)
9 (5.7, -)
13 (12, -)

7
17 (5.6)
10 (7.3, -)
10 (7.3, -)

8
6 (2)
7 (3.7, -)
(3.7, -)

9
2 (0.7)
7.3 (3, -)
10 (8.6, -)

14
1 (0.3)
8.6 (-, -)
14 (-, -)
TP53 Y220C mutations in advanced urothelial bladder cancer (UBC): A genomic landscape study.
Authors: Nadal Rosa , Jacob Joseph M , Bratslavsky Gennady , Basnet Alina , Ross Jeffrey S. , Lin Douglas I , Gjoerup Ole , Cheng Liang , Gupta Shilpa , Agarwal Neeraj , Spiess Philippe E. , Li Roger , Kamat Ashish M. , Necchi Andrea , Grivas Petros
Published: February 2025

821

Background:
TP53
is the most frequently altered gene in human cancers. Novel agents targeting the pathogenic
TP53-
Y220C mutation and p53-based cancer therapy have attracted significant interest. Evaluation of
TP53-
Y220C mutation and co-occurrent alterations in UBC is needed.
Methods:
FFPE tissue from 11,224 UBC patients (pts) underwent hybridization capture and comprehensive genomic profiling. A total of 324 cancer related genes including selected introns of 31 genes frequently rearranged in cancer were evaluated for genomic alterations (GA). We obtained an average sequencing depth of 650X. Microsatellite instability (MSI) status and tumor mutation burden (TMB) were estimated using next-generation sequencing. TMB-high was defined as ≥10 mutations/Mb. PD-L1 expression was measured by IHC (DAKO 22C3). Comparisons were performed using the χ
2
method with Yates correction.
Results:
TP53
Y220C mutation (Y220C+) was identified in 73 UBC (0.65%). Age/gender were comparable between
TP53
Y220C negative (Y220C-) and
TP53
Y220C+ pts; 8.4% of
TP53
Y220C+ and 8.2% of
TP53
Y220C- UBC cases exhibited ≥1 GA. In
TP53
Y220C+ UBC, the frequency of co-occurring GA was significantly lower for
FGFR3
(8.2% vs 18.3%; P = .038),
MTAP
loss (13.3% vs 25.1%; P = .035),
CDKN2A
(26% vs 37.8%; P = .05), and
CDKN2B
(19.2% vs 30.2%; P = .05) vs
TP53
Y220C- UBC.
BRCA1
GA was significantly higher in
TP53
Y220C+ UBC (8.2% vs 2.0%; P < .0001). In
TP53
Y220C+ UBC, trends were observed with numerically higher GA frequency in
ERBB2
(20.5% vs 17.6%; not significant [NS]),
RB1
(24.7% vs. 21.4%; NS) and numerically lower GA frequencies in
TERT
(61.1% vs 76.1%; NS),
PIK3CA
(15.1% vs 21.6%; NS). No significant differences in other GA frequencies:
TSC1
(8.2% vs 9.0%, NS),
ERBB3
(6.8% to 6.2%, NS),
BRCA2
(4.1% to 3.2%, NS),
FGFR2
(2.7% to 1.1%, NS), or in MSI / TMB status were detected between groups. PD-L1 low expression (1-49%) was observed in 7.3% of
TP53
Y220C+ UBC.
Conclusions:
The
TP53
Y220C mutation is rare in advanced UBC (< 1% of cases). In our study, this mutation was associated with specific co-occurring GA, notably with a significantly lower frequency of
FGFR3
and
higher BRCA1
GA.
TP53
Y220C mutation warrants further clinical investigation in basket trials, including UBC, e.g. NCT04585750.

TP53
Y220C+ UBCn=73

TP53
Y220C- UBCn=11,151

p
value

BRCA1

8.2%
2%
<.0001

FGFR3

8.2%
18.3%
.038

MTAP

13.3%
25.1%
.035

CDKN2A

26%
37.8%
.05

CDKN2B

19.2%
30.2%
.05

MSI-high
0%
0.7%
NS

TMB-high
34.2%
34.1%
NS
Efficacy outcomes 12 months after initiation of darolutamide in non-metastatic castrate resistant prostate cancer (nmCRPC) from the real world UK multi-centre RECORD study.
Authors: Challapalli Amarnath , Bahl Amit , Randhawa Manreet , Parikh Omi , Sundar Santhanam , Birtle Alison Jane , Malik Jahangeer , Prentice Mark , Muthukumar Dakshinmoorthy , Bhana Rajanee , Jayaprakash Kamalram Thippu , Syndikus Isabel , Mitra Anita , Elumalai Thiraviyam , Gray Emma , Glen Hilary , Beresford Mark , Khoo Vincent , Foulstone Emily , White Paul
Published: February 2025

83

Background:
Darolutamide has authorisation for treatment of non-metastatic Castrate Resistant Prostate Cancer (nmCRPC) based on the ARAMIS trial. The RECORD Study is a prospective real-world evaluation (RWE) of clinical outcomes in patients with nmCRPC treated with darolutamide in the UK. The study will improve understanding of treatment response and duration as well as inform regarding the use of next generation imaging (NGI) and effects of concomitant medication.
Methods:
Patients were enrolled from 19 centres over a 3-year period from November 2020. Data cut-off was 16 September 2024. Disease characteristics of patients and efficacy up to 12 months (m) after initiation of darolutamide are evaluated. Descriptive statistics will be used for patient demographics.
Results:
257 patients were analysed with a median age of 77 (range 52-94) years (y). 52% have a Gleason score ≥8. 30 patients (11.7%) had NGI prior to initiation of darolutamide and 41 (15.8%) were on anticoagulant/antiplatelet medication. ECOG 0:35%, 1:59% and 2:6.2%. Median pre-treatment PSA was 9.7ng/mL and pre-treatment PSA doubling time (PSAdT) was 5 months. The greatest reduction in median PSA values was seen within the first 3m on darolutamide but was still decreasing slightly at 12m. PSA response was as follows: PSA
50
reduction at 3, 6, 9 and 12 months was 74%, 77%, 75% and 73% respectively and PSA
90
reduction at 3, 6, 9 and 12 months was 28%, 38%, 43% and 42% respectively. No differential effect on PSA reduction was seen with Gleason score (<8, ≥8), PSAdT≤6m or >6m, previous treatment (RT or prostatectomy), anticoagulant/antiplatelet medication or those who had NGI. Median duration of treatment on darolutamide did not significantly differ (p=0.067) in patients with PSAdT>6m (104 patients) compared to those with PSAdT≤6m (135 patients). 46 patients (17.9%) have come off treatment within 12m of initiation: 26 (10.1%) disease progression, 8 (3.1%) toxicity (most frequent being fatigue and diarrhoea), 12 other unrelated causes including 1 death.
Conclusions:
This RWE shows that patients with nmCRPC in clinical practice have comparable outcomes to the ARAMIS trial. Response rates, tolerability and discontinuation rates are similar and in particular only 3.1% discontinuing treatment due to toxicity. Gleason score >8; PSAdT and the use of NGI had no differential impact on PSA response. This is valuable RWE enabling optimisation of treatment in nmCRPC.
Deciphering immune-genomic markers of hyperprogression in patients (Pts) with metastatic urothelial cancer (mUC) treated with immune checkpoint inhibitors (ICIs).
Authors: Pramod Nikhil , Pavicic Paul G. , Dawsey Scott , Patgunarajah Ubenthira , Maroli Kimberly , Malhotra Riya , Ornstein Moshe C. , Gilligan Timothy D. , Wee Christopher Eing , Mian Omar Y. , Nizam Amanda , Ni Ying , Nguyen Jane , Diaz-Montero C. Marcela , Gupta Shilpa
Published: February 2025

840

Background:
ICIs offer modest response rates (~20%) in mUC and there remains a critical need for validated biomarkers to predict patient benefit. Hyperprogressive disease (HPD), characterized by rapid tumor progression following ICI initiation, is a poorly understood phenomenon in mUC. No robust biomarkers currently exist to identify patients at risk for HPD, a condition that leads to unnecessary treatment and exacerbated toxicity. While patient factors associated with HPD have been studied, little is known about the tumor’s immune-genomic landscape in these cases. We investigate the immune-genomic features of mUC tumors associated with HPD to better understand and predict this response to ICI.
Methods:
We retrospectively analyzed 132 pts with mUC treated with atezolizumab or pembrolizumab between 2015-2023. All patients received at least 2 ICI cycles, and archival FFPE tumor samples were available for immune-genomic analysis. Pts were classified as responders (N=75, defined as complete/partial response or stable disease) or non-responders (N=57, progressive disease). HPD was defined as progression per RECIST within 14 weeks of ICI initiation. RNA was extracted from macrodissected FFPE samples, and transcriptomic profiling was performed using the Nanostring PanCancer IO 360 panel. Data were processed using nSolver 4.0 and nanostring data analysis service analyzed for differential gene expression. Receiver operator characteristic (ROC) analysis was conducted to assess the predictive power of immune signatures for HPD.
Results:
Of the 132 pts, 48 (36%) were classified as having HPD. Compared to non-responders without HPD, HPD tumors exhibited significant downregulation of immune signatures, including IFN Gamma, PD-L1, myeloid cells, and tumor inflammation signatures (TIS). Key chemokines and IFN downstream signaling were also downregulated (p-adj = 0.041). Single-gene analysis highlighted downregulation of CCL4 (logFC = -0.947, p = 0.00012), GBP1 (logFC = -0.8105, p = 0.00017), and NECTIN2 (logFC = -0.4792, p = 0.00032) in HPD tumors, though statistical significance was not reached after adjustment. ROC analysis demonstrated modest predictive power for HPD with AUCs of 0.66 for TIS and IFN Gamma, and 0.658 for the immunoproteasome.
Conclusions:
Our findings reveal a distinct immune-genomic profile in mUC tumors associated with HPD following ICI treatment, including reduced IFN Gamma, TIS, and myeloid cell signaling. These immune signatures may serve as potential biomarkers to identify pts at risk of HPD, warranting further validation in prospective trials. Ongoing analyses will continue to explore the genomic underpinnings of HPD and therapeutic resistance in mUC.
Protein analysis of urachal carcinoma tissue based on different antibody-drug conjugate therapeutic targets.
Authors: Han Tian , Cui Honglei , Bi Xingang , Shi Hongzhe , Guan Youyan , Shou Jianzhong , Zhou Aiping
Published: February 2025

852

Background:
Urachal carcinoma (UrC) is an extremely rare cancer, and there is still a lack of standard drug treatment models for advanced UrC. Antibody-drug conjugate (ADC) therapy represents a promising cancer treatment method. However, the efficacy of ADC on UrC remains unclear due to the scarcity of knowledge about the immunohistochemical features of relevant targets. This study focused on the immunohistochemical features of UrC based on ADC therapeutic targets and its relationship with overall survival (OS), providing a basis for UrC treatment.
Methods:
A total of 45 postoperative pathological specimens confirmed to be UrC were collected. Using immunohistochemistry, protein expression levels of ADC targets HER2, Nectin-4, Claudin18.2, Trop2, Mesothelin, and the immunotherapy target PD-L1 were assessed, with the proportion of high expression (2+ or 3+) of target proteins evaluated. 38 cases with complete clinical information were screened to evaluate the relationship between the expression of target proteins and OS.
Results:
Among the ADC therapeutic targets, Trop2 had the highest high expression rate (55.6%) in UrC tissues, followed by Mesothelin (46.7%), Claudin18.2 (31.1%), Nectin-4 (22.2%), and HER2 (15.6%). The high expression rate of PD-L1 was 15.6%. The median age of UrC patients was 53.5 years. Sheldon stage I, III and IV patients accounted for 2.6%, 89.5% and 7.9%, respectively. Survival analysis revealed that the five-year survival rate was 85.7% in the low Trop2 expression group and 49.2% in the high expression group. High expression of Trop2 was associated with poor OS (P=0.031).
Conclusions:
The target proteins of ADC are expressed in UrC tissue. Trop2 exhibits a significant high expression rate, and UrC patients with high Trop2 expression have a worse prognosis. Trop2 could be a pivotal target for future ADC treatment of UrC.
Impact of loss of PRLHR on aneuploidy and initiation of bladder cancer.
Authors: Zheng Xi , Yang Bingjie , Wang Wenya , Azoitei Anca , Wezel Felix , Bolenz Christian , Guo Hongqian , Günes Cagatay
Published: February 2025

854

Background:
The question still remains for the presence of yet unknown genetic modifiers in the initiation and/or progression of bladder cancer (BC). It remains challenging to identify the key factors, the mechanism and potential target behind. A genome-wide CRISPR library colony formation assay was performed using UROtsa cells, an immortalized ureter epithelium cell line, in order to identify novel genes that promote the transformation of normal urothelial cells. As one of the top candidate genes, the Prolactin Releasing Hormone Receptor (PRLHR) was identified. To date, only a few studies addressed the impact and the correlation of PRLHR in cancer and reports in the context of BC are missing altogether.
Methods:
We assessed the gene and protein expressions via public database, qPCR and Western blot analyses in a set of nontumour cell strains (Y235T, UROtsa) and a set of BC cell lines (RT4, T24). Following the shRNA knockdown in the PRLHR-proficient cells(Y235T) and the ectopic PRLHR expression in the cell lines with low/absent PRLHR expression(T24), we performed functional experiments, such as soft agar colony formation assay, MTT, invadopodia and gelatine degradation assays. We determined the invasion and migration abilities of these genetically modified cells by using the and wound-healing, Boyden chamber and porcine bladder ex vivo organ culture invasion assay. Metaphase spread assay and Immunofluorescence was performed in modified Y235T cells for chromosome counting and microscopy observation (centrsomes, chromosomal misalignments and lagging chromosomes).
Results:
The available in silico expression data and expression analyses in BC cell lines and matched normal/tumour patient samples revealed the repression of PRLHR early in BC tumorigenesis. Soft agar experiments confirmed that ectopic PRLHR impairs colony formation of T24 cells, providing indirect evidence that the CRISPR-Cas9 mediated deficiency of PRLHR promoted UROtsa cells transformation in the screening assay. Functional experiments using the MTT and the wound healing assays showed that ectopic PRLHR improved the viability and migration abilities of BC cells. The Boyden chamber assay and the porcine bladder organ culture model revealed that PRLHR impairs BC cell invasion, likely by the inhibition of the AKT/PKB pathway. Moreover, we observed an abnormal number of centrosomes, an increasing number of lagging chromosomes in the anaphase and telophase of the PRLHR-knockdown cells during mitosis.
Conclusions:
The screening procedure identified PRHLR as a new candidate tumour suppressor factor, and that loss/down-regulation of this protein contributes to the progression of bladder cancer. Downregulation of PRLHR leads to aneuploidy and genome instability in urothelial cells. PRLHR might serve as a novel biomarker or potential target for BC.