bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired renal function and cisplatin-based regimens as risk factors for neoadjuvant chemotherapy-induced acute kidney injury in muscle-invasive bladder cancer: A multicenter retrospective study.
Authors: Fujita Naoki , Hosogoe Shogo , Tanaka Toshikazu , Ishii Noritaka , Momota Masaki , Ito Hiroyuki , Yoneyama Takahiro , Ohyama Chikara , Hatakeyama Shingo
Published: February 2025

760

Background:
Neoadjuvant chemotherapy (NAC)-induced acute kidney injury (AKI) is one of the frequent complications in patients with muscle-invasive bladder cancer (MIBC) and we previously have reported the negative impact of NAC-induced AKI on oncological outcomes. However, its risk factors remain unclear.
Methods:
This multi-institutional retrospective study included 517 patients with MIBC who received 2–4 cycles of NAC followed by radical cystectomy. AKI was defined according to the KDIGO criteria. Patients were divided into two groups: patients who developed any stage AKI during NAC (AKI group) and patients who did not (non-AKI group). Multivariable logistic regression analysis was performed to identify the risk factors for NAC-induced AKI. The predictive abilities for AKI were evaluated using the area under the receiver operating characteristic (ROC) curve.
Results:
The median age was 69 years. Of the 517 patients, 188 (36%) received cisplatin-based regimens and 92 (18%) developed any stage AKI. Approximately 86% AKI were stage 1 AKI. eGFR in the AKI group was significantly lower than that in the non-AKI group (
P
<0.001). The rate of AKI development in patients who received cisplatin-based regimens was significantly higher than that in patients who received carboplatin-based regimens (
P
<0.001). In the multivariable analysis, hypertension, impaired renal function, and cisplatin-based regimen were independently and significantly associated with increased risk of AKI (Table). The optimal cutoff value of estimated glomerular filtration rate for AKI was 65.0 mL/min/1.73m
2
. ROC analysis showed that the area under the curve (AUC) of hypertension plus eGFR <65.0 mL/min/1.73m
2
plus cisplatin-based regimen was 0.748 (95% confidence interval: 0.697–0.799).
Conclusions:
Hypertension, impaired renal function, and cisplatin-based regimens were risk factors for NAC-induced AKI in patients with MIBC.

Multivariable analysis for AKI development.

Factor

P
value

Odds ratio
95% CI

Age
Continuous
0.462
0.989
0.959–1.019

Hypertension
Presence
0.016
1.894
1.128–3.179

eGFR
Continuous

<0.001

0.955

0.939–0.971

Cisplatin-based regimens
Positive

<0.001

6.530

3.725–11.45
Boosting survival in advanced urothelial carcinoma: The power of CBM588 probiotic and pembrolizumab combination.
Authors: Yoshino Hirofumi , Enokida Hideki
Published: February 2025

774

Background:
Immune checkpoint inhibitors (ICIs) is now standard cares for locally advanced or metastatic Urothelial Carcinoma (UC). One of the probiotics, CBM588 (MIYAIRI 588), is widely used in clinical practice and regulates the intestinal microbiota. Recently, the relationship between ICIs and probiotics in cancer therapy has attracted attention with prolonged prognosis reported in lung and renal cancers when combined with CBM588. However, there are no reports on the usefulness in UC.
Methods:
We retrospectively evaluated the effect of pembrolizumab plus CBM588 in patients with unresectable UC treated with pembrolizumab as second-line therapy at our institution, with and without CBM588. The analysis was divided into two groups: those taking CBM588 (n=33) and those not taking CBM588 (n=11) at the time of pembrolizumab initiation. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints.
Results:
The median follow-up was 12.0 months in the pembrolizumab alone group versus 12.2 months in the CBM588 group. The median PFS was 3.9 months in the pembrolizumab alone group versus 10.2 months in the CBM588 group. On multivariate analysis, the hazard ratio for the CBM588 arm was 0.074. The median OS was 12.2 months in the CBM588 arm versus 12.0 months in the pembrolizumab alone arm. On multivariate analysis, the hazard ratio for the CBM588 arm was 0.105 (95% CI 0.022-0.533, P=0.0056).
Conclusions:
The combination of CBM588 with pembrolizumab may prolong progression in UC. Although the sample size and follow-up period are limited, the positive outcomes observed emphasize the necessity for further studies to confirm these findings and investigate the underlying causes.

Multivariate analysis of PFS and OS.

Multivariate Analysis-PFS

Multivariate Analysis-OS

Variables
Groups
Hazard ratio
95% CI
P-value

Hazard ratio
95% CI
P-value

Treatment
PEM
reference

reference

PEM with CBM588
0.074
0.016-0.340
0.0008
**
0.105
0.022-0.533
0.0056
*

Age

0.947
0.901-0.995
0.030
*
0.992
0.944-1.043
0.738

Sex
male
reference

reference

female
1.410
0.546-3.643
0.4786

0.717
0.292-1.985
0.513

ECOG-PS
0 - 1
reference

reference

2 - 4
0.338
0.136-0.837
0.0191
*
1.067
0.400-2.712
0.894

Tumor location (primary)
Lower urinary tract
reference

reference

Upper urinary tract
1.455
0.577-3.662
0.426

0.666
0.228-1.986
0.461

T stage (primary)
0 - 2
reference

reference

3
3.634
1.340-9.835
0.011
*

1.210-8.763
0.019
*

unknown
7.623
1.291-45.00
0.025
*
6.368
1.069-37.93
0.042
*

N stage
0
reference

reference

1
0.976
0.380-2.505
0.958

1.328
0.521-3.389
0.552

M stage
0
reference

reference

1
1.407
0.298-6.652
0.666

1.579
0.313-7.944
0.579

Lung metastasis
1
0.871
0.297-2.55
0.801

0.497
0.151-1.633
0.249

Liver metastasis
1
5.465
1.516-19.70
0.0094
*
2.889
0.735-11.34
0.129

Bone metastasis
1
1.841
0.608-5.57
0.280

1.447
0.445-4.703
0.539

IrAE
1
0.133
0.03-0.586
0.0077
**
0.277
0.056-1.359
0.114

*p < 0.05; **p < 0.008.
Preliminary efficacy and safety of disitamab vedotin (DV) combined with bacillus Calmette-Guérin (BCG) in the treatment of high-risk non-muscle invasive bladder cancer with HER2 expression: A prospective, open label, single-center study.
Authors: Shen Yijun , Peng Liangju , Gu Weijie , Lu Xiaolin , Shen Ying , Ye Dingwei
Published: February 2025

775

Background:
Current treatment for high-risk non-muscle invasive bladder cancer (HR-NMIBC) involves Bacillus Calmette-Guérin (BCG) therapy, or radical cystectomy (RC) especially for patients with very-high-risk features. However, 40%-60% HR-NMIBC pts will relapse after BCG treatment. Moreover there are a high incidence of postoperative complications and a negative impact on health-related quality of life after RC. Disitamab Vedotin (DV) is a novel antibody drug conjugate (ADC) that targets the HER2 protein, however its efficacy and safety in HR-NMIBC are limited.We conducted a prospective, open label, single-center study to evaluate the value of RC48 combined with BCG in HR-NMIBC pts.
Methods:
In this study, two cohorts of BCG-naive pts with very-high-risk features who refused to undergo RC or did not meet the requirements of RC with HER2 expression (IHC 1+/2+/3+) were enrolled (Cohort A:pts were unable to undergo complete tumor resection or have CIS. Cohort B: pts underwent complete tumor resection). All pts will receive eight cycles of intravenous injection of DV (2mg/kg, once every three weeks) and at least one year of BCG intravesical instillation. The Primary endpoints included the 3-month cCR rate in Cohort A and the 6-month EFS rate in Cohort B. The secondary endpoints were to evaluate additional efficacy end points and safety.
Results:
From Dec 2023 to Aug 2024, twenty eligible pts(16 male;4 female)were enrolled, with 15 pts in Cohort A and 5 pts in Cohort B. 17 of pts had HER2 high expression (2+ or 3+), and 3 of them had HER2 low expression (1+). As a cut-off date (12-Sep-2024), the cCR rate at 3 months and 6 months were both 100% in 11 and 5 pts of Cohort A and the EFS rate at 6 months was also 100% in 3 pts of Cohort B. 65% (13/20) pts experienced treatment-related adverse events (TRAEs). The most common TRAEs included AST/ALT increase 40%(8/20) ,alopecia 45% (9/20), peripheral sensory neuropathy 35% (7/20), anorexia 10% (2/20) and rash 5% (1/20). Grade 3 TRAEs occurred in 10% (2/20) pts with one peripheral sensory neuropathy caused by DV and one hematuria caused by BCG. 60% (12/20) pts had BCG-related AEs including bladder irritation, fever, arthralgia, conjunctivitis and hematuria.
Conclusions:
This was the first study to evaluate DV in combination with BCG in the treatment for HR-NMIBC. Preliminary results showed the combination had promising efficacy with a manageable safety profile. This may potentially provide a new bladder-sparing therapy for very HR-NMIBC pts with HER2 expression who refused RC or did not meet the requirements of RC. Clinical trial information:
NCT06187506
.
Long-term results of a phase 2 study of neoadjuvant chemotherapy combined with tislelizumab followed by radiotherapy for bladder-preserving treatment in selected high-risk/locally advanced muscle invasive urothelial bladder cancer (HOPE-02).
Authors: Wen Feng , Lin Tianhai , Tan Ping , Deng Jiani , Ren Min , Zhang Mengni , Zheng Xiaonan , Zhang Peng , Shen Yali
Published: February 2025

786

Background:
The “bladder-sparing” trimodal therapy (TMT) has gained popularity among selected patients with muscle-invasive bladder cancer (MIBC) who are either unfit for or decline radical cystectomy (RC). This Phase 2 study aimed to evaluate the bladder-sparing efficacy of neoadjuvant chemotherapy combined with tislelizumab, followed by radiotherapy for high-risk, locally advanced MIBC, who were considered as non-ideal candidates for bladder-sparing treatment (Trial registration number: ChiCTR2100045213).
Methods:
Patients diagnosed with cT2-4bN0-3M0-1a MIBC will be included in the study if they demonstrate non-progression of disease (PD) after two cycles of neoadjuvant chemotherapy (gemcitabine and cisplatin or carboplatin) combined with tislelizumab. Radiotherapy will be administered to patients after one or two additional cycles of neoadjuvant therapy, and tislelizumab will continue for up to one year. The primary endpoint is the complete response rate (CR, including T0/Ta/Tis) after radiotherapy, while the secondary endpoints include progression-free survival (PFS), bladder-intact disease-free survival (BI-DFS), overall survival (OS), and toxicity.
Results:
Preliminary results of safety were presented at the ASCO-GU meeting in 2023, and we are now reporting the long-term outcomes. A total of 45 patients were enrolled. The median follow-up time was 36.10 ± 2.92 months. All participants completed 3 to 4 cycles of neoadjuvant therapy, resulting in a CR rate of 51.11%. Among the patients, 36 completed radiotherapy and underwent efficacy evaluations through imaging and cystoscopic biopsy. However, nine patients withdrew from the study due to personal requests for surgery, traditional Chinese medicine, or changes in systemic therapy. Of the 36 patients, 2 were Tis, and 31 were T0 after radiotherapy, indicating a primary CR rate of 100%. The 2 Tis patients received intravesical BCG vaccine therapy and achieved T0 by the time of the second therapeutic evaluation. No patient underwent radical cystectomy. 3-year PFS rate and 3-year BI-DFS were 76.0%, and 3-year OS was 81.0%. One patient experienced bladder recurrence with T1, while 3 patients developed distant metastases. Four patients died, with 2 deaths attributed to other reasons.
Conclusions:
Neoadjuvant chemotherapy combined with tislelizumab provides an opportunity for suboptimal candidates to become suitable for bladder-sparing approaches, and radiotherapy-based bladder-preserving treatment demonstrated excellent long-term efficacy and acceptable toxicity, making it a potentially optimal strategy for high-risk, locally advanced MIBC patients who wish to preserve their bladder. Clinical trial information: ChiCTR2100045213.
Phase II study of oral APL-1202 plus tislelizumab or tislelizumab alone as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC).
Authors: Galsky Matthew D. , Sfakianos John P. , Ye Dingwei , Konety Badrinath , He Dalin , Song Xiaodong , Hu Hailong , Li Hanzhong , Wang Gongxian , Yuan Xiaoliang
Published: February 2025

793

Background:
Interim results of the randomized phase II trial of neoadjuvant tislelizumab +/- oral APL-1202 (nitroxoline) revealed promising pathological complete response (pCR) rates and met prespecified thresholds for study expansion (ASCO GU 2024). Here, we report the final primary endpoint analysis of this trial.
Methods:
Patients with cT2-T4aN0M0 urothelial cancer of the bladder based on local assessment, planned for radical cystectomy (RC), and ineligible for or refusing cisplatin-based chemotherapy were eligible. Patients were randomly assigned to APL-1202 plus tislelizumab (A+T) or tislelizumab (T), stratified by PD-L1 expression. Neoadjuvant tislelizumab was administered q3weeks for 3 cycles and APL1202 was administered orally tid. The primary endpoint was centrally assessed (pCR, pT0N0) rate and secondary endpoints included central pathologic response (PaR, < ypT2N0) rate and safety.
Results:
A total of 103 patients were enrolled; 28 patients declined RC after neoadjuvant treatment (A+T=16, T=12). Consequently, 75 patients remained in the efficacy analysis set (EAS); RC was completed after A+T in 42/43 patients and after T in 31/32 patients. The pCR and PaR results in the EAS are presented in the table. On retrospective central pathology review of baseline TURBT specimens, a large subset of patients were determined to be ineligible due to <cT2 disease (33/75). There was a numerically higher pCR rate in an exploratory analysis of this retrospectively defined ‘protocol eligible’ subset (A+T: 9/22, T: 4/20). Treatment related adverse events (TRAEs) occurred in 35 (59%) on the A+T arm and 19 (44%) on the T arm. TRAEs (94%) were predominantly ≤ CTCAE grade 2.
Conclusions:
Neoadjuvant A+T in cisplatin-ineligible patients prior to RC was safe. Evaluation of the efficacy in MIBC is complicated by the large subset of patients enrolled retrospectively determined to have <cT2 disease but pCR rates were similar between groups in the EAS. A signal of higher activity of A+T may be present in PD-L1 “low” tumors supporting further exploration of the immunomodulatory effects of A+T. Evaluation of efficacy is further complicated by a large subset of patients declining RC after neoadjuvant treatment underlining the need for novel bladder-sparing approaches. Clinical trial information:
NCT04813107
.

pCR rate, pT0N0

PaR rate, < ypT2N0

EAS (n=75)

n(%)

A+T
(n=43)

T
(n=32)

A+T
(n=43)

T
(n=32)

All evaluable patients

12 (33)*
7 (26)*

19 (44)
13 (41)

PD-L1
h
igh

5/18 (28)
4/16 (25)

7/18 (39)
8/16 (50)

PD-L1
l
ow

7/25 (28)
3/16 (19)

12/25 (48)
5/16 (31)

*pCR rate is calculated using UMVUE method when the final sample size of Simon's two-stage is changed.
Effectiveness and safety of radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC): A systematic literature review of 48 real-world studies.
Authors: Lunan Michaela , Raval Amit D , Thi Nhan Phan Nguyen , Korn Matthew J. , Quintero Vanessa , McKay Rana R.
Published: February 2025

81

Background:
Radium-223 (Ra-223) has been approved for men with mCRPC with bone metastases since 2013. However, as the treatment landscape has significantly changed in the last decade, a comprehensive understanding of Ra-223's real-world outcomes could inform on treatment choice in routine clinical practice. This systematic literature review aims to fill this gap by summarizing the real-world (RW) effectiveness and safety in men with mCRPC treated with Ra-223.
Methods:
Electronic databases (PubMed, Embase, the Cochrane Library, trial registers) and the past-two years of relevant conferences were searched systematically for RW observational studies examining outcomes of Ra-223 in men with mCRPC published between 2014 and March 2024. Study results of interest included Ra-223 treatment pattern, real-world overall survival (rwOS) and progression-free survival (PFS), pain response, change in alkaline phosphatase (ALP) or prostate-specific antigen (PSA), and safety outcomes (any or grade 3+ skeletal-related events, myelosuppressive adverse events).
Results:
From 1085 citations identified, 48 studies with 15,368 men with mCRPC met inclusion criteria. Most studies were retrospective cohorts (n=39) from Europe (n=22) and North America (NA) (n=18), with sample size ranging from 104 to 1,628. Median age mostly ranged from 68 to 76 Ten studies reported tumor burden and included ≥ 25% of cohort with 20+ metastases. Over 50% of Ra-223 cohort received prior chemotherapy in 23 studies, and 50% received prior ARPIs in 22 studies. Most studies in NA and Europe reported ≥ 55% and 64% completion of ≥ 5 cycles of Ra-223, respectively. Earlier line, no prior chemotherapy or immunotherapy, hemoglobin and neutrophils within lower standard limit were key factors associated with completion of ≥5 cycles of Ra-223. Median rwOS varied widely from 11 to 24 months with two exceptions and nearly a 1/3
rd
reporting 15 months or longer. Completion of ≥ 5 cycles was associated with a 2 to 5-fold increase in the median rwOS. PFS ranged from 4.3 to 7.3 months with a median of 2 prior lines in the 7 studies reporting. 12 studies reporting pain outcomes showed a reduction in pain with varying magnitude. Of 13 studies reporting grade 3+ myelosuppression, incidence varied from 1-22%. Out of 14 studies reporting fractures, the incidence was <10% in most studies (N=12) with trends toward lower rates with bone health agent (BHAs) use.
Conclusions:
This is the most up-to-date and comprehensive review of the effectiveness and safety of Ra-223 in a modern era with more widespread use of ARPIs post landmark ALSYMPCA trial for Ra-223. Findings highlight the survival benefits of early use of Ra-223 with the completion of 5 or more cycles, along with a favorable safety profile and low rates of fracture when guideline recommended BHAs are used.
Clinical outcomes of lutetium-177-vipivotide tetraxetan in men with metastatic castration-resistant prostate cancer at a single academic center.
Authors: Khorasanchi Adam , Gheeya Jinesh S. , Gauntner Timothy D. , Xu Menglin , Hasanov Elshad , Collier Katharine A. , Meng Lingbin , Zimmerman Danielle Elise , Wang Peng , Folefac Edmund , Monk Paul , Mortazavi Amir , Clinton Steven K. , Yang Yuanquan
Published: February 2025

84

Background:
Lutetium-177-vipivotide tetraxetan (
177
Lu) was approved in 2022 for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with prior androgen receptor signaling inhibition (ARSI) and a taxane. The impact of
177
Lu in a non-trial setting is limited.
Methods:
We retrospectively reviewed records of mCRPC pts who received ≥1 dose of
177
Lu at The Ohio State University from 3/2022-3/2024. Demographics, tumor histology, metastasis sites (mets), treatment (Tx) history, standardized uptake value max (SUVm), and prostate-specific antigen (PSA), at baseline (BL) and post-Tx were collected. SUVm was defined as the highest SUV from a single lesion. Outcomes were PSA response, PSA50, radiographic progression-free (rPFS) by PCWG3, and overall survival (OS). Descriptive statistics, Mann-Whitney, Chi-square, and Cox regression model were used to assess impact.
Results:
A total of 152 pts were included with a median follow-up of 9 months (0.1-23 m). The median age was 70 years (46-92 y), with 39% having de novo metastatic disease, and 61% had Gleason grade group ≥4. The common mets were bone (91%), lymph node (68%), and visceral (34% with 17% liver and 8% lung). The majority received prior taxanes and ARSI, and 20% radium-223. The median lines of prior Tx was 5.The median BL PSA was 56.3 ng/mL, and the median BL SUVm was 30.4. Post-Tx, 64% showed a PSA response, and 46% achieved PSA50. Among the pts with available imaging, 17% had partial response, 12% stable disease, and 48% disease progression.Tx was discontinued in 62% for:radiographic progression (66%), PSA-only progression (7%), clinical decline (24%), and toxicity (3%). At the data cutoff, mortality was 50%. Median PFS and OS was 6.7 m, and 12.2 m respectively. BL SUVm was associated with improved PSA50 (p=0.01), rPFS (p<0.01), and OS (p=0.01), and liver mets associated with worse OS (p<0.01).
Conclusions:
In this retrospective study of
177
Lu, we see similar PSA and PSA50 responses to reported trials. However, PFS was shorter, and mortality was higher, likely related to the use of
177
Lu in heavily treated pts with few remaining options. Optimizing biomarkers to predict Tx benefit and resistance are needed.
A survival prediction model for veterans with advanced bladder cancer (BC) treated with immune checkpoint inhibitors (ICI).
Authors: Sabater Minarim Daniel , Morgan Kylie Margaret , Deshler Leah N. , Rose Brent S , Salmasi Amirali , Dosset Magalie , D’Antonio Matteo , Yuen Kit L. , Stewart Tyler F.
Published: February 2025

855

Background:
ICIs have been associated with improved survival for patients with BC and are now an integral part of the treatment paradigm. However, predictive biomarkers for ICI in BC have not been established. Here we report outcomes for veterans with BC treated with ICI and evaluate a prediction model based on clinical and genomic characteristics.
Methods:
We analyzed a cohort of 456 patients with BC treated with single agent anti-PD1/PDL1 therapies from 2019 to 2024 in the VA Informatics and Computing Infrastructure (VINCI) database, and also received FoundationOne CDx testing. Genomic analysis included gene mutations, copy number variants (CNV), and key biomarkers such as PDL1 CPS expression, and tumor mutational burden (TMB). PDL1 expression was stratified into high (>10) and low (<=10); TMB was stratified high (>=10) or low (<10). Genes and CNVs mutated in at least 5% of the population were used in univariate cox proportional hazards models predicting for overall survival (OS). Significant genes (p< 0.2) were then incorporated in a multivariate model adjusting for current biomarkers and demographic variables. OS analyses were conducted from the first immunotherapy to death or last follow-up date utilizing the cox proportions hazard model. Model performance before and after removing the significant genes was compared by concordance index with ANOVA.
Results:
In this cohort, the median follow-up time for patients alive was 17.5 months. The 2-year OS was 41.6% and the median time on treatment was 4.1 months. Gene mutations with a statistically significant association with OS in univariate analysis included: ERBB2 amplification, CDKN1A, CDKN2A.B loss, TP53, TERT promoter, ARID1A, FGFR3, CREBBP, and TRADD. In the multivariate analysis, low PDL1 expression (hazard ratio [HR] 1.82 95% confidence interval [CI] 1.26-2.64, p<0.005), TP53 mutation (HR 1.60, 95% CI 1.18-2.60, p<0.005), CDKN1A mutation (HR 1.66, 95% CI 1.06-2.61, p=0.02), and TERT mutation (HR 1.64, 95% CI 1.15-2.34, p=0.006) were significantly associated with decreased OS. Patients with FGFR3 wild type mutation were significantly associated with increased OS (HR 0.63, 95% CI 0.41-0.95 p=0.02). High TMB did not meet statistical significance for OS (HR 0.75, 95% CI 0.56-1.01, p=0.06). When all factors are included in the multivariable model the concordance index is 0.67.
Conclusions:
We report outcomes for veterans with BC treated with ICI. We highlight that PDL1 expression was associated with improved OS, while TMB did not meet statistical significance. We further highlight genomic variants that were associated with OS outcomes for patients with BC on ICI and propose a multivariable model. Current efforts are focused on training and validating machine learning algorithms to predict outcomes for patients with BC treated with ICI and ICI-combinations.
Biomarker analysis in localized urothelial cancer DUART patients post-treatment.
Authors: Ramos Medero Adriana Sophia , Zhu Junjia , Joshi Monika , Schell Todd D.
Published: February 2025

859

Background:
Patients with localized unresectable or cisplatin-ineligible urothelial cancer (UC) have limited treatment options. Biomarker identification can guide targeted therapies. In the DUART study, pre-treatment immune cell subsets were significantly linked to disease control. Our planned correlative aim was to evaluate the same biomarkers using post-adjuvant treatment (post-Rx) peripheral blood mononuclear cells (PBMCs).
Methods:
This was a prospective, multi-institutional study BTCRC-GU15-023. Our N=16 all had valid Post-Rx values and disease control status. Eligibility criteria: >18yrs, advanced/unresectable UC, and available tumor specimen. All received concurrent durvalumab and radiation therapy followed by adjuvant durvalumab in a Phase II study. Blood samples were taken at pretreatment, 12 weeks, and post-Rx. Biomarkers were detected using multicolor flow cytometry-based analysis of PBMCs to detect T lymphocyte subsets and by dimensionality reduction using FlowJo.
Correlative objective: Evaluate post-Rx time points for biomarkers that contribute to disease progression or response.
Two-sample T-tests were used to study the association. All tests were two-sided and the statistical significance level used was 0.05.
Results:
Standard flow cytometry analysis revealed a statistically significant increase in ICOS+ CD4 and CD8 T cells in post-Rx samples among patients with progression-free survival at one year. In addition, responder patients (CR/PR/SD, n=12) showed a significant decrease in CD8 central memory T cells compared to progressors (PD, n=4) in post-Rx samples. Although not statistically significant, additional trends were noted, including decreased PD-1+ CD4 T cells in responder patients, decreased CD4 T effector memory RA+ (TEMRA), and increased CD4 naïve T cells in responder patients. There was a slight increase in interferon gamma-producing CD8 T cell subsets in responder patients and a significant decrease in central memory CD8 T cells. tSNE analysis revealed similar trends in the data, including increased naïve CD4 T cells in responder patients and slight increases in some cytokine-producing CD8 T cell subsets.
Conclusions:
Our small cohort demonstrates some significant differences in post-Rx T cell populations linked to therapy response, and further evaluation in a larger cohort of patients is needed. The identification of predictive biomarkers could help a more personalized therapeutic approach.
A randomized phase 3 trial of docetaxel added to ADT plus ARTA in patients with metastatic hormone-sensitive prostate cancer (Adding Docetaxel, KCSG- GU22-24).
Authors: Park Kwonoh , Park Inkeun , Lee Jae Lyun
Published: February 2025

TPS276

Background:
The doublet regimen, which adds docetaxel or androgen receptor-targeted agent (ARTA) such as abiraterone, enzalutamide, or apalutamide to androgen deprivation therapy (ADT) has been a standard of care in metastatic hormone-sensitive prostate cancer (mHSPC). A triplet regimen, adding abiraterone or darolutamide to ADT and docetaxel, has also demonstrated efficacy. However, while the benefit of docetaxel in mHSPC has been established in doublet regimen (ADT + docetaxel), the efficacy of adding docetaxel to ADT + ARTA has not been confirmed. Notably, the addition of docetaxel to ADT has shown benefit primarily in patients with high-volume disease. Pivotal trials of triplet regimens were based on administering ADT + docetaxel to all mHSPC patients. However, docetaxel is associated with significant toxicity and a reduction in quality of life, especially among elderly prostate cancer patients. Considering the limited evidence for adding docetaxel to ADT + ARTA and considerable toxicity of docetaxel, this phase 3 study aims to evaluate the effectiveness of adding docetaxel to ADT + ARTA.
Methods:
This study is a randomized, multicenter, open-label, investigator-initiated phase 3 study. Patients diagnosed with de novo mHSPC and initiated on ADT and ARTA are enrolled and randomized within 16 weeks of starting ADT. Patients are randomized 1:1 to either the Adding-Docetaxel arm or the Non-Docetaxel arm. Randomizations is stratified by ARTA type (abiraterone vs. apalutamide vs. enzalutamide), ECOG PS (0-1 vs. 2), disease volume (high vs. low). The Adding-Docetaxel arm adds 6 cycles of docetaxel 75 mg/m
2
in addition to ADT + ARTA, while the Non-Docetaxel arm receives only ADT + ARTA. The primary endpoint is clinical progression-free survival (cCFS), which defined the time from randomization to progression of soft tissue lesions (per RECIST v1.1), development of cancer pain requiring opioids for more than 7 days, worsening of ECOG PS, need for a change in prostate cancer-specific therapy, need for radiotherapy or surgical treatment, or death. The study is designed to detect a hazard ratio of 0.7 for cPFS, with a significance level of 5%, power of 80%, and an anticipated drop-out rate of 10%. A total of 430 patients (215 per arm) will be enrolled. Patient recruitment began in November 2023. This trial has been registered on the Clinical Research Information Service (http://cris.nih.go.kr) under ID No. KCT0008726 (Release date: August 22, 2023). Clinical trial information:
KCT0008726
.
OMAHA-003: A phase 3 study of CYP11A1 inhibitor opevesostat versus next-generation hormonal agent (NHA) switch in metastatic castration-resistant prostate cancer (mCRPC) after NHA and taxane-based chemotherapy.
Authors: Yu Evan Y. , Song Yue , Garratt Chris , Poehlein Christian Heinrich , Schloss Charles , Antonarakis Emmanuel S.
Published: February 2025

TPS286

Background:
The androgen receptor (AR) plays a pivotal role in prostate cancer pathogenesis, even after progression on androgen-directed therapies (ADT). In patients with mCRPC, activation of AR ligand binding domain (AR-LBD) somatic point mutations is a common mechanism of resistance to ADTs. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), which catalyzes the first and rate-limiting step of steroid biosynthesis. By inhibiting CYP11A1, opevesostat suppresses the production of all steroid hormones and their precursors that may promiscuously activate the AR signaling pathway. Opevesostat showed antitumor activity in patients with heavily pretreated mCRPC, and in those with AR-LBD mutations, in the phase 1/2 CYPIDES trial (Fizazi et al.
NEJM Evid.
2024). The randomized, open-label, phase 3 OMAHA-003 study (NCT06136624) is evaluating the efficacy and safety of opevesostat versus NHA switch in patients with mCRPC who received NHA and taxane-based chemotherapy.
Methods:
Eligible patients havemCRPC (unselected for AR-LBD mutations) that progressed on ADT ≤6 months of screening and during/after treatment with 1 NHA or 1-2 taxane-based chemotherapies. Approximately 1200 patients (300 with, 900 without AR-LBD mutations) will be randomly assigned 1:1 to opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg QD) or enzalutamide 160 mg PO QD (if prior abiraterone) or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide). Primary endpoints are radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR) and overall survival in patients with AR-LBD mutation-positive and -negative disease, separately. Secondary endpoints include time to initiation of first subsequent anticancer therapy or death; objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR; and safety. Enrollment is ongoing. Clinical trial information:
NCT06136624
.
Darolutamide plus androgen-deprivation therapy (ADT) in patients with high-risk biochemical recurrence (BCR) of prostate cancer: A phase 3, randomized, double-blind, placebo-controlled study (ARASTEP).
Authors: Morgans Alicia K. , Niazi Tamim , Shore Neal D. , Gschwend Jürgen E. , Ross Ashley , Hope Thomas A. , Chehrazi-Raffle Alex , Supiot Stephane , Barthelemy Philippe , Røder Andreas , Gomes Andrea Juliana , Herrera Imbroda Bernardo , Gratton Matthieu , Congregado Ruiz Carmen Belen , Joensuu Heikki , Dimova-Dobreva Miryana , Le Berre Marie-Aude , Kuss Iris , Fizazi Karim
Published: February 2025

TPS432

Background:
Patients with prostate cancer treated with radiotherapy (RT) or radical prostatectomy (RP) as primary therapy may develop BCR, defined by a prostate-specific antigen (PSA) increase with no evidence of metastases on conventional imaging. Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) may detect lesions in patients with BCR. Patients with BCR are at high risk of disease progression, and lesions identified by PSMA PET/CT need effective treatment to delay progression. Darolutamide, a structurally distinct and highly potent androgen receptor inhibitor, significantly improved metastasis-free survival (MFS) and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (CRPC). ARASTEP (NCT05794906) will evaluate whether darolutamide when added to ADT improves radiologic progression-free survival (rPFS) by PSMA PET/CT vs placebo plus ADT in patients with BCR following primary therapy and PSMA PET/CT-positive lesions.
Methods:
Eligible patients were treated by primary RT or RP +/- adjuvant RT (ART) or salvage RT (SRT), present with high-risk BCR (PSA doubling time [PSADT] <12 months and PSA ≥0.2 ng/mL after primary RP [± ART/SRT] or PSA ≥2 ng/mL above nadir after primary RT only), and must have ≥1 PSMA PET/CT-positive lesion of prostate cancer without visible lesions on conventional imaging, and serum testosterone ≥150 ng/dL. Approximately 750 patients from 221 global sites will be randomized 1:1 to oral darolutamide 600 mg twice daily or placebo, both with ADT, for 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent. Patients with detectable PSA values (≥0.2 ng/mL) after 24 months will continue study treatment until PSMA PET/CT progression by blinded independent central review (BICR). Stratification factors are PSADT <6 vs ≥6–<12 months, intent to treat baseline PSMA PET/CT lesions with image-guided RT/surgery (Yes vs No) and distant ± locoregional vs locoregional-only lesions. The primary endpoint is rPFS by PSMA PET/CT assessed by BICR. Secondary endpoints include MFS on conventional imaging by BICR, time to CRPC, OS, quality of life, and safety. As of October 2024, 248 patients have been randomized. Clinical trial information:
NCT05794906
.
Neoadjuvant darolutamide and relugolix combination preceding radical prostatectomy for high risk localized and locally advanced prostate cancer: A phase I/Ib trial.
Authors: Sonpavde Guru P. , Moschovas Marcio , Alemany Carlos A. , Sehgal Rajesh , Khan Qamar , Emtage Justin , Russell Christopher , Smith Zachary , Williams Steve , Andrich John , Morales Neley , Behera Ritika , Valerio Felipe , Mosqueda Lindley , Zhu Jianbin , Patel Vipul
Published: February 2025

TPS433

Background:
Intensive androgen blockade with combination novel hormonal agent (NHA) + androgen deprivation therapy (ADT) appears promising as neoadjuvant therapy for high-risk localized prostate cancer (PCa) undergoing radical prostatectomy (RP). An all-oral regimen combining relugolix and darolutamide may be feasible, convenient, efficacious and exhibit no significant drug-drug interactions as neoadjuvant therapy for high-risk localized PCa and may convert patients who were initially inoperable to operable. Additionally, the rapid reversibility of castration will allow the reliable determination of post-operative PSA nadir to inform tailored adjuvant therapy. Moreover, given the convenience, this regimen may constitute an excellent backbone to develop additional combinations in future. Hence, a rationale may be made to evaluate the combination of relugolix and darolutamide as neoadjuvant therapy for 12 weeks preceding RP for high-risk localized/locally advanced PCa.
Methods:
This is a Phase I/Ib non-randomized, uncontrolled, open-label clinical trial evaluating the primary objective of safety and feasibility of combination darolutamide (600 mg PO BID) and relugolix (360 mg on day 1, then 120 mg PO once daily) for 12 weeks as neoadjuvant therapy preceding RP which is to be performed ≥48 hours after and within 2 weeks after completion of neoadjuvant therapy. Patients included in this study must be a candidate for RP with stage cT2-4, N0-1, high risk (defined as Gleason score (GS) ≥ 4 + 3 with ≥ 6 positive systematic biopsies (SB); GS ≥ 4 + 3 with ≥ 3 SB and prostate-specific antigen (PSA) ≥ 20 ng/mL; GS ≥ 9 in ≥ 1 SB or targeted biopsies (TB); or ≥ 2 SB or TB with continuous GS ≥ 8, each with ≥ 80% involvement), histologically or cytologically confirmed adenocarcinoma of the prostate. The Phase I component will accrue 10 patients. If ≥7 patients complete neoadjuvant combination therapy followed by RP with no severe therapy-related adverse events for up to 4 weeks following RP, the regimen is considered feasible and accrual of 20 additional patients continues in the Phase Ib expansion component of the trial to achieve a total of 30 patients. Secondary objectives include clinical response, pathologic complete response with comparison with control matched untreated group that underwent upfront RP, rate of achieving undetectable PSA nadir and testosterone recovery to normal within 8 weeks after RP and post-operative complications. Pharmacokinetic studies are performed in the Phase I component. Blood, tumor and urine are stored for future correlative studies. The trial was activated in October 2024. Clinical trial information:
NCT06631521
.
P3BEP (ANZUP 1302): An international randomized phase 3 trial of accelerated versus standard BEP chemotherapy for individuals aged 11-50 years with intermediate and poor-risk metastatic germ cell tumours (GCTs).
Authors: Mak Blossom , Tran Ben , Thomas Hayley , Pashankar Farzana D. , Hansen Aaron Richard , Feldman Darren R. , Huddart Robert A , Wheater Matthew , Dunwoodie Elaine , Mazhar Danish , Lawrence Nicola Jane , Stevanovic Amanda Gwendolyn , Birtle Alison Jane , Oladipo Olabode , Wyld David , Balagtas Jay Michael S. , Stockler Martin R , Grimison Peter S. ,   The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: February 2025

TPS653

Background:
Bleomycin, etoposide, and cisplatin (BEP) given 3-weekly x 4 is standard first-line chemotherapy for intermediate and poor-risk metastatic GCT. Acceleration of standard chemotherapy regimens by shortening the cycle length to 2-weekly improved cure rates in other cancers. P3BEP is the first international, randomized trial of chemotherapy for intermediate and poor-risk metastatic GCT to include adults and children of both sexes. It aims to determine the superiority of accelerated BEP versus standard BEP in this setting.
Methods:
This open label, randomized, phase 3 trial is conducted seamlessly in 2 stages. The primary endpoint for stage 1 (n = 150) was favourable response; and for stage 2 (n = 500) is progression free survival (PFS). These sample sizes provide > 80% power with a two-sided type I error rate of 5% to detect an absolute improvement of 21% in the favourable response rate (stage 1) and of 7% in the PFS (stage 2). The target population is males and females aged 11 to 50 with intermediate-risk or poor-risk metastatic GCT of the testis, ovary, retroperitoneum, or mediastinum. Participants are randomized (1:1) to 4 cycles of standard BEP (3-weekly) or accelerated BEP (2-weekly) with cisplatin 20mg/m
2
D1-5, etoposide 100mg/m
2
D1-5, bleomycin 30 KIU weekly x 12, and pegylated G-CSF 6mg D6 or filgrastim daily. Study assessments occur at 30 days after completing chemotherapy, 6 months from randomization, and after completion of all post-chemotherapy treatments (e.g. surgery). Tumour tissue and baseline blood samples are collected for translational substudies. As of 26 September 2024, 321 participants have been recruited from 21 ANZ sites, 22 UK sites (led by Cambridge Clinical Trials Unit), and 148 USA sites (led by Children’s Oncology Group). The first planned interim analysis for safety (n = 76) identified no safety concerns. The stage 1 analysis of safety and activity (response rate) for the first 150 patients was reviewed by the Independent Data Safety Monitoring Committee, which recommended continuation of the trial as per protocol. Clinical trial information:
NCT02582697
.
A phase III randomized trial of eribulin (E) with gemcitabine vs standard of care (SOC) for patients (pts) with metastatic urothelial carcinoma (mUC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937—Updated design.
Authors: Sadeghi Sarmad , Callis Samuel , Lara Primo N , Berg Stephanie A. , Brown Jason Robert , Bangs Rick , Nakagawa Darrell , Daneshmand Siamak , Ian Murchie Jr.  , Flaig Thomas W. , Petrylak Daniel P. , Lerner Seth P.
Published: February 2025

TPS887

Background:
UC is the 2nd most common genitourinary cancer. Enfortumab vedotin (EV) + pembrolizumab became a SOC in 2023 in frontline mUC setting. There is not established standard of care for the subsequent lines of therapy limiting treatment options to platinum-based chemotherapy, docetaxel, paclitaxel, gemcitabine, or Sacituzumab govitecan monotherapy. Erdafitinib remains an option for pts with FGFR3 alterations. A phase I/II CTEP study of eribulin (E) for mUC established the activity of E with an objective response rate (ORR) of 37.5%, median progression-free survival (PFS) of 4.1 months (mo), and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo, and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included neutropenia (63%), anemia and fatigue (29% each). Pts with liver metastases benefited from therapy with an ORR of 71% (n=7) for GE vs. 24% for E (N=49). This trial has now been amended to account for first-line treatment changes and to include SG as a control arm option. In this amendment the eribulin alone arm was closed to simplify the design and reduce the sample size.
Methods:
This is an updated phase III, randomized trial comparing GE vs. SOC (SG, docetaxel, paclitaxel, or gemcitabine monotherapy). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. Gemcitabine is added to E at 1000 mg/m2 on D 1 and D 8. SOC follows approved dosing. There is no limit to the number/sequence of prior regimens. All pts must have: received systemic therapy with EV; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab. The study seeks to find at least a 50% increase in the primary endpoint of OS (Hazard Ratio (HR) = 0.667). Secondary endpoints include ORR and PFS. This design has a power of 80% and a one-sided alpha of 0.05 to detect a HR=0.667. We require 92 pts in each arm for a total of 168 eligible pts. The amended and restructured study was approved in January of 2024. Funding: National Institutes of Health/National Cancer Institute grants U10CA180888, U10CA180819. Eribulin is provided by Eisai. Clinical trial information:
NCT04579224
.
Phase 1/2 INTerpath-005 study: V940 (mRNA-4157) plus pembrolizumab with or without enfortumab vedotin (EV) for resected high-risk muscle-invasive urothelial carcinoma (MIUC).
Authors: Sonpavde Guru P. , Valderrama Begoña P. , Chamie Karim , Gupta Shilpa , De Santis Maria , Banerjee Joydeep K. , Ojalvo Laureen , Ren Yixin , Bavle Abhishek , Powles Thomas
Published: February 2025

TPS893

Background:
It is hypothesized that V940 (mRNA-4157), an individualized neoantigen therapy consisting of an mRNA encoding up to 34 tumor neoantigens, will work in synergy with immune checkpoint inhibitors by generating de novo tumor-specific T-cell activity. In a phase 2 trial of patients with high-risk melanoma, adjuvant V940 + pembrolizumab had a manageable safety profile and improved recurrence-free and distant metastasis–free survival versus pembrolizumab monotherapy. The phase 1/2 INTerpath-005 study (NCT06305767) has 2 cohorts. The phase 1 open-label, single-arm perioperative cohort will evaluate perioperative (neoadjuvant and adjuvant) V940 + pembrolizumab + EV for muscle-invasive bladder cancer (MIBC). The phase 2 double-blind, randomized adjuvant cohort will evaluate adjuvant V940 + pembrolizumab versus placebo + pembrolizumab for high-risk MIUC.
Methods:
Eligibility criteria for the perioperative cohort include age ≥18 years, diagnosis of MIBC (T2-T4aN0M0 or T1-T4aN1M0) with urothelial carcinoma histology, eligibility and willingness to undergo radical cystectomy (RC) + pelvic lymph node dissection (PLND), and cisplatin ineligibility. Eligibility criteria for the adjuvant cohort include age ≥18 years, diagnosis of MIUC with predominant UC histology, radical resection ≤7 weeks before providing informed consent and ≤14 weeks before randomization, high-risk pathologic disease (ypT2-4a and/or ypN+ after neoadjuvant chemotherapy [NAC]; pT3-4a and/or pN+ without NAC), and cisplatin ineligibility. In the perioperative cohort, approximately 30 patients will receive neoadjuvant pembrolizumab 200 mg IV on day 1 Q3W × 4 cycles + EV 1.25 mg/kg IV on days 1 and 8 Q3W × 4 cycles + V940 1 mg IM on day 1 Q3W × 1-4 doses. Patients will undergo RC + PLND followed by adjuvant pembrolizumab 200 mg IV on day 1 Q3W × 13 cycles + EV 1.25 mg/kg IV on days 1 and 8 Q3W × 5 cycles + V940 1 mg IM on day 1 Q3W × 5-8 doses, depending on number of doses administered in neoadjuvant period, for a total of 9 doses. In the adjuvant cohort, approximately 200 patients will be randomly assigned 1:1 to receive pembrolizumab 400 mg IV Q6W × 9 cycles + V940 1 mg IM Q3W × 9 doses or pembrolizumab 400 mg IV Q6W x 9 cycles + placebo IM Q3W x 9 doses. Randomization in the adjuvant cohort will be stratified by circulating tumor DNA status at screening (positive vs negative vs not evaluable) and prior NAC (yes vs no). The primary end points are safety (perioperative cohort) and DFS per investigator assessment (adjuvant cohort). Secondary end points are pathologic complete response and pathologic downstaging (perioperative cohort); overall survival, distant metastasis–free survival per investigator, safety, and tolerability (adjuvant cohort). Clinical trial information:
NCT06305767
.