bluuebunny/crossref_metadata_2025 huggingface dataset:
In-field progression following radiation therapy as a prognostic biomarker for lutetium-177-PSMA-617 response in metastatic castration-resistant prostate cancer.
Authors: Howell Jackson Neal , Wilkes Jacob , Maughan Nichole M , Morton Kathryn , Hu Eric , Gill David Michael , Samuelson Scott James , Boothe Dustin
Published: February 2025

86

Background:
Prostate cancer often expresses prostate-specific membrane antigen (PSMA), which serves as a diagnostic and therapeutic target. Lutetium-177 (
177
Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing sites. The prognostic implications of in-field progression (IFP) following prior radiation treatment (RT) on
177
Lu-PSMA-617 response in metastatic castration-resistant prostate cancer (mCRPC) are unknown.
Methods:
We retrospectively reviewed our experience with
177
Lu-PSMA-617 in mCRPC delivered at multiple community-based practices in the Mountain West. Exclusion criteria included death unrelated to prostate cancer before cycle 3 of
177
Lu-PSMA-617 and completing < 4 cycles by June 1
st
, 2024. Baseline characteristics and treatment history were collected. Baseline PSMA PET/CTs were evaluated for maximum SUV, visceral metastases, and lesional heterogeneity (LH) and correlated with radiation records to determine IFP. Progression-free survival (PFS) and overall survival (OS) were determined using Kaplan-Meier and Logrank analysis, and Cox proportional hazard model was used for univariate (UV) and multivariate (MV) analysis of suspected risk factors.
Results:
In total, 72 patients were evaluated with a median follow-up of 10.9 months. Median PFS was 6.5 months (95%CI [4.4 – 9.3]), and median OS was 15.0 months (95%CI [10.9 – undefined]). Fifty-nine patients received either palliative or definitive RT courses for prostate cancer prior to receiving
177
Lu-PSMA-617. Of the 59 patients, 25 patients demonstrated IFP, 34 did not. In-field progression (UV: HR 2.5, p=.003; MV: HR 2.7, p=.003) and LH (UV: HR 1.9, p=.025; MV: 2.1, p=.036) were found to be risk factors for progression during
177
Lu-PSMA-617 therapy. Median PFS among patients with IFP was 3.9 mo (95%CI [2.6 – 6.3]) versus 10.3 mo (95%CI [4.4 – 13.0]) among those without (p=.002). Median PFS among patients with LH was 4.6 mo (95%CI [2.9 – 6.5]) versus 11.6 mo (95%CI [6.9 – 13.0]) for those without (p=.023). IFP (UV: HR 2.5, p=.016; MV: 2.7, p=.021; median OS = 10.2 mo, 95%CI [6.2 – 12.8]) and LH (UV: HR 2.45, p=.027; MV: HR 4.17, p=.018; median OS = 11.7 mo, 95%CI [9.3 – 15.0]) were similarly prognostic for OS. At the current follow-up, median OS has not been reached for patients without IFP or LH, but Logrank testing shows statistically significant improvements in OS for these groups (p=.013 and p=.022, respectively) over those with them.
Conclusions:
In our real-world experience, PFS and OS for
177
Lu-PSMA-617 in mCRPC were similar to the VISION study results. IFP following RT and LH on baseline PSMA PET/CT were negative prognostic biomarkers. Validation in a larger, prospective cohort is warranted.
A prognostic model for survival of patients with metastatic upper tract urothelial carcinoma with first-line systemic therapy.
Authors: Wei Jinchang , Li Siming , Xu Huayan , Wu Xiaowen , Li Juan , Zhou Li , Yan Xieqiao , Tang Bixia , Si Lu , Cui Chuanliang , Chi Zhihong , Guo Jun , Sheng Xinan
Published: February 2025

868

Background:
Upper tract urothelial carcinoma (UTUC) presents distinct clinicopathological, molecular features, and biological behaviors compared to urothelial bladder carcinoma (UBC). Currently, no prognostic model exists for metastatic UTUC (mUTUC). This study aimed to develop a prognostic model for mUTUC patients receiving first-line systemic therapy.
Methods:
A total of 476 patients with mUTUC who received first-line systemic therapy at Peking University Cancer Hospital from January 2005 to March 2024 were included in the analysis. Patients were randomly assigned to development and validation cohorts in a 3:1 ratio, with potential prognostic factors recorded prospectively. Univariate Cox regression analysis identified clinical and laboratory factors significantly associated with median overall survival (mOS) in the development cohort, followed by multivariate Cox regression analysis to determine independent prognostic factors. These factors were utilized to develop a prognostic model. Internal validation was conducted using the validation cohort.
Results:
After a median follow-up of 51.8 months, 321 patients (67.4%) had died, with a mOS of 26.6 months. The median age at diagnosis was 63 years, with 58.4% males. Common visceral metastatic organs included lung (37.8%), liver (17.9%), and adrenal gland (7.4%). The most frequent first-line treatment option was platinum-containing chemotherapy (63.7%). The number of metastatic organs ≥ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) > 1, time to distant metastasis (TTDM) < 12 months, white blood cell (WBC) count > upper limit of normal (ULN), and alkaline phosphatase (ALP) level > ULN were identified as independent prognostic risk factors for mUTUC (Table). A prognostic model for mUTUC was developed, in which the patients were stratified into three risk categories: favorable (0 risk factors, mOS 65.0 months [95% CI 35.5–94.6]), intermediate (1 risk factor, mOS 32.0 months [95% CI 25.8–38.2]), and poor (2+ risk factors, mOS 16.0 months [95% CI 12.1–19.9]) (
p
< 0.05). The model's concordance statistic (c-statistic) was 0.71 in the development cohort and 0.72 in the validation cohort.
Conclusions:
We developed and validated a prognostic model for mUTUC patients receiving first-line systemic therapy, which can inform future clinical practice and trial designs.

Results of multivariate analysis.

Variables

P

Hazard Ratio (95% CI)
Reference Category

TTDM
<0.01
3.01 (2.13 ~ 4.26)
≥ 12 months

ECOG PS
<0.01
2.28 (1.30 ~ 3.97)
≤ 1

Number of Metastatic Organs
0.01
1.41 (1.04 ~ 1.91)
< 3

WBC
<0.01
1.89 (1.21 ~ 2.95)
≤ ULN

ALP
0.02
1.71 (1.10 ~ 2.64)
≤ ULN
Avelumab first-line maintenance (1LM) in patients (pts) with advanced urothelial carcinoma (aUC) with or without diabetes mellitus (DM): Long-term outcomes from JAVELIN Bladder 100.
Authors: Gupta Shilpa , Grivas Petros , Park Se Hoon , Petrylak Daniel P. , Tyroller Karin , Hoffman Jason , Bellmunt Joaquim
Published: February 2025

869

Background:
In the JAVELIN Bladder 100 phase 3 trial, avelumab 1LM + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in pts with aUC that had not progressed with 1L platinum-based chemotherapy (PBC). In some cancers, the presence of DM has been associated with reduced efficacy of immunotherapy; however, data in UC are limited. We report post hoc exploratory analyses from JAVELIN Bladder 100 in pts with or without DM at randomization.
Methods:
Eligible pts with unresectable locally advanced or metastatic UC without progression after 1L PBC were randomized 1:1 to receive avelumab + BSC or BSC alone. The primary endpoint was OS measured from randomization; secondary endpoints included PFS measured from randomization and safety.
Results:
At randomization in the avelumab + BSC (n=350) and BSC alone (n=350) arms, 55 (15.7%) and 59 (16.9%) pts had documented controlled DM, and 295 and 291 pts did not have documented DM, respectively. Median follow-up in both arms was ≥38.0 months (data cutoff, June 4, 2021). In pts with or without DM, OS and PFS (investigator assessed) were prolonged with avelumab + BSC vs BSC alone (Table). In the safety analysis set of avelumab-treated pts with (n=54) or without (n=290) DM, respectively, treatment-related adverse events (AEs) of any grade occurred in 75.9% and 78.6% (grade ≥3 in 24.1% and 18.6%) and led to avelumab discontinuation in 9.3% and 12.1%; immune-related AEs of any grade occurred in 31.5% and 32.4%. Limitations include the exploratory nature of the analysis and the potential for missing DM diagnosis.
Conclusions:
In exploratory analyses, avelumab 1LM was associated with long-term efficacy and consistent safety in pts with aUC with or without DM. Clinical trial information:
NCT02603432
.

Pts with DM
Pts without DM

Avelumab + BSC
(n=55)

BSC alone
(n=59)

Avelumab + BSC
(n=295)

BSC alone
(n=291)

Median OS (95% CI), months
20.8 (18.0-32.4)
14.5 (11.7-21.3)
24.7 (19.9-30.0)
15.8 (13.3-18.7)

2-year OS (95% CI), %
44.5 (30.7-57.3)
34.1 (22.2-46.3)
50.7 (44.8-56.4)
39.4 (33.6-45.2)

3-year OS (95% CI), %
33.1 (20.4-46.4)
20.3 (10.8-31.9)
36.6 (30.6-42.6)
31.9 (26.3-37.7)

Hazard ratio (95% CI)
0.60 (0.37-0.95)
0.78 (0.64-0.96)

Median PFS (95% CI), months
5.6 (3.7-9.3)
2.0 (1.9-3.7)
5.4 (3.8-7.2)
2.1 (1.9-3.5)

2-year PFS (95% CI), %
18.5 (9.1-30.6)
9.2 (3.4-18.6)
24.3 (19.3-29.7)
6.5 (3.8-10.2)

3-year PFS (95% CI), %
13.5 (5.5-25.1)
5.5 (1.4-13.8)
16.3 (11.7-21.6)
5.3 (2.9-8.9)

Hazard ratio (95% CI)
0.50 (0.33-0.77)
0.54 (0.45-0.65)
Characterization of genitourinary drug approvals by the FDA, 2020-2024.
Authors: Benjamin David Joseph , Rezazadeh Arash
Published: February 2025

872

Background:
There were 255 cancer drug approvals by the US Food and Drug Administration (FDA) between January 2020 and October 2024. Although genitourinary (GU) cancers (prostate, urothelial, renal and testicular) compromise some of the most prevalent malignancies, it is unclear how many of these drug approvals were intended for treatment of genitourinary cancers.
Methods:
Using the list of FDA cancer drug approvals, we identified approvals for GU cancer indications between January 2020 and October 2024. We collected data on tumor type, line of treatment, control arm, primary endpoint(s) as studied in the corresponding clinical trial, and phase of clinical trial.
Results:
We identified a total of total of 26 drug approvals for GU cancer indications (10.2%) among the total 255 drug approvals for all cancer types. Among these approvals, 12 were for urothelial, 9 for prostate, and 5 for renal. There was variation in the line of setting for each approval’s intended use as shown in the table. No cancer drug approvals were for testicular, penile or adrenal cancer. Most trials were phase III (n = 20), followed by phase II (n = 4) and then one each for phase IB/II and II/III. Overall survival was the most common endpoint (n = 10), followed by response rate and duration of response (n = 7), radiographic progression-free survival (n = 5), disease-free survival (n = 2), and one each for castration rate and metastasis-free survival.
Conclusions:
Drug approvals for GU cancers compromised approximately 10% of drug approvals by the FDA over the past five years. While OS continues to be the most commonly used endpoint in clinical trials, response rate and duration of response are commonly employed in BCG-refractory non-muscle invasive bladder cancer trials and radiographic progression-free survival in prostate cancer trials. Given the high incidence and mortality from GU cancers, continued drug development is warranted.

Intended setting of use for genitourinary cancer drug approvals by tumor type, 2020-2024.

Tumor Type
Number
Indication

Urothelial
12
First line (n = 3), adjuvant (n = 1), maintenance (n = 1), BCG-refractory/UTUC (n = 4), second- or later-line (n = 3)

Prostate
9
Hormone-sensitive (n = 2), hormone-resistant (n = 1), biochemical recurrence (n = 1), BRCA/HRD mutated (n =5)

Renal
5
First-line (n = 2), adjuvant (n = 1), second- or later-line (n = 2)

Testicular
0
No applicable

Penile
0
Not applicable

Adrenal
0
Not applicable

26
Primary sarcomas of urinary bladder: A SEER analysis.
Authors: Han Joseph , Lee Hyun , Kaushish Ayush , Baralo Bohdan , Paul Asit KR
Published: February 2025

878

Background:
Primary bladder sarcoma (PBS) is a rare entity. In this study, we analyzed demographics, clinical characteristics, and survival outcomes of PBS using the Surveillance, Epidemiology and End Results (SEER) database.
Methods:
We identified patients with urinary bladder sarcoma in the SEER database from the years 2000 to 2020 using the primary cancer site codes for urinary bladder as well as histological codes (ICD-O-3) that match the list of sarcoma histology found in the NCCN soft tissue sarcoma and bone cancer guidelines. Data for demographics, disease extent, median overall survival (OS), and treatment modalities were obtained. Sarcomas mixed with carcinomas, so-called carcinosarcomas, were included in the analysis. From the same database, OS data on urothelial carcinomas were obtained for comparison.
Results:
During the period of analysis, a total of 349,326 patients with primary bladder neoplasms were identified. Among them, 707 (0.002%) patients had PBS. The majority were Caucasian (71.9%) followed by Hispanics (12.9%) and African Americans (11.0%). There were 445 males (62.9%) with PBS. The most common histology was carcinosarcoma (40.9%), followed by leiomyosarcoma (20.4%), rhabdomyosarcoma (13%), and unspecified sarcoma (9.3%). Among the 654 patients with known extent of disease, 56.7%, 24.9%, and 18.3% had localized, locoregional, and distant metastatic disease, respectively. OS for patients with localized, regional, and distant diseases were 32, 12, and 4 months, respectively (P<0.0001). Bladder sarcomas were associated with worse survival than urothelial carcinomas (14 months vs. 92 months, P<0.01). OS was longer in patients with pure sarcomas compared to patients with mixed sarcomas (26 months vs. 9 months, P< 0.001). Among the 697 patients with treatment data available, 34 (4.9%) received chemotherapy only, 468 (67.1%) received surgical resection only, 152 (21.8%) received both, and 43 (6.2%) received neither. Both chemotherapy and surgery were associated with longer median OS. Those who received chemotherapy showed a median OS of 42 months compared to 9 months seen in the no chemotherapy group (P<0.001). As for surgical resection, median OS of those who underwent surgery was 16 months compared to 8 months in those who did not (P=0.014).
Conclusions:
Bladder sarcomas are rare and associated with worse outcomes when compared to urothelial carcinoma. Carcinosarcomas are associated with worse survival when compared with pure sarcomas. More than half of the bladder sarcomas were diagnosed as localized disease and survival was better when compared with locoregional or distant disease. Chemotherapy and surgical resection were associated with longer median OS, but prospective studies are needed to ascertain these findings after controlling for confounders.
First next-generation sequencing (NGS) testing at the end of life in patients with metastatic prostate cancer.
Authors: Ozay Zeynep Irem , Jo Yeonjung , Hage Chehade Chadi , Sayegh Nicolas , Gebrael Georges , Ostrowski Micah , Lin Edwin , Galarza Fortuna Gliceida M , Nordblad Blake , Li Haoran , Mathew Thomas Vinay , Graf Ryon P , Riaz Irbaz Bin , Guha Avirup , Maughan Benjamin L. , Roy Soumyajit , McKay Rana R. , Antonarakis Emmanuel S. , Swami Umang , Agarwal Neeraj
Published: February 2025

90

Background:
Poly(ADP) ribose polymerase inhibitors and pembrolizumab are approved for patients with metastatic prostate cancer (mPC) with susceptible genomic alterations based on NGS testing. We recently reported that the rate of NGS testing in mPC remains low at 29.3% in the United States (1). Herein, we investigated the rates of NGS testing at the end of life in a real-world patient population.
Methods:
This study utilized the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Eligibility: diagnosis of mPC, with information on receipt of NGS testing (blood/tissue) and recorded date of death. The time between each patient’s first NGS testing result date and date of death was measured and categorized into 3 groups: NGS test results delivered more than 3 months (mo) before death, within 3 mo of death, and delivered after death. Frequencies and percentages of these 3 categories were reported, also by the year of death.
Results:
Out of 24,105 patients with mPC in the database, 3,397 had both a recorded date of death and underwent NGS testing and were eligible and included. The median age was 74 (IQR 67–80), 70% were White non-Hispanic, and 83% were treated in a community-based practice. In these patients, 2,901 (85.4%) NGS results were reported more than 3 mo before death, 457 (13.5%) within 3 mo of death, and 39 (1.1%) after death. From 2015 to 2024, the percentage of patients receiving their result more than 3 mo before death increased from 27% to 91%, while those receiving it within 3 mo before death decreased from 55% to 8.5%, and the percentage of NGS results reported after death declined from 18% to 0.6%. Baseline characteristics (including race-ethnicity, insurance plan, practice type [academic vs. community]) in these categories will be presented at the meeting.
Conclusions:
Despite the availability of life-prolonging targeted therapies based on NGS testing results for patients with mPC, in ∼14% of patients, the first NGS testing results were reported within 3 mo before death or after death. The lack of timely NGS testing limits patients' access to life-prolonging personalized treatments in earlier settings, resulting in missed opportunities for improved outcomes. 1. Hage Chehade, Swami, JAMA Network Open, 2024.
Real-world evidence for factors associated with development of castration-resistant prostate cancer (CRPC).
Authors: Ryan Charles J. , Lacuna Kristine Peregrino , Yoo Lena , Szmukier Zuzanna , Boldt-Houle Deborah M
Published: February 2025

92

Background:
Androgen deprivation therapy (ADT) is foundational for advanced prostate cancer (PCa); luteinizing hormone-releasing hormone (LHRH) agonists and gonadotropin-releasing hormone (GnRH) antagonists are widely used. ~20% of PCa patients on LHRH analogs develop castration-resistant prostate cancer (CRPC) within 3 years. We evaluated factors associated with CRPC onset and time to CRPC onset for agonists vs. antagonist using real-world dataset.
Methods:
Data were collected from an EMR database purchased from Decision Resources Group. Analysis set included PCa patients who received ≥1 ADT 1991-2020 and excluded those who received both LHRH agonist and a GnRH antagonist and/or developed CRPC on the same day/before ADT initiation. CRPC onset date was defined as the earlier of 2 options: CRPC diagnosis or first CRPC therapy (standard of care treatments e.g., androgen pathway inhibitors, immunotherapy, chemotherapy, radiotherapy). Associations between CRPC and each available factor were evaluated using MV Cox regression. Time to CRPC onset was assessed for agonists vs. antagonist.
Results:
41,379 patients were analyzed. Factors associated with MV HR >1.4, p<0.001 were oncology setting, metastatic disease, absence of diabetes, and no statin use (Table 1). Antagonist use had an adjusted HR of 1.4 (95% CI 1.06-1.85, p=0.02). Median time to CRPC onset after ADT initiation is 10.9 months for antagonist (n=238) vs. 17.3 months for agonists (n=5,231).
Conclusions:
Treatment-related (oncology setting; antagonist use) and comorbidity factors (older age, no diabetes, no statin use) were associated with CRPC onset. Oncology setting and antagonist use may reflect practice patterns in higher risk individuals. The association between diabetes and CRPC risk is under further evaluation e.g., whether antecedent diabetes therapies confer protection.

Hazard ratio (95% CI) and P-value of CRPC for top 10 significant factors
1
in multivariable analysis.

Multivariable (n=9,554)
2,3

Factors

HR (95% CI)

P-value

Oncology vs Urology (Setting)
3.04 (2.56-3.59)
<0.001

W vs W/o Metastasis (Baseline)
2.20 (1.58-3.05)
<0.001

W/o vs W Diabetes
4

1.45 (1.22-1.73)
<0.001

W/o vs W Statin
4

1.43 (1.25-1.63)
<0.001

Antagonist vs Agonist
1.40 (1.06-1.85)
0.02

W/o vs W Hypertension
4
(HTN)

1.17 (1.01-1.36)
0.041

Decreasing ADT Exposure per Year
1.09 (1.05-1.13)
<0.001

Increasing Age per Year (Older vs Younger)
1.02 (1.02-1.03)
<0.001

1
Significant for multivariable analysis.

2
Excluded patients with CRPC on the same day/before ADT Start.

3
Excluded patients with both agonist and antagonist use; without BMI, PSA, and age data; non-white/black race; with unknown urology/oncology or with both urology/oncology setting.

4
Has taken statins/hypertension/diabetes medication or diagnosed with hypertension/diabetes disease.
Real world outcomes of
177
Lu-PSMA-617 PSMA in a racially diverse cohort of patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Gerke Margo , Marra Angelo , Liu Yuan , Muzahir Saima , Brown Jacqueline T , Nazha Bassel , Berchuck Jacob E , Parikh Ravi Bharat , Ciuro Jordan Alana , Hartman Caitlin , McClintock Greta Russler , Caulfield Sarah , Kucuk Omer , Carthon Bradley Curtis , Schuster David M. , Bilen Mehmet Asim
Published: February 2025

97

Background:
177
Lu-PSMA-617 is approved for treatment of mCRPC based on the VISION trial cohort with limited racial diversity. We analyzed real-world outcomes of
177
Lu-PSMA-617 in a diverse cohort. We aim to determine patient characteristics predictive of a clinical response to
177
Lu-PSMA-617.
Methods:
A retrospective analysis was conducted on patients with mCRPC treated with
177
Lu-PSMA-617 at Emory Winship Cancer Institute between 2022-2024. Primary endpoints were PFS, OS, and PSA reduction ≥ 50% (PSA50). Univariate association by survival analysis and logistic regression was carried out.
Results:
We analyzed 84 patients with PSMA PET+ mCRPC treated with
177
Lu-PSMA-617; 47.6% identified as Caucasian and 42.9% identified as Black. The median cohort age was 71.5 (IQR: 64-77.5). 35.6% had grade group 5 disease. Median number of prior lines of therapy was 5 (range: 4-7). 98.8% of patients had prior treatment with novel hormonal agents; 84.5% received prior taxane treatment. 84.5% were characterized as high-volume diseases using the CHAARTED trial criterion. Median baseline PSA was 105.5 (IQR: 20.4-454.8), and ALP was 103.5 (IQR: 72-177.5). The cohort completed a median number of 4 cycles of
177
Lu-PSMA-617; 35.7% completed six cycles. The overall cohort had a 12-month survival of 84.4%. 12-month survival rate was 88.3% in the white cohort compared to 81.4% in the non-white cohort. mPFS for the overall cohort was 6 months with a 12-month PFS rate of 41.9%. 12-month mPFS for the non-white cohort was 42.7% compared to 41.5% in the white cohort. 50.0% of the overall cohort had a PSA50 response. 56.1% of the non-white cohort had a PSA50 compared to 43.9% of the white cohort (p=0.377). Net BMI decline during treatment was associated with a 56% increased risk of mortality (OS HR 1.56, CI 1.18-2.06, p<0.002).
Conclusions:
With similar PFS, OS, and PSA50 in this racially diverse cohort of patients with mCRPC, our results demonstrate
177
Lu-PSMA-617 effectiveness in a real-world patient population. Prospective studies are needed for further validation.
Detection of mutations in homologous recombination repair (HRR) pathway genes using liquid biopsy in metastatic, castration-resistant prostate cancer (mCRPC) patients without tumor tissue availability.
Authors: Lim Yoojoo , Kyung Dong Soo , Ko Won Yeong , Kim Hwang-Phill , Kim Tae-You
Published: February 2025

98

Background:
Accurate detection of mutations in HRR pathway genes among patients with mCRPC is essential for selecting patients who would benefit with poly (ADP-ribsose) polymerase (PARP) inhibitor therapies. Traditional tissue-based detection methods can be associated with practical challenges as acquisition of specimens can involve significant risk or high costs. For prostate cancer patients, obtaining adequate tissue samples can be even more difficult, considering the unique characteristics of the disease. This study aimed to evaluate the real-world performance of liquid biopsy using circulating tumor DNA (ctDNA) in detecting mutations in HRR genes, among mCRPC patients who did not have tissue available for genomic evaluation.
Methods:
Blood samples (20ml of whole blood) were collected from 760 mCRPC patients in 10 Asian countries. Samples were collected once for each patient, regardless of treatment type or cycles as long as the patients were followed up for their mCRPC. All patients included were confirmed from each participating site to have no tissue available for genomic analysis. Blood samples were analyzed using a next-generation sequencing (NGS) based ctDNA assay, covering 15 genes in the HRR pathway (
ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L)
.
Results:
ctDNA NGS testing was successfully performed in all 760 mCRPC patients. Any mutations in the HRR pathway genes were detected in 63.7% of the included patients and deleterious or suspected deleterious HRR pathway gene mutations were detected in 32.5% with the assay. Deleterious/suspected deleterious
BRCA1/2
mutations were detected in 68/760 (8.95%) of the cases. Other detected deleterious/suspicious deleterious mutations included mutations in
CDK12
, detected in 59/760 (7.76%) patients, followed by
ATM
mutation in 39/760 (5.13%), and
CHEK2
in 31/769 (4.08%) by frequency.
Conclusions:
ctDNA testing for HRR gene mutations offers a practical tool for therapy selection in mCRPC patients. This non-invasive approach enables testing for patients who were not eligible for evaluation by tissue-based methods and can expand access to adequate targeted therapies.
Precision diagnostics in prostate cancer treatment (PREDICT): A phase 2 multi-arm biomarker-based study (Alliance A032102).
Authors: McKay Rana R. , Heller Glenn , Zhao Shuang , Wulff-Burchfield Elizabeth Marie , Shah Dhaval , Tan Alan , Galsky Matthew D. , Rosenberg Jonathan E. , Beltran Himisha
Published: February 2025

TPS281

Background:
Advances in genomic sequencing have allowed for a deeper understanding of the molecular complexity of metastatic castration resistant prostate cancer (mCRPC) with several actionable alterations now identified, fueling new biomarker-based treatment strategies. For this reason, it is recommended that all patients with mCRPC undergo germline and somatic tumor profiling. In addition to DNA aberrations, gene expression changes can capture actionable targets and activated pathways. The phase 2 PREDICT trial is using both DNA and RNA aberrations to select patients with mCRPC for rationally-designed biomarker-based therapeutic strategies.
Methods:
This is a multi-center, multi-arm, biomarker-driven phase 2 umbrella study with a primary objective of objective response rate for patients with mCRPC and measurable disease. Secondary objectives include radiographic progression-free survival, PSA response, time to first symptomatic skeletal event, overall survival, safety, and correlative studies. Eligible patients must have progressive mCRPC of any histology, received a prior androgen receptor pathway inhibitor (ARPI), and received or refused taxane chemotherapy. Patients with measurable and non-measurable disease are eligible. Patients must have standard of care next generation DNA sequencing via any CLIA-certified tissue or circulating tumor DNA assay for initial trial enrollment. For arm allocation based on RNA alterations, testing will be via the CLIA-certified Caris MI Tumor Seek assay, which includes whole exome and whole transcriptome sequencing, derived from tissue obtained within 12 months of enrollment. A real-time molecular tumor board will convene to review genomic reports and confirm arm allocation on a rolling basis as biomarker results become available. Patients with Rb loss (DNA), Rb functional loss signature (RNA), NEPC signature (RNA) will be allocated to treatment with the EZH1/2 inhibitor valemetostat. Patients with at least 2 of 3 tumor suppressor gene DNA alterations (TP53, RB1, PTEN), FANC alteration (DNA), or SLFN11 overexpression (RNA) will be allocated to cabazitaxel plus carboplatin. Patients without any study-defined alterations will be allocated to physician choice treatment with either cabazitaxel, ARPI, or
177
Lu-PSMA-617. The study is designed to accommodate future biomarker arms. A maximum of 64 patients with measurable disease and 94 patients with non-measurable disease for a total of 158 patients, will be accrued to each treatment arm. This Simon two-stage minimax design has a type 1 error equal to 0.05 when the probability response is 0.20 and has power of 0.90 if the probability of response is 0.37. Clinical trial information: NCT.
ACCEL: [Ac-225]-PSMA-62 phase Ia/Ib/II clinical trial to characterize efficacy, safety, tolerability, and dosimetry in oligometastatic hormone-sensitive and metastatic castration-resistant prostate cancer.
Authors: Saleh Ramy , Chi Kim N. , Jiang Di Maria , Castonguay Vincent , Abbaspour Farzad , Metser Ur , Wilson Don , Ma Junsheng , Cioci Richard , Nacerddine Karim , Beauregard Jean-Mathieu
Published: February 2025

TPS282

Background:
Actinium-225 (Ac-225)-based, prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) represents a promising treatment modality for prostate cancer. First-generation PSMA-targeting ligands (e.g., PSMA-617 and PSMA-I&T) paired with Ac-225 have been associated with myelosuppression, renal toxicity, and xerostomia (1). LY4181530 (previously PNT2001) pairs Ac-225 with PSMA-62, a next-generation ligand, which was specifically designed to overcome these limitations. It employs an improved linker technology that increases cellular internalization, leading to improved biodistribution, tumor delivery of Ac-225, and efficacy in preclinical models (2).
Methods:
ACCEL (NCT06229366) is a multi-center, open-label, multiple-arm, Phase Ia/Ib/II study evaluating the safety, tolerability, and efficacy of [Ac-225]-PSMA-62 in patients with oligometastatic hormone-sensitive prostate cancer (OmHSPC) and metastatic castration-resistant prostate cancer (mCRPC). Eligible patients with OmHSPC have metachronous disease, up to 5 PSMA-positive lesions, and have not initiated life-long ADT. Eligible patients with mCRPC have PSMA-positive lesions and have received prior androgen receptor pathway inhibitor, taxane chemotherapy (unless ineligible or declined), and up to 3 prior systemic therapy regimens in the mCRPC setting. Prior PSMA-targeted RLT, baseline Grade ≥1 xerostomia, and Grade ≥1 xerophthalmia are not permitted. In the Phase 1a, dose escalation decisions follow the Bayesian optimal interval (BOIN) design to separately determine the maximum tolerated dose of [Ac-225]-PSMA-62 for each patient population. In the Phase 1b, patients will be randomized to 2 or more arms to optimize dosing/schedule and inform the selection of the recommended Phase II dose of [Ac-225]-PSMA-62 for each patient population. The phase II aims to evaluate the efficacy of [Ac-225]-PSMA-62 compared to best standard of care in patients with mCRPC, with the primary endpoint being radiographic progression-free survival. The study is currently enrolling in Canada with plans to open in other countries. 1. Sathekge MM. et al.
Lancet Oncol
. 2024 Feb;25(2):175-183. 2. Vito A. et al. EP-039. Presented at EANM Oct 2022, Barcelona, Spain. Clinical trial information:
NCT06229366
.
PRO-XL: A phase II study of zanzalintinib (XL092) in patients with metastatic castration-resistant prostate cancer (mCRPC) after progression on lutetium-177 (177Lu)-PSMA-617.
Authors: Swami Umang , Boucher Kenneth M , Jo Yeonjung , Moynier Colin , Clement Susan , Phunrab Tenzin Kunsang , Batten Julia , Quertinmont Joshua , Mahlow Jon , Mathew Thomas Vinay , Gupta Sumati , Kohli Manish , Maughan Benjamin L. , Agarwal Neeraj
Published: February 2025

TPS285

Background:
177Lu-PSMA-617 has been approved for patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy after demonstrating improvement in overall survival (OS) in the phase III VISION trial (PMID: 34161051). However, the tumor eventually develops resistance to 177Lu-PSMA-617 and progresses, and therefore, therapies are needed to treat 177Lu-PSMA-617 refractory mCRPC. Prior studies have demonstrated a significant VEGF expression in LNCaP tumors and locally recurrent prostate cancer after radiotherapy. Also, tumor recurrence largely depends on new vessel formation through angiogenesis when radiation inhibits angiogenesis. Zanzalintinib is a novel, potent, orally bioavailable small molecule multi-targeted inhibitor of kinases, including the receptor tyrosine kinases (RTKs), VEGFR2, MET, and TAM kinases AXL, and MER, which have been shown to be overexpressed in radiation-resistant tumors. Therefore, zanzalintinib is expected not only to inhibit tumor angiogenesis but also to mitigate resistance to antiangiogenic therapy over time. We initiated a phase 2 trial of zanzalintinib in pts with mCRPC after progression on 177Lu-PSMA-617.
Methods:
This IRB-approved, investigator-initiated, single-arm, single-center, non-randomized, open-label study will enroll 30 patients. Zanzalintinib will be administered orally at 100 mg once daily. Eligibility criteria: ≥ 18 years of age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, progression on or after prior treatment with 177Lu-PSMA-617, ECOG performance status ≤ 2, and adequate organ function. Any number of prior therapies will be allowed. Primary Endpoint: Proportion of participants with non-progressive disease at 16 weeks of treatment with zanzalintinib as assessed by Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1. Thirty patients will ensure that the disease control rate can be estimated via a 95% confidence interval with a margin of error <0.20. Secondary Endpoints: safety, tolerability, PSA 50% response rate, and OS. Tissue and blood samples will be collected for correlative studies. Clinical trial information:
NCT06568562
.
A phase 1b/2 study evaluating the activity of tinengotinib in combination with androgen receptor pathway inhibitors (ARPIs) in patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Abida Wassim , Chen Yu , McHugh Deaglan Joseph , Morris Michael J. , Wu Frank , Peng Peng , Hennessy Katie , Wang Hui , Fan Jean , Zaidi Samir
Published: February 2025

TPS290

Background:
Androgen receptor pathway inhibitors (ARPIs) are standard life-prolonging therapies for patients with metastatic castration-resistant prostate cancer (mCRPC), but patients ultimately progress on these agents. Resistance has been shown to occur in part via lineage plasticity mediated by increased activity of kinases including JAK1 and FGFR. Preclinical studies have shown that ARPI sensitivity can be restored by inhibiting these kinases. Tinengotinib is an orally bioavailable, potent multi-kinase inhibitor that targets JAK1 and receptor tyrosine kinases (FGFRs, VEGFRs). We hypothesize that in patients with mCRPC who are progressing on ARPIs, the addition of tinengotinib will restore sensitivity to ARPIs and result in objective responses.
Methods:
This is a multi-center, phase 1b/2 study of tinengotinib plus either abiraterone/prednisone or enzalutamide in patients with mCRPC. Eligible patients must be on ongoing therapy with abiraterone/prednisone or enzalutamide started at least 90 days prior to study participation consent and progressing by Prostate Cancer Working Group 3 (PCWG3) criteria. Tinengotinib will be added to abiraterone/prednisone or enzalutamide at the time of progression. Phase 1b (N = up to 24) uses a 3+3 de-escalation schema to assess the safety and tolerability of tinengotinib with either abiraterone/prednisone or enzalutamide. The starting dose of tinengotinib will be 10 mg PO QD, with the possibility of de-escalation to 8 mg PO QD if a combination is not tolerated. Phase 2 employs a two-stage Simon minimax design; patients will be enrolled to evaluate the safety and efficacy of the recommended phase 2 dose (RP2D) of tinengotinib with abiraterone acetate/prednisone or enzalutamide (N = 32). Since abiraterone acetate and enzalutamide target the same pathway, response will be evaluated in combination in the signal-seeking phase 2 portion of the study. As of October 2024, 2 patients have been enrolled in phase 1b across 1 site. Enrollment for phase 2 is expected to begin in January 2025. Clinical trial information:
NCT06457919
.
A phase I/II study of neoadjuvant, intra-arterial administration of (177Lu)lutetium vipivotide tetraxetan in subjects with high-risk, localised or locally advanced prostate cancer (LUPUS).
Authors: Kesch Claudia , Meyer Volker , Praus Christine , Fragoso Costa Pedro , Ingenwerth Marc , Darr Christopher , Radtke Jan Philipp , Theysohn Jens M , Schaarschmidt Benedikt , Reis Henning , Fendler Wolfgang Peter , Grünwald Viktor , Hadaschik Boris A. , Herrmann Ken
Published: February 2025

TPS431

Background:
The recent LuTectomy trial suggested that intra-venous [177Lu]Lu-PSMA-617 prior to surgery in men with high-risk localised or locally advanced prostate cancer (HRCaP) is safe and effective. We hypothesise that intra-arterial infusion will further enhance target lesion uptake and efficacy without compromising safety. LUPUS is the first trial investigating (177Lu)Lutetium vipivotide tetraxetan intra-arterial infusion and will help to further evaluate if there is a role for neoadjuvant radioligand therapy in HRCaP.
Methods:
Phase I/II study of neoadjuvant, pre-surgical (177Lu)Lutetium vipivotide tetraxetan as intra-arterial infusion in men with HRCaP who are candidates for radical prostatectomy (EU CTR 2022-500838-28-00). Intra-arterial perfusion is performed via a catheter into A. iliaca interna without concomitant embolization. In the first cohort, 10 patients will receive one cycle of 200 mCi (7.4 GBq) (177Lu)Lutetium vipivotide tetraxetan followed by radical prostatectomy 6 weeks thereafter. If less than 4 out of 10 patients have to delay surgery or suffer from CTCAE Grade ≥3 adverse events (AEs) due to the treatment, 10 additional patients will be included and receive one cycle of 400 mCi (14.8 GBq) (177Lu)Lutetium vipivotide tetraxetan. Enrolment began in September 2024. Primary endpoints are AEs and days of delay of scheduled surgery related to intra-arterial (177Lu)Lutetium vipivotide tetraxetan therapy. Secondary endpoints are PSA-response and pathological response. Other endpoints include imaging changes, changes in quality of life and dosimetry. Clinical trial information:
EU Clinical Trial no.: 2022-500838-28-00
.
A phase 1b, open-label, multicenter study of xaluritamig in patients with newly diagnosed localized intermediate- or high-risk prostate cancer in the neoadjuvant setting.
Authors: Oh David Yoonsuk , Kilari Deepak , Darr Christopher , Zarrabi Kevin Kayvan , Hawley Jessica E. , Pachynski Russell Kent , Tagawa Scott T. , Yang Yuanquan , Buetikofer Simon , Xia Qing , Von Amsberg Gunhild
Published: February 2025

TPS434

Background:
There are currently no standard neoadjuvant treatments for patients with localized prostate cancer despite improved outcomes with neoadjuvant therapy in multiple other solid tumors. Xaluritamig is a bispecific T-cell engager (TCE) that simultaneously engages the six-transmembrane epithelial antigen of the prostate 1 (STEAP1) expressed on prostate cancer cells and the CD3 complex on T cells, thereby leading to T-cell mediated lysis of the STEAP1 expressing prostate cancer cells. In an ongoing trial (NCT04221542), xaluritamig has demonstrated deep, early, and durable responses in patients with metastatic castration-resistant prostate cancer. Notably, TCEs as a class of therapy have demonstrated the potential to have even greater efficacy and safety when used in earlier stages of disease where the overall disease burden is less and immune fitness is generally better. These data suggest that xaluritamig may be safely administered in the neoadjuvant setting and lead to pathologic responses with subsequent improvement in disease control and long-term clinical outcomes. In the current study, safety and feasibility as well as preliminary efficacy of neoadjuvant xaluritamig are being evaluated in patients with newly diagnosed localized intermediate or high-risk prostate cancer.
Methods:
This Phase 1b, open-label, multicenter study plans to enroll approximately 30 patients diagnosed with localized intermediate or high-risk prostate cancer and are planned for radical prostatectomy. Eligibility criteria includes histologically or cytologically confirmed prostate adenocarcinoma with Gleason Score ≥4+3 and an initial prostate specific antigen (PSA) of ≥10 ng/ml, no evidence of metastasis outside of the surgical resection field (PSMA-PET positive locoregional lymph nodes or less or equal 5 local lymph nodes on MRI can be enrolled), or use of any prior therapy for prostate cancer. The study includes a 28-day screening period, a two-cycle neoadjuvant treatment period (each cycle lasting 28 days), a safety follow-up visit (up to 42 days) after surgery, and a long-term follow-up period (up to 42 months). The last dose of xaluritamig will be administered about 14 to 28 days prior to undergoing radical prostatectomy. Primary outcomes will evaluate xaluritamig through treatment-emergent and treatment-related adverse events, and feasibility of radical prostatectomy. Secondary outcomes will assess PSA response, imaging-based response on multiparametric magnetic resonance imaging (mpMRI) prior to prostatectomy, pathologic response and the pharmacokinetics of xaluritamig. The study is open for enrollment as of October 2024. Clinical trial information:
NCT06613100
.
First-in-human phase 0 safety, imaging, pharmacokinetics, and dosimetry study of
64
Cu-PD-32766, a carbonic anhydrase IX (CAIX)-targeting peptide, in patients with clear cell renal cell carcinoma (ccRCC).
Authors: Horii Toshihiro , Yoshimoto Mitsuyoshi , Kobayashi Akinori , Kondo Chihiro , Matsubara Nobuaki , Funasaka Chikako , Nakajima Hiromichi , Kuboki Yasutoshi , Ito Kimiteru , Murakami Masato , Ito Shoko , Higuchi Tomoaki , Kanazawa Naoki , Funase Yuichi , Kano Daisuke , Inagaki Akira , Mochinaga Saeko , Inagawa Hikari , Kobayashi Tatsushi , Inaki Anri
Published: February 2025

TPS605

Background:
Carbonic Anhydrase (CA)IX is a type of carbonic anhydrase and is expected to be a useful target for detecting tumors with poor prognosis. Particularly in clear cell renal cell carcinoma, high CAIX expression has been reported in a large proportion of patients. In this study, we developed a novel radioligand agent called PD-32766 that specifically binds to CAIX and administered it to recurrent cases of clear cell renal cell carcinoma (ccRCC) patient. Safety, imaging, pharmacokinetics and dosimetry are evaluated.
Methods:
Between May 2024 and September 2024, PD-32766 labeled by positron-emitting 64Cu (64Cu-PD-32766) was intravenously administered at a dose of 148 MBq (±20%) to five patients with clear cell renal cell carcinoma who had either distant metastasis or local recurrence, and who met other eligibility criteria. PET/CT imaging was performed at 5, 60, 120, 240 minutes, 24, and 48 hours after administration, with vital signs, blood tests, and urinalysis performed as needed. The primary endpoint was the patient-level PET uptake positivity rate of target tumor regions. Secondary endpoints included the number of positive lesions, pharmacokinetics, estimated radiation dose, and the frequency and types of adverse events. This trial is registered under the jRCT trial identifier:jRCTs031240046.
Results:
64Cu-PD-32766 demonstrated good tolerability, with no serious complications observed. The average patient-level PET uptake positivity rate at 120 minutes was 75%. The average lesion-level PET positivity rate was 96.2%. Tumor uptake was highest at 60, 120 minutes post-administration. The effective dose for whole body was 0.102±0.036 mSv/MBq. The stomach and small intestine had the highest absorbed doses among all organs, with 0.712±0.287 mGy/MBq and 0.304±0.067 mGy/MBq, respectively.
Conclusions:
64Cu-PD-32766 demonstrated an excellent positivity rate in ccRCC patients with no significant adverse events and tolerated radiation dose to normal organs, proving high diagnostic capability and suggesting future therapeutic uses by labeling with therapeutic radionuclides. Clinical trial information:
jRCTs031240046
.
The CABOLD study: A real life prospective cohort evaluating the combination of cabozantinib and nivolumab among older patients with renal-cell carcinoma.
Authors: Frelaut Maxime , Naoun Natacha , Pages Arnaud , Flippot Ronan , AP Thomas Zoé , Baldini Capucine , Albiges Laurence
Published: February 2025

TPS607

Background:
In the era of combination therapy, and due to age-related physiological changes, management of older patients with Clear-cell renal cell carcinoma (ccRCC) is a challenge. The combination of cabozantinib and nivolumab is one of the recommended treatments in untreated metastatic or locally advanced ccRCC. However, data regarding the use of this treatment among 70 years old or more (70+) patients are scarce. The CABOLD study seeks to address these gaps by assessing the real-life use of this combination in older patients.
Methods:
The CABOLD study is a prospective, multicentric, single-arm cohort trial conducted across 10 centers in France. It aims to enroll 50 patients aged 70 years and above with advanced or metastatic ccRCC, who are treatment-naïve in this setting. Eligible participants must have a Performance Status (PS) of 0 to 2. Patients will receive standard-of-care treatment consisting of cabozantinib at 40 mg daily and nivolumab on a 28-day cycle (240 mg on Days 1 and 15 for the first two cycles, followed by 480 mg on Day 1 for subsequent cycles). The starting dose of cabozantinib may be reduced to 20 mg daily at the investigator’s discretion. Patients will benefit of a multi-modal follow-up including medical oncologists, geriatricians and trained nurses to monitor safety closely. Abbreviated geriatric assessment, using G-CODE, will be performed at inclusion, under treatment, and during follow-up, along with quality of life (QoL) evaluation. Optional pharmacological monitoring for cabozantinib will be conducted to assess potential associations with clinical outcomes. Patients will be followed for 12 months in the study, followed by a long-term follow-up after one year. Primary objective is to describe real-life treatment patterns of nivolumab-cabozantinib, including dose modifications and interruptions due to toxicity. Main secondary objectives include efficacy, survival, tolerance, QoL. Enrollment for the study has not yet begun at the time of submission. The CABOLD study is designed to provide insights into the real-world use of cabozantinib and nivolumab in 70+ patients with metastatic ccRCC. By incorporating geriatric assessments and pharmacological monitoring, the trial aims to improve our understanding of treatment tolerability, efficacy, and quality of life in this vulnerable population, potentially guiding tailored therapeutic strategies for older adults with RCC.