tbuckley/cabot-search huggingface dataset:
Role of liquid biopsy in the detection of homologous recombination repair gene mutations (HRRm) in metastatic prostate cancer (mPC).
Authors: Soumaya Labidi, Parvaneh Fallah, Aida Salehi, Raghu Rajan, Mona Alameldine, Fadi Brimo, William D. Foulkes, Andreas I Papadakis, Alan Spatz, Cristiano Ferrario, Ramy Saleh, April A. N. Rose
Journal: Journal of Clinical Oncology (2025)

51 Background: The treatment landscape of mPC is rapidly evolving to include more precision therapies for patients with actionable genomic alterations. Specifically, deleterious aberrations in HRR genes (HRRm) confer sensitivity to PARP inhibitors (PARPi) which have demonstrated survival benefit in this context. Therefore, accurate identification of potentially actionable HRRm is indicated. Somatic testing for HRRm in archival tissue is inadequate due to poor DNA quality or lack of tissue availability in 30-40% of cases. We evaluated whether circulating tumor DNA (ctDNA) testing using liquid biopsies is associated with an increased rate of HRRm detection. Methods: This was a multi-institutional retrospective cohort study of mPC patients (pts) treated at the Jewish General Hospital or the McGill University Health Center, Montreal Canada, between 2021-23. Molecular data and treatment information was abstracted from chart review. Fisher’s exact test and Wilcoxon test were used to assess differences between groups. Results: We identified 282 mPC pts, mostly castration resistant (n=181, 64.2%). Median age was 67 years (43-92). Somatic and germline testing for HRRm was performed in 78.3% (n=224) and 23.4% (n=66) pts, respectively. Somatic testing was performed on tissue (n=164, 73.2%) or ctDNA from liquid biopsies (n=17, 7.5%) or both (n=43, 19.3%). Pathogenic somatic HRRm were detected in 37 pts (13.2%): BRCA2 (n=13), ATM (n=8), CHEK2 (n=4), PALB2 (n=4), CDK12 (n=4) and BRCA1 (n=2). Amongst pts with germline testing 10/66 (15.1%) had pathogenic HRRm, mostly BRCA2 (n=9) and 4/10 had detectable HRRm in tissue. The somatic HRRm detection rate was 14.6% (24/164) on tissue and 11.7% (2/17) in ctDNA, respectively. Pts who had both tissue and liquid biopsy experienced a higher detection rate (25.5%, 11/43) vs. either modality alone (P=0.064). Inconclusive results were less frequent in pts who had both liquid and tissue testing vs. tissue alone (2.3% vs 7.3%). Amongst the 10 pts who had discordant results between liquid and tissue tests, HRRm were more frequently identified in ctDNA (n=7) vs. tissue (n=3). Pts who had HRRm detected only in ctDNA, had significantly older tissue samples (median 5.1 years) compared to those who had HRRm detected only in tissue (median 0.2 years, P=0.0156). Conclusions: Our data highlight a potential role of implementing liquid biopsy to improve the detection rate of HRRm. We are currently conducting a multi-center prospective study to determine if liquid biopsy increases the rate of detection of HRRm compared to routine tissue testing, and therefore allows to identify more patients who are eligible to receive precision therapies.
Phase II study of oral APL-1202 plus tislelizumab or tislelizumab alone as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC).
Authors: Matthew D. Galsky, John P. Sfakianos, Dingwei Ye, Badrinath Konety, Dalin He, Xiaodong Song, Hailong Hu, Hanzhong Li, Gongxian Wang, Xiaoliang Yuan
Journal: Journal of Clinical Oncology (2025)

793 Background: Interim results of the randomized phase II trial of neoadjuvant tislelizumab +/- oral APL-1202 (nitroxoline) revealed promising pathological complete response (pCR) rates and met prespecified thresholds for study expansion (ASCO GU 2024). Here, we report the final primary endpoint analysis of this trial. Methods: Patients with cT2-T4aN0M0 urothelial cancer of the bladder based on local assessment, planned for radical cystectomy (RC), and ineligible for or refusing cisplatin-based chemotherapy were eligible. Patients were randomly assigned to APL-1202 plus tislelizumab (A+T) or tislelizumab (T), stratified by PD-L1 expression. Neoadjuvant tislelizumab was administered q3weeks for 3 cycles and APL1202 was administered orally tid. The primary endpoint was centrally assessed (pCR, pT0N0) rate and secondary endpoints included central pathologic response (PaR, &lt; ypT2N0) rate and safety. Results: A total of 103 patients were enrolled; 28 patients declined RC after neoadjuvant treatment (A+T=16, T=12). Consequently, 75 patients remained in the efficacy analysis set (EAS); RC was completed after A+T in 42/43 patients and after T in 31/32 patients. The pCR and PaR results in the EAS are presented in the table. On retrospective central pathology review of baseline TURBT specimens, a large subset of patients were determined to be ineligible due to &lt;cT2 disease (33/75). There was a numerically higher pCR rate in an exploratory analysis of this retrospectively defined ‘protocol eligible’ subset (A+T: 9/22, T: 4/20). Treatment related adverse events (TRAEs) occurred in 35 (59%) on the A+T arm and 19 (44%) on the T arm. TRAEs (94%) were predominantly ≤ CTCAE grade 2. Conclusions: Neoadjuvant A+T in cisplatin-ineligible patients prior to RC was safe. Evaluation of the efficacy in MIBC is complicated by the large subset of patients enrolled retrospectively determined to have &lt;cT2 disease but pCR rates were similar between groups in the EAS. A signal of higher activity of A+T may be present in PD-L1 “low” tumors supporting further exploration of the immunomodulatory effects of A+T. Evaluation of efficacy is further complicated by a large subset of patients declining RC after neoadjuvant treatment underlining the need for novel bladder-sparing approaches. Clinical trial information: NCT04813107 . pCR rate, pT0N0 PaR rate, &lt; ypT2N0 EAS (n=75) n(%) A+T (n=43) T (n=32) A+T (n=43) T (n=32) All evaluable patients 12 (33)* 7 (26)* 19 (44) 13 (41) PD-L1 h igh 5/18 (28) 4/16 (25) 7/18 (39) 8/16 (50) PD-L1 l ow 7/25 (28) 3/16 (19) 12/25 (48) 5/16 (31) *pCR rate is calculated using UMVUE method when the final sample size of Simon's two-stage is changed.
The significance of androgen receptor signaling pathway in mCRPC patients receiving olaparib monotherapy or combined treatment with abiraterone.
Authors: Bin Yang, Li Ding, Baijun Dong, Wei Chen, Hanxu Guo, Chengqi Jin, Jing Xu, Wentao Luo, Shiyu Mao, Changcheng Guo, Bo Peng, Xudong Yao
Journal: Journal of Clinical Oncology (2025)

197 Background: Our previous research confirmed that for metastatic castration-resistant prostate cancer (mCRPC) patients with DNA damage repair (DDR) deficiency who have developed resistance to prior abiraterone, the combination of olaparib and abiraterone improves survival compared to olaparib monotherapy. However, further research is needed to identify subgroups who may benefit from olaparib alone or in combination with abiraterone, and to pinpoint risk factors significantly associated with poor prognosis in these patients. This study aims to explore the value of androgen receptor (AR) variant and androgen receptor activity (AR-A) at the transcriptomic level in evaluating the prognosis of mCRPC patients treated with olaparib alone or in combination with abiraterone. Methods: This study included 142 mCRPC patients who underwent targeted next-generation sequencing. Among them, 73 patients received olaparib monotherapy, while 69 patients received combined therapy. Bulk transcriptome sequencing was performed for 62 patients. Kaplan-Meier analysis was employed to evaluate patients' progression-free survival (PFS) and overall survival (OS). The AR-A score was calculated through a weighted linear sum of nine typical AR transcriptional target genes. Results: The combination of olaparib and abiraterone significantly improved PSA response and survival (PFS and OS) compared to olaparib monotherapy. Among mCRPC patients receiving olaparib monotherapy, those without AR pathogenic variant (AR-PV) had superior PFS and OS compared to those with AR-PV (median PFS: 5 months vs 3 months; median OS: 23 months vs 17 months). At the transcriptome level, for mCRPC patients receiving combined therapy, the average AR-A group exhibited better PFS and OS compared to the lower AR-A group (median PFS: 7 months vs 3 months; median OS: 17 months vs 10 months). Conclusions: For mCRPC patients treated with olaparib monotherapy, the absence of AR-PV can obtain better survival benefits. For patients treated with combined therapy, the average AR-A indicates a better survival benefit. For mCRPC patients with AR-PV or lower AR-A score, large-scale prospective randomized controlled clinical trials are needed to further explore therapy strategies that can improve their prognosis.
Targeting TROP2 in aggressive variant and neuroendocrine prostate cancer.
Authors: Gunhild Von Amsberg, Moritz Kaune, Lina Bergmann, Tobias Busenbender, Nadja Strewinsky, Finn-Ole Paulsen, David Dum, Derya Tilki, Markus Graefen, Carsten Bokemeyer, Stefan Werner, Sergey Dyshlovoy
Journal: Journal of Clinical Oncology (2025)

171 Background: Aggressive variant prostate cancer (AVPC) including neuroendocrine prostate cancer (NEPC) is characterized by rapid, androgen-independent tumor growth. Standard therapies often show limited efficacy. Alternative treatment strategies are therefore urgently required. Here, we present preclinical and first clinical results on the potential impact of TROP2 targeting in AVPC/NEPC. Methods: TROP2 expression was assessed in AVPC/NEPC cell lines, circulating tumor cells (CTCs) and metastatic biopsies. Efficacy of the TROP2 targeted antibody drug conjugate (ADC) Sacituzumab Govitecan (SG) was evaluated in prostate cancer (PC) cell lines with high and low/- TROP2 expression. TROP2+ AVPC/NEPC patients with exhausted standard therapy options are currently undergoing treatment with SG in an individual approach. Results: TROP2 expression was detected at varying levels in PC cell lines, with increased expression in docetaxel-resistant cells. CTCs of AVPC and NEPC patients were TROP2+ in 74.0% (37/50) and 48.6% (17/35), respectively, while the vast majority of biopsies from both cohorts expressed TROP2. SG was highly effective in TROP2+ cells in vitro , regardless of their degree of resistance to standard therapies while reduced activity was seen in TROP2 low/- cells after short-term exposure. Remarkably, SG exhibited a pronounced antiproliferative effect and/or apoptosis induction in TROP2-low LNCaP and PC3 cells, when co-cultured with TROP2+ DU145-DR or PC3-DR cells, indicating a bystander effect. The antiproliferative activity of SG was attributed to an increased G2/M cell cycle arrest. Proteomic analyses suggested suppression of cell cycle related processes and proliferation as well as signaling pathways involved in neuronal dedifferentiation and cell stemness. First clinical results of heavily pretreated TROP2+ AVPC/NEPC patients (n=9) revealed partial remission (PR) or stable disease in 44% and 33% at radiological follow-up, with a disease control rate of 78% and 44% at 3 and 6 months, respectively. Of note, in a NEPC patient with sudden, rapid progression following initial PR, loss of TROP2 expression on CTCs was detected. In addition, preclinical data suggested AKT activation and upregulation of p-glycoprotein as further possible resistance mechanisms. Conclusions: TROP2-directed therapy with SG demonstrates promising preclinical and clinical activity in AVPC and NEPC. A clinical trial evaluating a TROP2-directed ADC in AVPC is in preparation.
In-field progression following radiation therapy as a prognostic biomarker for lutetium-177-PSMA-617 response in metastatic castration-resistant prostate cancer.
Authors: Jackson Neal Howell, Jacob Wilkes, Nichole M Maughan, Kathryn Morton, Eric Hu, David Michael Gill, Scott James Samuelson, Dustin Boothe
Journal: Journal of Clinical Oncology (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 &lt; 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 phase 1, first-in-human, dose escalation and expansion study to evaluate the safety and tolerability of XmAb541 (claudin-6 x CD3) T-cell engaging bispecific antibody in subjects with germ cell tumors and other advanced solid tumors.
Authors: David Levitz, Martin Gutierrez, Ira Seth Winer, Matthew Reilley, Linda R. Duska, Vivek Subbiah, Debra L. Richardson, Chet Bohac, MICHAEL CHIARELLA, Carlos Naranjo, Jitendra Kanodia, Jacky Woo, Nicole Nevadunsky
Journal: Journal of Clinical Oncology (2025)

TPS652 Background: Claudin-6 (CLDN6) is overexpressed in solid tumors including germ cell tumors (GCTs) with minimal expression in healthy tissue. This differential expression profile makes CLDN6 a suitable tumor-associated antigen for a T-cell engaging bispecific antibody (bsAb). XmAb541 is a first-in-class humanized, anti-CLDN6 x anti-CD3 bsAb that directs T-cell cytotoxicity. The XmAb 2+1 format provides avid tumor targeting and selectivity. Importantly, XmAb541 selectively binds CLDN6, with reduced binding to other claudin family proteins (e.g., CLDN9) and non-CLDN6-expressing healthy tissue [1]. This study focuses on subjects with GCT and other CLDN6+ solid tumors who have failed standard therapy and have a high unmet medical need. The primary objective of the trial is to determine an optimal and tolerated dose(s) for further evaluation. Methods: This is a first-in-human, Phase 1, open-label study to evaluate the safety and tolerability of XmAb541 in advanced solid tumors. The study will be conducted in 2 Parts. Part 1, Dose Escalation, will establish a dosing regimen inclusive of a priming dose, step-up dose(s), and the target dose. Part 2 Dose Expansion will further evaluate safety and tolerability and provide an initial evaluation of preliminary antitumor activity for the dose regimen(s) established in Part 1. XmAb541 will be administered intravenously. Key inclusion criteria are age ≥ 18 years (for subjects with GCTs, age ≥15 years). Have histological evidence of locally advanced, recurrent, or metastatic GCT, ovarian, fallopian tube, peritoneal cancer, or adenocarcinoma of the endometrium. Have documented progressive disease on standard-of-care therapies; exhausted therapies with a survival benefit, or the standard therapy has no survival benefit or proven to be ineffective, intolerable, or subject is not a candidate for such available therapy. Subjects must have an Eastern Cooperative Oncology Group performance status of 0-2 and a life expectancy ≥ 3 months with adequate liver, kidney, and bone marrow function. Key exclusion criteria include the following: known active central nervous system metastases and/or carcinomatous meningitis. Subjects with treated brain metastases may participate, provided they are radiologically stable. Ethics approval: This study was approved by WCG IRB. References: 1. Faber, M. Bispecific claudin-6 x CD3 antibodies in a 2+1 format demonstrate selectivity and activity on human ovarian cancer cells. (AACR 2021, Abstract No. 1860). Clinical trial information: NCT06276491 .
Prognostic value of preoperative fibrinogen in metastatic clear cell renal cell carcinoma patients undergoing cytoreductive nephrectomy: A propensity score-matched study.
Authors: Jianzhong Shou, Honglei Cui, Xingang Bi, Youyan Guan, Hongzhe Shi, Aiping Zhou
Journal: Journal of Clinical Oncology (2025)

563 Background: The measurement of serum fibrinogen (FIB) levels is often overlooked in metastatic clear cell renal cell carcinoma (mccRCC). This study aims to investigate the prognostic value of preoperative serum FIB levels in mccRCC patients undergoing cytoreductive nephrectomy (CN) followed by systemic therapy. Methods: This retrospective study analyzed 209 mccRCC patients who underwent CN from 2010 to 2022. The optimal cutoff value of preoperative serum FIB levels was determined via receiver operating characteristic (ROC) curve. Survival outcomes were evaluated by the Kaplan-Meier method and Cox proportional hazards models. The predictive ability was evaluated by ROC curve. Propensity Score Matching (PSM) was performed to equate demographic and clinical characteristics. Results: An optimal cutoff value of 4.39 g/L for the FIB levels was determined and patients were categorized into high and low FIB groups. With a median follow-up time of 61.1 months, patients in the low FIB group exhibited significantly higher median OS compared with the high FIB group (53.1 vs 27.9 months, p &lt; 0.001). The ROC curve demonstrated that the serum FIB predicted a 36-month overall survival with an AUC of 0.652, while the AUC for the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk category was 0.558. After PSM matching, high FIB levels remained significantly associated with poorer OS (24.0 vs 50.2 months; p = 0.019). Conclusions: Serum FIB level is a significant prognostic factor for mccRCC patients undergoing CN followed by systemic therapy. This finding underscores the potential of FIB as a biomarker that could be integrated into the prognostic model for preoperative risk stratification and management strategies.
Timely next-generation sequencing testing in patients with metastatic prostate cancer: A comparative analysis between Medicare Advantage and traditional Medicare.
Authors: Jonathan Wenbin Ji, Baqir Jafry, Chuan Angel Lu, Raj Bhanvadia, Qian Qin, Joseph Vento, Kevin Dale Courtney, Jue Wang, Waddah Arafat, Daniel X. Yang, Suzanne Cole, Tian Zhang, Changchuan Jiang
Journal: Journal of Clinical Oncology (2025)

320 Background: Next-Generation Sequencing (NGS) testing has become a cornerstone of personalized medicine in cancer care. With Medicare Advantage (MA) now covering nearly half of all beneficiaries, understanding differences in access to timely NGS testing between MA and Traditional Medicare (TM) is crucial, particularly given MA’s potential restrictions. This study aims to evaluate the effectiveness of MA plans on timely NGS testing in patients with metastatic prostate cancer (mPCa). Methods: This retrospective cohort study was based on the Flatiron Health deidentified Database, comprising electronic health record-derived data from ~280 cancer practices across the US. Our study included patients aged 65 or older, diagnosed with mPCa since 2018, and exclusively enrolled in TM or MA, either before or within 90 days following mPCa diagnosis. We compared the rates between TM and MA, using three timeframes—45-, 90-, and 180-days post-mPCa diagnosis. NGS testing was defined as any tissue or liquid genomic testing resulted within the time frame of interest. Multivariate logistic regression with inverse probability of treatment weighting was used, adjusting for demographics, year of mPCa diagnosis, practice setting, and baseline ECOG score. Results: Among the 1,582 MA patients (mean age: 75.9 ± 5.8) and 2,749 TM patients (mean age: 75.4 ± 5.8), significant proportions were from community practice (MA: 78%, TM: 80%) and were characterized by being White (MA: 59%, TM: 65%), aged 75 to 85 (MA: 54%, TM: 57%), having higher socioeconomic status (SES 4 or 5: MA: 40.3%, TM: 47.5%), presenting with de-novo mPCa (MA: 53%, TM: 54%), and having better baseline functional performance (ECOG 0 or 1: MA: 70%, TM: 69%). Since 2018, 8.8%, 14.5%, 18.8% of MA patients and 10%, 14.6%, 17.6% of TM patients received NGS testing at 45, 90 and 180 days, respectively. Notably, 63.4% and 60.8% of MA and TM patients, respectively, did not have any NGS testing. After adjusting for covariation, MA was associated with a 26.2% (OR=0.74, 95%CI 0.59-0.92), 16% (OR=0.84, 95%CI 0.7-1.01), 7.8% (OR=0.92, 95%CI 0.78-1.09) lower chance to receive timely NGS testing at 45 days, 90 days and 180 days, respectively. Conclusions: Patients with mPCa enrolled in MA are less likely to receive timely NGS testing compared to TM. The high rate of delayed or no testing underscores disparities in access, especially among MA patients. Policymakers should streamline approvals to ensure timely, high-quality care for all Medicare beneficiaries.