bluuebunny/crossref_metadata_2025 huggingface dataset:
The Oncopig bladder cancer model, an innovative large animal platform for evaluating treatment effects.
Authors: Jayalath Viranda , Autlitzky Andreas , Kudinova Natalia , Coleman Jonathan , Schook Lawrence B , Schachtschneider Kyle
Published: February 2025

857

Background:
Bladder cancer carries a high recurrence rate despite availability of several treatment options including surgery, chemotherapy, radiation, and immunotherapy, resulting in the highest cost of lifelong treatment per patient and highlighting the need for development of novel diagnostic and therapeutic strategies. Unfortunately, results from current bladder cancer models do not effectively translate to clinical practice (mouse models) or are rare and not inducible (canine models). This, in addition to the use of endoscope-based approaches for bladder cancer treatment highlights the critical need for large animal bladder cancer models to improve patient outcomes. Pigs represent an ideal platform that provide both regulatory acceptable and clinically relevant large animal cancer models due to their similar physiology, size, genetics, immunity, and metabolism in relation to humans. The Oncopig bladder cancer model is an ideal tool for testing endoscopic and other oncolytic-based treatments.
Methods:
The Oncopig cancer model develops tumors following induced expression of

KRAS
G12D

and

TP53
R167H

driver mutations utilizing an adenoviral vector encoding Cre recombinase (AdCre). Two procedures for cystoscope-based AdCre delivery were evaluated. In procedure I (Proc-I) a combination of AdCre and N-Dodedcyl-beta-maltoside, a sugar-like surfactant utilized to dissolve the glycoaminoglycans layer, was instilled into the bladder (1h; n=3). In procedure-II (Proc-II) the bladder urothelium was superficial denuded at 3 sites and subsequent AdCre was instilled into the bladder (1h; n=4). Oncopigs underwent CT scans and follow-up cystoscopy, and were euthanized at 3 timepoints (day 14, 21, and 28) to assess temporal bladder tumor growth. Tumor samples were collected at necropsy for histopathological evaluation (H&E, TP53, Ck34be12, vimentin, and CD3) and to evaluate tumor stage.
Results:
In total 6/7 Oncopigs developed endoluminal tumors. Tumor-induction efficacy was 100% for Proc-I (n=3/3) and 75% for Proc-II (n=3/4). Two tumor types were observed: urothelial cell carcinomas of sarcomatoid variant (Proc-I: n=3/3; Proc-II: n=2/4) and inflammatory tumors (Proc-II: n=1/4). After 14 days, pT1 tumors were observed for Proc-I, while pT2 tumors were observed for Proc-II. After 21 days, both pT1 and pT2 tumors were observed for Proc-I, while Proc-II tumors remained pT2.
Conclusions:
The Oncopig bladder cancer model can develop both superficial and muscle invasive urothelial cell carcinomas with sarcomatoid variant. Tumors develop rapidly (within 2 weeks), with tumor invasiveness correlated with time post tumor induction and procedure used, making this an ideal model for evaluation of novel therapeutic approaches. Further exploration and development of additional tumor models including further translational characterization will be important for broader utility.
Pilot study evaluating duplex sequencing of urinary DNA as a biomarker for recurrence in non-muscle invasive bladder cancer.
Authors: Ghali Fady , Blaha Ondrej , Lam Hung-Ming , Kennedy Scott , Wright Jonathan L.
Published: February 2025

865

Background:
The detection of tumor-associated urinary DNA (uDNA) as a biomarker for non-muscle invasive bladder cancer (NMIBC) has shown promise, but is significantly limited in sensitivity due to replication errors inherent in next-generation sequencing (NGS). Duplex sequencing is an ultrasensitive/accurate sequencing technology which may provide a solution to this problem. We present a pilot study applying duplex sequencing technique to uDNA in NMIBC for use as a biomarker of recurrence.
Methods:
Urine samples from a total of 30 patients with NMIBC were collected following complete transurethral resection of bladder tumor and prior to intravesical therapy (pre-tx) and following six weeks of intravesical therapy (post-tx). Detection of ten commonly mutated NMIBC genes was carried out using next generation duplex sequencing. Results were correlated with recurrence of tumor.
Results:
Median age for our cohort was 71 [41, 88] and 80% were male. A total of 16 (53.3%) of the cohort experienced a recurrence within the first year, with a median time to recurrence of 10 months. Tumor-associated uDNA was successfully detected to variant allele fraction (VAF) below 0.001. Presence of any pathogenic variant in the pre-tx urine >0.006 VAF was associated with a 72.7% sensitivity and 78.9% specificity for recurrence within one year. The highest VAF of pathogenic variant in uDNA trended with time-to-relapse. Post-tx uDNA assessment did not correlate with recurrence. Further analysis is limited by small sample size.
Conclusions:
This pilot study demonstrates potential utility of ultrasensitive duplex sequencing on NMIBC uDNA in the detection of recurrence.
Sarcopenia as a marker to assess the surveillance necessity after a 5-year cancer-free period in patients who undergo radical cystectomy: A multi-institutional retrospective study.
Authors: Fujita Naoki , Tanaka Toshikazu , Hosogoe Shogo , Ishii Noritaka , Momota Masaki , Yoneyama Takahiro , Ito Hiroyuki , Ohyama Chikara , Hatakeyama Shingo
Published: February 2025

871

Background:
Although continuous surveillance after a 5-year cancer-free period in patients with bladder cancer (BC) who undergo radical cystectomy (RC) is recommended, optimal candidates for continuous surveillance remain unclear. Sarcopenia is associated with unfavorable prognosis in various malignancies. Thus, we hypothesized that sarcopenia, characterized by low muscle quantity, might be a useful marker to assess the necessity of surveillance after a 5-year cancer-free period in patients who underwent RC.
Methods:
This multi-institutional retrospective study included 274 patients with muscle-invasive bladder cancer (MIBC) who had a 5-year cancer-free period after RC. Muscle quantity was evaluated using the psoas muscle index (PMI) using computed tomography images five years after RC. The optimal cut-off values for all-cause mortality were calculated separately for men and women using receiver operating characteristic curves. Patients with lower PMI values than the cut-off values were diagnosed with sarcopenia. Recurrence-free survival (RFS) and overall survival (OS) after a 5-year cancer-free period were evaluated using the Kaplan–Meier method and compared using the log-rank test. Moreover, univariable and multivariable Cox proportional hazards regression analyses were performed to evaluate the impact of sarcopenia on OS.
Results:
The median age and follow-up period after the 5-year cancer-free period were 73 years and 63 months, respectively. Of the 274 patients, 129 (47%) were diagnosed with sarcopenia five years after RC. By the end of the follow-up period after the 5-year cancer-free period, 14 (5.1%) and 77 (28%) patients experienced recurrence and died from any cause, respectively. The 10-year RFS rate was 93%. RFS was not significantly different between the two groups, whereas OS in the sarcopenia group was significantly shorter than that in the non-sarcopenia group. After adjustment for confounding variables, sarcopenia was significantly associated with shorter OS (Table).
Conclusions:
Patients with sarcopenia might not need continuous surveillance after a 5-year cancer-free period, considering the high mortality rate.

Multivariable analysis for OS.

Factor

P
value

Hazard ratio
95% CI

Age
Continuous
<0.001
1.065
1.027–1.105

Performance status
Continuous
0.012
1.829
1.145–2.922

Hypertension
Positive
0.011
1.897
1.157–3.110

eGFR
Continuous
0.168
0.990
0.976–1.004

Urinary diversion
Neobladder
0.033
0.546
0.313–0.953

Sarcopenia
Positive

0.025

1.801

1.076–3.012
Platelet-to-lymphocyte ratio as a useful biomarker of recurrence and mortality risks in patients with muscle-invasive bladder cancer who achieved ypT0 to neoadjuvant chemotherapy: A multicenter retrospective study.
Authors: Fujita Naoki , Hosogoe Shogo , Tanaka Toshikazu , Ishii Noritaka , Ito Hiroyuki , Yoneyama Takahiro , Ohyama Chikara , Hatakeyama Shingo
Published: February 2025

873

Background:
Platelet-to-lymphocyte ratio (PLR), a novel inflammatory marker, has been suggested to predict recurrence and mortality in several malignancies. Patients with muscle-invasive bladder cancer (MIBC) who achieved a pathological complete response (ypT0) to neoadjuvant chemotherapy (NAC) have a favorable prognosis. However, the risk factors for recurrence and mortality remain unclear.
Methods:
This multi-institutional retrospective study assessed 950 patients with MIBC who underwent radical cystectomy (RC). Of the 950 patients, 128 patients who achieved a pathological complete response (ypT0) to 2–4 cycles of NAC were included. Univariable and multivariable Cox proportional hazards regression analyses were performed to identify the risk factors for recurrence and mortality.
Results:
The median age and follow-up period were 69 years and 80 months, respectively. Of the 128 patients, 15 (12%) and 30 (23%) experienced recurrence and died from any cause, respectively. The most frequent recurrence site was lymph nodes (n = 11, 73%), followed by urothelium (n = 4, 27%). The 10-year recurrence-free survival (RFS) and 10-year overall survival (OS) rates were 85.9% and 73.1%, respectively. In the univariable and multivariable analyses, clinical lymph node involvement, neobladder reconstruction, and PLR were independently and significantly associated with RFS (Table). In the univariable and multivariable analyses, age and PLR were independently and significantly associated with OS.
Conclusions:
Recurrence was not a rare event in patients with MIBC who achieved ypT0. PLR may be a useful biomarker to assess recurrence and mortality risks.

Multivariable analysis for RFS.

Factor

P
value

Hazard ratio
95% CI

Clinical lymph node involvement
Positive
0.021
3.732
1.219–11.42

Urinary diversion
Neobladder
0.281
0.281
0.094–0.842

PLR
Continuous

0.029

1.003

1.000–1.006
Evaluating clinical and pathologic predictors for pathologic lymph node positivity (pN+) in patients with clinical T1-4N0M0 bladder cancer undergoing cystectomy.
Authors: Jaime-Casas Salvador , Barragan-Carrillo Regina , Zugman Miguel , Zang Peter D. , Ebrahimi Hedyeh , Castro Daniela V. , Mercier Benjamin , Li Xiaochen , Dizman Nazli , Salgia Nicholas , Hsu Joann , Nguyen Charles B , Yip Wesley , Chehrazi-Raffle Alex , Zengin Zeynep Busra , Meza Luis A , Pal Sumanta Kumar , Tripathi Abhishek
Published: February 2025

877

Background:
Occult pathological lymph node involvement at radical cystectomy (RC) in patients with clinical (cN0) bladder cancer (BC) remains a diagnostic and therapeutic challenge. We sought to evaluate clinical and pathological predictors of lymph node positivity (pN+) and its correlation with outcomes in patients with cT1-4N0M0 BC at RC.
Methods:
The study included patients with cT1-4N0M0 BC undergoing RC and pelvic lymph node dissection between 2004 and 2020. Patients were grouped as pN+ vs. pN0 at surgery. Baseline characteristics like age at surgery, sex, ethnicity, body mass index, concomitant carcinoma in situ (CIS) on TURBT, and lymphovascular invasion (LVI) were summarized using descriptive statistics. We performed logistic, univariable, and multivariable Cox regression models to identify independent predictors for pN+ at surgery. Kaplan Meier analysis and multivariable Cox proportional hazards model were used to analyze recurrence-free survival (RFS) and overall survival (OS).
Results:
440 patients with T1-4N0M0 bladder cancer undergoing RC were evaluated, of which 359 (81.6%) were pN0 and 74 (16.8%) were pN+. Seven patients (1.6%) had incomplete information and were not included in the final analysis. Most patients were male (79.8%), White (87.7%), and had a median age of 71 years at surgery. Most patients had T2 (54.5%) disease, followed by T1 (24.8%) and T3 (5.7%) disease. On multivariable analysis, LVI [HR 3.02 (95% CI 1.21-7.54); p = 0.018] and positive surgical margins [HR 15.38 (95% CI 4.69-50.41); p < 0.001] at RC were independent predictors for lymph node positivity at surgery. Interestingly, pN+ was not significantly associated with concomitant CIS, preoperative hydronephrosis, and preoperative renal function on multivariable analysis. pN+ demonstrated significantly worse RFS [HR 7.48 (95% CI 4.89-11.42); p < 0.001] and OS (HR 7.86 (95% CI 5.20-11.89); p < 0.001]. Preoperative hydronephrosis [HR 1.76 (95% CI 1.16-2.69); p = 0.008] was an independent predictor for RFS. Preoperative hydronephrosis [HR 1.60 (95% CI 1.19-2.15); p = 0.002] and positive surgical margins [HR 2.31 (95% CI 1.26-4.25); p = 0.007] were independent predictors for OS.
Conclusions:
LVI and positive surgical margins were significant predictors for pN+ at surgery in patients with cT1-4N0M0 BC. These features could inform perioperative therapy considerations and bladder preservation approaches in cN0 BC.
Prospective real world data evaluation of clinical outcomes in metastatic hormone sensitive prostate cancer (MHSPC) patients treated as part of triplet therapy with darolutamide: UK multicenter RECOMMEND study.
Authors: Bahl Amit , Challapalli Amarnath , Das Prantik , Sharma Anand , Bhana Rajanee , Birtle Alison Jane , Muthukumar Dakshinmoorthy , Randhawa Manreet , Sundar Santhanam , Prentice Mark , Bianchini Diletta , Renninson Emily , CapoMir Miguel , Syndikus Isabel , Jayaprakash Kamalram Thippu , Elumalai Thiraviyam , Goodwin Sarah , Parikh Omi , White Paul , Foulstone Emily
Published: February 2025

89

Background:
Darolutamide has authorisation for treatment of metastatic hormone sensitive prostate cancer (MHSPC) in combination with docetaxel chemotherapy and androgen deprivation therapy (triplet therapy) based on ARASENS trial results. The RECOMMEND study is a prospective real-world evaluation (RWE) of clinical outcomes in patients with MHSPC treated with this regimen in the UK.
Methods:
318 patients were enrolled from 21 UK centres over 20 months from November 2022. Data cut-off was 14 August 2024. Disease characteristics were evaluated. Descriptive statistics have been used for patient demographics and PSA changes with treatment were analysed.
Results:
Patients on the study had a median age of 67 (range 38-84) years. Majority of the patients were de novo metastatic (91.2%). 68.2% have a Gleason score ≥8. 76 patients (23.9%) had next generation imaging (NGI) at diagnosis. Performance score was 0 (62.7%) or 1 (37.3%). The distribution of metastases (%) were: bone (84.9), nodal (60.4), lung (12.6) and liver (2.5). The median PSA level was 134 (range 1 to 5628) ng/mL at diagnosis. At the end of docetaxel chemotherapy median PSA was 0.35 ng/mL. PSA response see in the 226 patients who had completed 6 cycles of docetaxel chemotherapy at the data cut-off, PSA
50
was seen in 87.6% (198/226) and PSA
90
in 53.2%. PSA responses in those who only completed 4/5 cycles of docetaxel (n=14) did not significantly differ compared to those who completed all 6 cycles (PSA
50
p=0.445 and PSA
90
p-0.664). At 6 months from darolutamide initiation, quality of life (QoL) data is currently available for 173 patients, of these 88.4% reported either stable or improved QoL and 11.6% had a decline in QoL at the end of chemotherapy.
Conclusions:
The tolerability and efficacy profile of treatment with ADT+Darolutamide+Docetaxel in MHSPC in the RECOmMEnD study is similar to that reported in the ARASENS trial. The QoL data available for 173 patients to date reports either stable or improved QoL at 6 months for 88.4% cases. This provides important prospective RWE data, enabling patients and clinical teams to make informed choices in this setting.
Association between sociodemographic marginalization and receipt of intensified treatment for metastatic castrate-sensitive prostate cancer.
Authors: Wallis Christopher J.D. , Nguyen David-Dan , Satkunasivam Raj , Aminoltejari Khatereh , Hird Amanda Elizabeth , Roy Soumyajit , Morgan Scott C. , Malone Shawn , Shayegan Bobby , Kulkarni Girish S. , Trinh Quoc-Dien , Rosella Laura , Breau Rodney H , Lalani Aly-Khan A.
Published: February 2025

96

Background:
Intensified treatment beyond androgen deprivation therapy (ADT) has been shown to improve survival in patients with metastatic castrate-sensitive prostate cancer (mCSPC). However, real-world utilization remains inadequate. To assess potential differential access to such life-prolonging treatments, we assessed the association between sociodemographic marginalization and receipt of intensified treatment in patients newly diagnosed with mCSPC within a universal healthcare system.
Methods:
We performed a population-based cohort study of men aged 66 years or older diagnosed with de novo mCSPC in Ontario, Canada from Jan 2014-Nov 2021. Hierarchical regression models adjusting for patient, tumor, and physician characteristics were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between patient marginalization, measured by the Ontario Marginalization Index (ON-MARG), and receipt of intensified treatment, within 6 months of diagnosis. ON-MARG, a validated measure created using Canadian census data, provides area-level measures of marginalization in four domains: (1) households and dwellings; (2) material resources; (3) age and labour force; and (4) racialized and newcomer populations.
Results:
Among 6,051 patients, 1,465 (24%) received intensified treatment. Higher levels of composite marginalization were associated with a lower likelihood of receiving intensified treatment (OR 0.91, 95% CI 0.83–0.99, p=0.03). When examining individual domains of marginalization (Table 1), the racialized and newcomer populations domain showed the strongest negative association with the receipt of intensified treatment (OR 0.89, 95% CI 0.81–0.97, p=0.01).
Conclusions:
Sociodemographic marginalization, particularly among racialized and newcomer populations, is associated with lower rates of intensified treatment in patients with de novo mCSPC, even within a universal healthcare system, further contributing to known disparities in prostate cancer outcomes.

Association between ON-MARG domains and treatment intensification among patients with de novo mCSPC in adjusted models.*

ON-MARG Domain
Effect Estimate (95% CI)

Households & Dwellings
OR 0.92 (0.85-0.98), p=0.02

Material Resources
OR 0.93, (0.86-0.99), p=0.03

Age & Labour Force
OR 0.99, (0.94-1.04), p=0.65

Racialized & Newcomer Populations
OR 0.89, (0.81-0.97), p=0.01

*Each ON-MARG Domain was modelled in separate multivariable models adjusting for patient characteristics including age at diagnosis, Charlson comorbidity category, and area; tumor characteristics including Gleason score at diagnosis; as well as physician age, sex, years in practice, specialty, and group volume.
Mevrometostat (PF-06821497) in combination with enzalutamide for androgen receptor pathway inhibitor (ARPI)-naïve patients with metastatic castration-resistant prostate cancer (mCRPC): The phase 3, randomized MEVPRO-2 trial.
Authors: Schweizer Michael Thomas , Chakrabarti Jayeta , Narayanan Sujata , Lin Stella
Published: February 2025

TPS287

Background:
Mevrometostat (PF-06821497) is a potent, selective inhibitor of the histone methyltransferase enhancer of zeste 2 (EZH2), which is canonically involved in epigenetic repression of target genes. In prostate cancer, EZH2 overexpression is associated with poor prognosis, contributing to disease progression through transcriptional repression of tumor suppressor genes and androgen receptor (AR) activation, co-regulation of AR-mediated transcriptional programs, and cell cycle deregulation through methylation of non-histone targets. Given the associations between EZH2 and the AR, the addition of an EZH2 inhibitor to ARPI is hypothesized to extend the duration of clinical response and delay antiandrogen resistance compared with ARPI alone. In a nonrandomized, phase 1 dose-escalation study, objective responses to mevrometostat with enzalutamide were observed in patients with CRPC and prior abiraterone or enzalutamide treatment (NCT03460977; Schweizer MT, et al.
J Clin Oncol
. 2024;42(16_suppl):5061). Despite guideline recommendations of treatment intensification with ARPIs or chemotherapy for metastatic castration-sensitive prostate cancer (mCSPC), many patients do not receive ARPIs at the mCSPC stage. MEVPRO-2 (NCT06629779) will evaluate mevrometostat plus enzalutamide compared with enzalutamide alone in ARPI-naïve patients with mCRPC.
Methods:
MEVPRO-2 is a global, double-blind, randomized, phase 3 trial. Key inclusion criteria are males, ≥18 years, with progressive mCRPC, castrate testosterone of ≤50 ng/dL, Eastern Cooperative Oncology Group performance status of 0 or 1, and life expectancy of ≥12 months. Patients with systemic treatments for mCRPC (except androgen deprivation therapy and first-generation antiandrogens) are excluded. Approximately 900 patients will be randomized 1:1 to receive mevrometostat (875 mg, twice daily) with enzalutamide (160 mg, once daily) or placebo with enzalutamide. The primary endpoint is blinded independent central review-assessed radiographic progression-free survival per Response Evaluation Criteria in Solid Tumours 1.1 (soft tissue) or Prostate Cancer Working Group 3 (bone). Key secondary endpoints are overall survival and time to pain progression (Brief Pain Inventory – Short Form question 3 or opioid use). Hazard ratios and 95% confidence intervals will be estimated using a Cox proportional hazard model, stratified by prior docetaxel and presence of hepatic metastases. P-values will be provided using a stratified log-rank test. Safety and tolerability will also be assessed. Clinical trial information:
NCT06629779
.
A prospective phase II study to evaluate olaparib plus abiraterone and prednisone combination therapy in metastatic hormone sensitive prostate cancer patients with HRR gene mutation: Updated analysis of PROact.
Authors: Zhuang Junlong , Zhang Shun , Zhang Xuyu , Qiu Xuefeng , Zheng Xi , Gao Jie , Guo Hongqian
Published: February 2025

TPS292

Background:
Approximately 10% - 15% of patients with metastatic hormone sensitive prostate cancer (mHSPC) harbor loss-of-function mutations in homologous recombination repair (HRR) genes. Although olaparib plus abiraterone and prednisone has significantly prolonged radiographic progression-free survival (rPFS) in metastatic castration resistant prostate cancer patients, there is a lack of evidence regarding the efficacy of this combination therapy in patients with mHSPC. Here, we report the updated analysis of PROact study, the first phase II trial to evaluate the effects of olaparib plus abiraterone and prednisone in mHSPC patients with HRR gene mutation.
Methods:
This was a single center, single arm, phase II trial (NCT05167175) conducted in male patients with mHSPC who had at least one
HRR
gene mutation (
BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD 51C, RAD51D and RAD54L
) as determined by tissue-NGS. Patients were administered olaparib 300 mg BID plus abiraterone 1000 mg QD and prednisone 5 mg QD. Previous treatment with new hormonal agent (NHA) was not allowed. The primary endpoint was 1-year radiographic progression-free survival (rPFS) rate per PCWG3-modified RECIST 1.1 by investigator assessment. The secondary endpoint included prostate-specific antigen (PSA) response rate, objective response rate (ORR), and adverse events. Safety and efficacy data with a median follow-up of 9.5 months have been reported. Here, we present the updated efficacy data categorized by gene.
Results:
Thirty patients were enrolled, all of whom had
de novo
mHSPC, consisting of 30% (9/30) with low-volume and 70% (21/30) with high-volume disease. As of the data cut-off (September 6, 2024), the median follow-up duration was 14.0 months. 13 patients had measurable disease; the confirmed ORR was 84.6% (11/13). One patient with
ATM
mutation achieved complete response. Ten patients obtained partial response, including four with
BRCA2
, two with
ATM
, two with
CDK12
, one with
RAD51B
mutations and one with co-mutation of three pathogenic genes. Furthermore, two patients harboring
BRCA2
mutation experienced progressive disease (Table). Clinical trial information:
NCT05167175
.

Gene by gene efficacy evaluation.

HRR mutation
Totally number
RECIST assessment
CR
PR
PD

BRCA2

11
6
0
4
2

CDK12

7
2
0
2
0

ATM

6
3
1
2
0

PALB2

2
0
-
-
-

CHEK2

1
0
-
-
-

RAD51B

1
1
0
1
0

RAD51D

1
0
-
-
-

CDK12, CHEK2, RAD51B

1
1
0
1
0
CLARIFY: Positron emission tomography using
64
Cu-SAR-bisPSMA in patients with high-risk prostate cancer prior to radical prostatectomy—A phase 3 diagnostic performance study.
Authors: Gorin Michael A. , Lengyelova Eva , Nordquist Luke , Morrish Glynn , Gervasio Othon , Miller Robert M. , Shore Neal D.
Published: February 2025

TPS429

Background:
Prostate cancer (PC) is the second most prevalent cancer in men globally. In men with newly diagnosed, high-risk disease, PC most often spreads to the pelvic lymph nodes (LNs) before becoming widely metastatic. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is strongly overexpressed in PC, making it an ideal target for imaging and therapy.
64
Cu-SAR-bisPSMA may offer several advantages over the currently approved PSMA positron emission tomography (PET) agents due to its bivalent structure (SAR-bisPSMA) and longer half-life of
64
Cu (12.7h vs. <2h for
18
F and
68
Ga).
64
Cu-SAR-bisPSMA has demonstrated higher tumor uptake (2-3x), prolonged retention and detection of additional PC lesions compared to approved PSMA agents. This Phase 3 diagnostic trial aims to establish the diagnostic performance of
64
Cu-SAR-bisPSMA PET to detect regional nodal metastases in men with high-risk PC.
Methods:
CLARIFY (NCT06056830) is a multi-center, single-arm, non-randomized, open-label Phase 3 diagnostic study of
64
Cu-SAR-bisPSMA. The target population is patients with untreated, histopathology-confirmed PC with high-risk features, who are proceeding to radical prostatectomy (RP) with pelvic lymph node dissection (PLND). The primary endpoint is to assess the sensitivity and specificity of
64
Cu-SAR-bisPSMA PET to detect pelvic nodal metastases. Secondary objectives include assessment of safety and determining the positive and negative predictive value of
64
Cu-SAR-bisPSMA PET. A total of 383 patients will be enrolled. Standard of care (SOC) imaging will be acquired at screening (e.g. computed tomography [CT], approved PSMA PET/CT). Eligible patients will receive a single administration of
64
Cu-SAR-bisPSMA (200 MBq) followed by a PET/CT scan on Day 1 (1-4h post-dose, same-day imaging) and on Day 2 (24±6h post-dose, next-day imaging). Patients will then proceed to RP with PLND. The specimens from surgery will be processed and analyzed locally to derive the Standard of Truth (SOT). The
64
Cu-SAR-bisPSMA PET/CT scans will be interpreted locally and by 3 independent, blinded, central readers. Each reader will assess the scans for the presence of abnormal
64
Cu-SAR-bisPSMA uptake in the pelvic LNs, prostate gland, extra-pelvic LNs, visceral/soft tissue and bone. The diagnostic performance of
64
Cu-SAR-bisPSMA will be based on the PET result on the respective day independently (Day 1 and 2) matched against the SOT. The study is open for recruitment in sites in the United States and in Australia. Clinical trial information:
NCT06056830
.
Neoadjuvant androgen deprivation therapy with enzalutamide plus the glucocorticoid receptor modulator relacorilant versus placebo for patients with high-risk localized prostate cancer.
Authors: Atiq Mohammad O. , Stadler Walter Michael , Page Ashley , Catenacci Meghan , Patnaik Akash , Paner Gladell P , Eggener Scott , Szmulewitz Russell Zelig
Published: February 2025

TPS436

Background:
Despite definitive local treatment, high risk localized prostate cancer (PC) patients (pts) have a 36-46% risk of biochemical recurrence (1). Neoadjuvant (NAJ) treatment with androgen receptor signaling inhibition (ARSI) improves pathologic outcome at the time of prostatectomy (2), and 3-year biochemical recurrence-free survival (bRFS) was strongly tied to pathologic complete response (pCR) plus minimal residual disease (MRD). One way to improve on this strategy is to target potential mechanisms of resistance to ARSI. A study of localized high-risk prostate cancer treated with NAJ ARSI plus androgen deprivation therapy (ADT) showed enrichment of glucocorticoid receptor (GR) expression in residual tumors (3). Inhibiting GR signaling decreases resistance to the ARSI enzalutamide (4). We previously demonstrated the safety of the combination of the selective GR modulator (SGRM) relacorilant plus enzalutamide (5). We have thus designed a study evaluating the efficacy of this combination given neoadjuvantly.
Methods:
This phase 2 study is a placebo-controlled randomized trial of 6 months of NAJ ADT and enzalutamide plus relacorilant/placebo (2:1). The primary objective of this study is response, measured by pCR and MRD at radical prostatectomy (RP). Eligible patients include those with localized histologically confirmed prostatic adenocarcinoma classified as high risk or very high-risk per NCCN guidelines. Enlarged lymph nodes below the iliac bifurcation are allowed. Following randomization pts will be treated with LHRH agonist plus enzalutamide with or without relacoriliant and undergo RP 1 month later. The total sample size is 90 patients with an interim analysis for futility conducted after 45 pts undergo RP. A chi-square test will be used to compare the proportion of patients achieving pCR/MRD. Assuming a true CR/MRD rate of 15% in the control group, 90 patients total would yield a power of 80% with a hypothesized CR/MRD of 32% in the relacorilant group, based on a one-sided test at the alpha=0.15 significance level. As secondary endpoints, we will evaluate radiographic response within the prostate with multiparametric MRI (mpMRI) imaging and the 3-year bRFS and MFS rates in both arms. Exploratory endpoints include demonstrating correlation between enhanced mpMRI imaging and pathologic response, as well showing decreased nuclear hormone receptor-driven proliferative gene expression in viable PC due to combined NAJ GR antagonism and ARSI compared to ARSI alone. The study is currently open and is seeking additional sites. 1. Falgario U, JAMA Netw Open 2023. 2. McKay R, J Urol 2021. 3. Efstathiou E, Eur Urol 2019. 4. Isikbay M, Horm Cancer 2014. 5. Desai,
CCR
, 2024. Clinical trial information:
NCT05726292
.
A phase II study bolstering outcomes by optimizing immunotherapy strategies with evolocumab and nivolumab in patients with metastatic renal cell carcinoma (BOOST-RCC).
Authors: Zhang Tian , Qin Qian , Cole Suzanne , Wang Andrew Zhuang , Msaouel Pavlos , Hahn Andrew Warren , Shah Amishi Yogesh , Campbell Matthew T. , Zhang Song , Tidwell Rebecca Slack , Issa Wadih , DeVilbiss Andrew , Jiang Changchuan , Vento Joseph , Courtney Kevin Dale , Hammers Hans J. , Brugarolas James , Tannir Nizar M. , Jonasch Eric
Published: February 2025

TPS612

Background:
While metastatic renal cell carcinoma (mRCC) is known to be immunogenic, and there have been several recent advances with combinations of immunotherapy, the disease often progresses and immunotherapy resistance mechanisms remain unclear. For patients with mRCC refractory to immunotherapy checkpoint inhibitors (ICIs), further treatment options are not curative and improvements are needed. Proprotein convertase subtilisin/kexin type 9 (PCSK9) directs MHC-I molecules to the lysosome, and inhibition of PCSK9 improves MHC-I expression and tumor antigen presentation. Evolocumab is a PCSK9 inhibitor which was shown in preclinical studies to improve tumor antigen presentation, intratumoral CD8 T-cell infiltration (and activation), and overall tumor control. We designed a phase 2 trial with safety lead in adding evolocumab to the PD-1 inhibitor nivolumab in mRCC refractory to first-line ICI combinations.
Methods:
BOOST-RCC is an investigator-initiated, phase 2, multicenter, single cohort study investigating the efficacy of evolocumab and nivolumab for ICI refractory mRCC. A Simon 2-stage design will be used, with 10 patients treated in the first cohort. If at least 1 objective response is observed among the first 10 patients, enrollment will continue with 19 more patients, for a total of 29 patients. Primary endpoints are objective response rates based on RECIST v1.1 as well as trial limiting toxicities for the safety profiling of the combination of treatment. Patients will be treated until progression of disease, unacceptable toxicity, or up to 2 years if ongoing response. The study is funded by CPRIT and open within the DOD-supported Kidney Cancer Research Consortium. Enrollment is ongoing at UT Southwestern Simmons Comprehensive Cancer Center and MD Anderson Cancer Center (NCT06284564). Clinical trial information:
NCT06284564
.
Phase 1b/2 study of combination
177
Lu girentuximab plus cabozantinib and nivolumab in treatment naive patients with advanced clear cell RCC.
Authors: Jonasch Eric , Hasanov Elshad , Flynt Lesley , Tidwell Rebecca Slack , Hwang Hyunsoo , Brooks Roserika , Wood Lauren Michelle , Solley Travis , Mack Dahlia , Yamamura Yuko , Venkatesan Aradhana M.
Published: February 2025

TPS614

Background:
Complete response (CR) is a rare event in advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently approved for first-line treatment of ccRCC, demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, CR is only 9%. Drugs that could synergize with T cell anti-tumor activity can improve CR rates. Radiation-induced DNA damage to activate the cGAS-STING pathway is a promising mechanism.
177
Lu-girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase 9, expressed in >90% ccRCC, to deliver targeted radiation to cancer with minimal damage to surrounding healthy cells. As a single agent in metastatic ccRCC,
177
Lu-girentuximab was safe and effective in stabilizing disease in 57% of patients. We hypothesize
177
Lu-girentuximab-induced DNA damage will potentiate the STING pathway, synergizing with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells and achieve higher CR rates.
Methods:
Up to 100 patients with treatment naive, biopsy-proven ccRCC with adequate organ/marrow function with 1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta (0.09, 0.91) prior. Secondary endpoints are ORR, PFS by RECIST 1.1, and overall survival.
177
Lu-girentuximab 1480 MBq/m
2
(61% of single agent MTD) will be administered every 12 weeks for up to 3 cycles. Starting with the second cycle, nivolumab and cabozantinib will be added at standard dose. To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with
18
F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics, and proteomics studies. Clinical trial information:
NCT05663710
.
Implementing precision oncology in renal cell carcinoma (RCC): Prospective identification of clinical, tissue-based, and circulating factors to refine outcome prediction and support therapeutic choices (SIGNS-RCC TRIAL).
Authors: Zampiva Ilaria , Fantinel Emanuela , Mollica Veronica , Rebuzzi Sara Elena , Bimbatti Davide , Bertolotti Francesca , Brunelli Matteo , Manduca Stefano , Marchetti Pierpaolo , Marchetti Andrea , Menis Jessica , Martignoni Guido , Nasso Cecilia , Piacentini Michela , Pierantoni Francesco , Rosellini Matteo , Verlato Giuseppe , Vesentini Roberta , Milella Michele , Caliò Anna
Published: February 2025

TPS617

Background:
At diagnosis, 55% of RCC are localized, and 25% are locally advanced/metastatic (aRCC); an additional 30% develop metastases during follow-up. Prognosis is highly variable in both resectable and advanced disease. All patients’ stratification tools are based on clinical risk scores. For resected patients, only pembrolizumab has demonstrated OS benefit in the adjuvant setting. For metastatic disease, first-line combos (IO-IO and IO-TKI) have dramatically improved outcomes in intermediate/poor-risk patients but have shown no additional OS benefit over TKI in good-risk patients.
Methods:
We designed a multicentric trial to identify novel prognostic/predictive biomarkers to refine current therapeutic algorithms for systemic therapy in both early-stage and aRCC in three different cohorts of patients. Cohort (A) includes patients who underwent radical surgery for RCC (resected, rRCC). Cohort (B) is a retrospective cohort that reclutes aRCC treated with VEGFR TKI monotherapy in I line. The prospective cohort (C) enrolls aRCC patients who are candidate to receive current I-line IO-TKI combos. In the first part, we will correlate patient- and tumor-related factors with the risk of recurrence after surgery for rRCC and progression-free survival and overall survival for aRCC. Tissue-based signatures will be obtained using IHC (PD-L1 expression, tumor immune microenvironment - TiME - composition), an NGS custom panel (mutational profiling), and FISH (for recurrent RCC alterations, such as 9p loss). Multiplex IHC and RNA-ISH will assess cytokine production by specific TiME components. Correlations between the obtained signatures and clinical outcomes will be calculated. In cohort C, the prognostic role of circulating factors (serum cytokine levels and mononuclear cell subpopulations, focusing on MDSC and TReg) will also be evaluated in addition to clinical and tissue-based factors. Blood samples will be collected before and during I-line treatment at pre-planned timepoints. Biomarkers will be quantitatively analyzed to evaluate their relationship with outcomes. Enrollment is ongoing.
THERATEST: A multi-centre observational cohort feasibility study of de-escalation therapies for stage II seminoma.
Authors: Abdul Aziz Nasreen , Ng Kenrick , Alifrangis Constantine , Tran Ben , Conduit Ciara , Liow Elizabeth Chien Hern , Ackerman Charlotte , Georgescu Ramona , Jamal Tanim , Relton Clare , Mayer Erik , Nicol David , Cazzaniga Walter , Huddart Robert A , Reid Alison Helen , Shamash Jonathan , Rajan Prabhakar ,   THERATEST Study Group
Published: February 2025

TPS651

Background:
Standard of care (SOC) for stage II seminoma involves primary orchidectomy with combination chemotherapy or external beam radiotherapy, and yield high survival rates but with significant toxicities. Three cycles of Carboplatin AUC10 or robotic retroperitoneal lymph node dissection (rRPLND) with or without adjuvant chemotherapy are promising de-escalation strategies to minimise treatment associated toxicities whilst maintaining oncological outcomes. However, they are not widely adopted due to a lack of comparative data in prospective clinical trials. Therapy De-escalation for Testicular Cancer (THERATEST) aims to assess the feasibility of recruitment for de-escalation strategies for stage II seminoma.
Methods:
Thirty participants will be recruited over 12 months and treated with either Carboplatin AUC10 or rRPLND with or without adjuvant treatments based on whether the institution offers this treatment as a de-escalation strategy. If participants decline or are not eligible, they will be offered SOC but remain within the study. Both cohorts will be followed up for 2-years. Data collection includes recruitment and retention rates, disease status, surgical outcomes, adverse events and patient-reported outcomes using validated questionnaires which are EORTC QLQ-TC26, EORTC QLQ-C30, the Brief Male Sexual Function Inventory (BMSFI) and additional enquiries on anejaculation.
Results:
THERATEST has recently commenced recruitment at Barts Health and the Royal Marsden Hospital NHS Trusts.
Conclusions:
THERATEST is the first endeavour to prospectively evaluate Carboplatin AUC10 and rRPLND as de-escalation strategies for stage II seminoma in a single study. Feasibility of recruitment and retention as well as qualitative and quantitative outcomes data will inform a large-scale multicentre trial. Clinical trial information:
ISRCTN61007118
.
A phase 1, first-in-human, open label, dose escalating study of B440, an oral cancer vaccine using a WT1-expressing
Bifidobacterium
, in patients with advanced urothelial cancer.
Authors: Shirakawa Toshiro , Furukawa Junya , Kakei Yasumasa , Ueki Hideto , Hara Takuto , Teishima Jun , Hinata Nobuyuki , Miyake Hideaki , Fujisawa Masato
Published: February 2025

TPS883

Background:
B440, an oral cancer therapeutic vaccine, is based on an innovative oral vaccine platform utilizing gut microbiota (
B. longum; Bifidobacterium longum
) that can efficiently deliver the heterogeneous antigen protein to dendritic cells (DCs) in Peyer's patches in gut-associated lymphoid tissue (GALT). B440 is a lyophilized powder of inactivated
B. longum
440, a recombinant
B. longum
expressing a partially modified human WT1 tumor-associated antigen protein (amino acids 117-419 with a single amino acid substitution at 236 from M to Y to enhance immunogenicity). In preclinical studies, B440 showed superior anti-tumor activity to the WT1 peptide vaccine (WT1
126-134
peptide, human HLA-A02 or mouse H-2Db restricted CD8 epitope) due to the large length of the WT1
117-419
protein, including multiple CD8 and CD4 epitopes without HLA restriction, and its ability to internalize into DCs (1, 2). Furthermore, our extensive preclinical studies showed that B440 alone or as an adjunct to an anti-PD1 antibody can induce potent WT1-specific cellular immunity and anti-tumor activity in several mouse syngeneic tumor models (urothelial cancer (3), prostate cancer (4), and renal cell carcinoma (5)).
Methods:
This first-in-human, multicenter, open-label, single-arm, investigator-initiated phase 1 study will evaluate the safety and initial efficacy of B440 monotherapy in patients with advanced urothelial cancer who are refractory to all standard therapies, including chemotherapeutic agents, PD-1/PD-L1 inhibitors and antibody-drug conjugates (ADCs). A total of 12 patients will receive B440 orally once daily for 5 consecutive days followed by a 2-day rest for a total of 20 doses for 4 weeks. The study consists of 2 escalating doses of 6 patients each; the low dose group will receive 800 mg (4 capsules) per dose and the high dose group will receive 1,600 mg (8 capsules) per dose. One enteric capsule contains 200 mg of B440, equivalent to 2X10
10
colony forming units (cfu) of
B. longum
440. The primary endpoint is the determination of dose-limiting toxicity (DLT) with an assessment period of 4 weeks during treatment. Secondary endpoints are safety as assessed by adverse events (AEs) using CTCAE 5.0 and efficacy as assessed by best overall response and progression-free survival (PFS) using RECIST ver1.1. In addition, the immunological response to B440 will be evaluated by enzyme-linked immunosorbent assay (ELISPOT). The study was registered with the Japan Registry of Clinical Trials under the number jRCT2051220143 on December 27, 2022. Patient enrollment was completed in September 2024. Research Sponsor: Immunorock Co., Ltd., Grant: the Japan Agency for Medical Research and Development (AMED); 23ym0126081h0002. Clinical trial information:
jRCT2051220143
.
Phase 2 study of perioperative sacituzumab govitecan in combination with zimberelimab and domvanalimab for patients with muscle invasive bladder cancer ineligible or who refuse cisplatin-based chemotherapy: The PRISMA-1 study.
Authors: Duran Ignacio , Climent Duran Miguel A. , García Carbonero Iciar , Villares Angela , Sánchez-Escribano Ricardo , Calleja Jesus , Sagastibelza Naiara , Villafruela Ainara , Galante Isabel , Dominguez Jose Luis , Font Pous Albert , Servian Pol , Lainez Nuria , Grasa Vicente , Anido Urbano , Cimadevila Anton , Dominguez Mario , Garcia del Muro Xavier , Buisan Oscar , Puente Javier
Published: February 2025

TPS884

Background:
Neoadjuvant cisplatin-based chemotherapy (NACT) has demonstrated a 5-8% improvement in 5-year overall survival (OS) in patients (pts) with muscle invasive bladder cancer (MIBC). However, its routine implementation is still low due to concerns about toxicity/efficacy. Also, about 50% of pts are considered cisplatin ineligible and therefore unable to receive NACT. Immune-checkpoint inhibitors (ICI) and antibody drug conjugates (ADC) have demonstrated separately clinical activity in the perioperative setting and recently remarkable efficacy of ADC-ICIs combos has been shown in pts with advanced urothelial cancer. Therefore, combining ICIs with ADCs as a neoadjuvant therapy results an interesting approach. PRISMA-1 study will evaluate safety and efficacy of the Trop-2 directed ADC, sacituzumab govitecan (SG) in combination with the anti-PD1 zimberelimab (Z) and the anti-TIGIT domvanalimab (D) in MIBC. This study will also search for predictive biomarkers of response and will evaluate the role of ctDNA in the perioperative setting to better select for patients who need post operative treatment.
Methods:
PRISMA-1 study (NCT06133517) is a phase II, single arm, multicenter clinical trial that will enroll 70 adult pts with MIBC, [cT2-T4cN0-1cM0], ECOG PS 0-2, non-eligible or who refuse to receive NACT. The primary endpoint is pathological complete response (pCR) rate. Downstaging, relapse free survival and OS along with ctDNA clearance are some of the secondary endpoints. The study has two stages: First 8 pts will receive the combination of neoadjuvant SG+Z to confirm tolerability. Once safety has been confirmed additional 8 pts will receive the triplet SG+Z+D. If no dose limiting toxicities are observed recruitment will continue to enroll a total of 70 patients. Patients will receive three Q3W neoadjuvant cycles of Z (360 mg day 1) + D (1200 mg day 1) plus SG (7.5 mg/m2 days 1 & 8) followed by cystectomy. After surgery, only those pts who do not achieve a pCR or that achieving a pCR still have positive ctDNA will receive 12 additional cycles of adjuvant treatment with only Z + D. The remaining will be followed with serial ctDNA and imaging. Clinical trial information:
NCT06133517
.