tbuckley/cabot-search huggingface dataset:
T suppression and recovery with AAP after early discontinuation of LHRH-A in high-risk localized (HRL), lymph node-positive (N+), or oligometastatic (OM) prostate cancer (PC).
Authors: Autumn Gagnon, Caiwei Zhong, Wanling Xie, Lynne Morlock, Dory Freeman, Rachel Trowbridge, Kerry L. Kilbridge, Bradley Alexander McGregor, Mary-Ellen Taplin, Atish Dipankar Choudhury
Journal: Journal of Clinical Oncology (2025)

55 Background: Intensified androgen deprivation therapy (iADT) with the addition of abiraterone acetate + prednisone (AAP) to a luteinizing hormone releasing hormone agonist or antagonist (LHRH-A) is commonly used in conjunction with radiation therapy for HRL, N+ or OM hormone-sensitive PC. However, prolonged LHRH-A has been associated with delayed or incomplete testosterone (T) recovery after discontinuation (dc). As AAP monotherapy leads to castrate T, we investigated T kinetics with early discontinuation of LHRH-A when given in combination with AAP. Methods: The Dana-Farber/Harvard Cancer Center (DF/HCC) Oncology Data Retrieval System (OncDRS) was queried to identify patients (pts) planned to receive 18-24 mo of AAP for HRL, N+ or OM PC. Pts who previously received AAP for &gt; 12 mo, with baseline T &lt;150 ng/dl, received AAP for castration-resistant PC, received AAP &gt;30 mo, or LHRH-A dc &gt; 3 mo after AAP were excluded. T values at AAP end of treatment (EOT) and at each clinical follow up visit were tabulated to assess time to T recovery (TTR) to ≥150 ng/dl in pts with LHRH-A dc ≤3 mo, 3-12 mo and ≥12 mo prior to AAP EOT. Gray’s competing risk regression model was applied to assess the relationship between TTR and time between LHRH-A dc and AAP EOT. Results: The OncDRS query returned 350 pts, 105 meeting eligibility criteria with available T follow up after AAP EOT. 99 of 105 pts had available T at EOT, 99/99 (100%) with T &lt; 20 ng/dl across the three groups. TTR was statistically significantly shorter for pts with LHRH-A dc ≥12 months prior to AAP EOT (median 3.2 mo [95% CI 1.8, 4.1]) compared to ≤3 mo prior to LHRH-A dc (median 20.0 mo [9.0, 27.6]) with all T recovery events within 6 months of EOT in the former group (Table). Conclusions: In this real-world cohort, early discontinuation of LHRH-A when given in combination with AAP led to ongoing T suppression while on AAP and shorter TTR after AAP EOT. This strategy warrants consideration when iADT is indicated but the patient seeks rapid and reliable T recovery after completion of treatment for the actual duration of T suppression desired. DF/HCC protocol # 23-322. TTR outcome summary. Timing of discontinuation of LHRH-A ≥ 12 months (N=13) 3 – 12 months (N=36) ≤ 3 months (N=56) No. T recovery events 10 26 26 No. competing events* 0 1 6 6-month cumulative TTR rate (95% CI) 82% (38%, 96%) 39% (23%, 55%) 15% (6.8%, 26%) 12-month cumulative TTR rate (95% CI) 82% (38%, 96%) 64% (46%, 78%) 39% (25%, 52%) Median (95%), month 3.2 (1.8, 4.1) 7.5 (3.7, 15.5) 20.0 (9.0, 27.6) Hazard ratio (95% CI) ref 0.40 (0.16, 1.02) 0.20 (0.08, 0.49) p-value ref 0.06 0.01 *New treatment without T recovery.
Dose finding study of CBM588 in combination with nivolumab and ipilimumab in patients with metastatic renal cell carcinoma: A phase I study.
Authors: Ruchi Agarwal, Hedyeh Ebrahimi, Zeynep Busra Zengin, Regina Barragán Carrillo, Nazli Dizman, Miguel Zugman, Salvador Jaime-Casas, Luis A Meza, Xiaochen Li, Joann Hsu, Daniela V. Castro, Benjamin Mercier, Peter P. Lee, Motomichi Takahashi, Abhishek Tripathi, Tanya B. Dorff, Gregory Caporaso, Keehoon Lee, Sumanta Kumar Pal, Alex Chehrazi-Raffle
Journal: Journal of Clinical Oncology (2025)

TPS611 Background: The combination of nivolumab and ipilimumab is currently one of the standard-of-care treatments for patients with metastatic renal cell carcinoma (mRCC). However, in the vast majority of patients, disease progression eventually occurs. Thus, novel methods to increase the efficacy of nivolumab/ipilimumab are being explored. Recent evidence suggests that the gut microbiome can remarkably influence the efficacy of immune checkpoint inhibitors (ICI) in patients with mRCC, particularly through the modulation of microbial diversity and the presence of key bacterial species (Routy et al . Science 2018; Salgia et al . Eur Urol 2020). The current study explores the use of CBM588, Clostridium butyricum MIYARI588, which has demonstrated the potential to enhance clinical outcomes when combined with ICI therapy (Dizman et al . Nature Medicine 2022; Ebrahimi et al . Nature Medicine 2024). This ongoing phase I study aims to determine the maximum tolerated dose (MTD) of CBM588 in combination with nivolumab/ipilimumab in previously untreated mRCC patients, and to evaluate the biological effects of CBM588. Methods: This investigator-initiated, phase I, open-label, single-arm, dose-escalation study is being conducted in patients with untreated, histologically confirmed mRCC. Eligible patients must be ≥18 years old, have an ECOG performance status ≤2, and be diagnosed with clear cell and/or sarcomatoid histology. The study is open to all IMDC risk groups. Patients must have measurable disease by RECIST 1.1 and no prior systemic therapy for metastatic disease. The study follows a 3+3 dose-escalation design with three planned dose levels for CBM588 (4 × 10 8 CFU, 1.2 × 10 9 CFU, and 4 × 10 9 CFU), administered twice daily orally. Nivolumab (3 mg/kg every 3 weeks for four cycles, followed by 480 mg every 4 weeks) and ipilimumab (1 mg/kg every 3 weeks for four cycles) are administered intravenously. The primary objective is to assess the safety and tolerability with escalating doses of CBM588 in combination with nivolumab and ipilimumab. Secondary objectives include evaluating changes in the gut microbiome, modulation of immune pathways, alterations to the systemic metabolome, and clinical outcomes such as overall response rate (ORR) and progression-free survival (PFS). Responses are assessed by CT every 12 weeks. Dose level one has been completed without dose-limiting toxicities. Enrollment at dose level two began in October 2024. Clinical trial information: NCT06399419 .
Updated results of the Tide-A study evaluating avelumab (Ave) plus intermittent axitinib (Axi) in previously untreated patients with metastatic renal cell carcinoma (mRCC).
Authors: Daniela Arduini, Chiara Ciccarese, Alessandro Acunzo, Matteo Perrino, Marco Maruzzo, Elena Verzoni, Caterina Accettura, Lucia Bonomi, Consuelo Buttigliero, Malvina Cremante, Stefania Pipitone, Mario Scartozzi, Cristina Masini, Veronica Mollica, Francesca Primi, Alessandro Strusi, Sebastiano Buti, Paolo Andrea Zucali, Emanuela Fantinel, Roberto Iacovelli
Journal: Journal of Clinical Oncology (2025)

551 Background: Combinations of therapies with VEGFR-TKI (TKI) and anti-PD1/PDL1 immunotherapy (IO) are considered the standard of care for first line treatment of patients (pts) with mRCC. The Tide-A trial previously reported the feasibility of TKI interruption and immunotherapy maintenance in pts achieving tumor response after TKI+IO combination, achieving its primary endpoint. Here we reported the updated results with a longer follow-up. Methods: Pts with surgery for primary tumor, without symptomatic/bulky disease or liver mets, were treated with Ave 800 mg flat dose IV Q2W + Axi 5 mg PO BID for 36 weeks (W). At W36, pts who achieved partial response (PR) interrupted Axi and continued Ave until progression of disease (PD) or unacceptable toxicity. In case of PD while on Ave, Axi was restarted and interrupted again in case of new PR. Pts without PR at W36 continue the combo until PD. Here we reported the updated results for mPFS and mOS in the overall population and in those pts who interrupted Axi. The outcome after Axi reintroduction was also described. Results: 75 pts were evaluated in the efficacy analysis (40% favorable risk, 60% intermediate/poor risk). At the cutoff data Apr 2024, after a median follow up of 31.7 mos, the mPFS was 27.9 mos (95%CI, 23.0 - 32.8) while the mOS was not reached and the 24-mos OS rate was 85%. The median duration of 1 st avelumab maintenance was 16 weeks. Among the 29 pts who interrupted Axi at W36, the mPFS and the mOS were not reached; while the 24-mos PFS and OS rates were 68% and 82%, respectively. After Axi interruption 5 pts were ongoing with avelumab without evidence of PD; 1 discontinued Ave for toxicity after 35.8 mos of maintenance; 2 patients continue Ave alone despite the evidence of PD;21 restarted Axi. Among these 21 pts, after the restart of axitinib, the ORR was 50% (10 pts PR; 8 pts SD; 2 pts PD; 1 pt NA), and the mPFS was 17.2 mos (95%CI, 11.9 – 22.5). Conclusions: Updated results of the TIDE-A study confirmed the feasibility of TKI interruption and IO maintenance in selected mRCC pts after initial response to first line combination of Ave plus Axi. The progression during maintenance with IO alone did not affect the response to the subsequent TKI reintroduction. This strategy warrants further investigation in a randomized trial. Clinical trial information: NCT04698213 .
Prevalence of germline variants of uncertain significance in DNA repair genes and their potential impact on prostate cancer outcomes following radical prostatectomy.
Authors: Giuseppe Chiarelli, Vittorio Fasulo, NicolòMaria Buffi, Giuseppe Garofano, Alessio Finocchiaro, Marco Paciotti, Pier Paolo Avolio, Miriam Cieri, Giulia Soldà, Piergiuseppe Colombo, Alberto Saita, Rodolfo Hurle, Federica Maura, Pietro Cavalli, Rosanna Asselta, Paolo Casale, Giovanni Lughezzani, Massimo Lazzeri
Journal: Journal of Clinical Oncology (2025)

421 Background: Pathogenic variants (PVs) in DNA repair genes (DRG) are linked to a higher risk of aggressive prostate cancer (PCa). Understanding and managing variants of uncertain significance (VUS), however, remains a challenge. This study investigates the prevalence of germline VUS in PCa patients and their potential link to prognosis following robot-assisted radical prostatectomy (RARP), aiming to enhance clinical management and risk stratification. Methods: This is part of an ongoing PCa screening project in the Italian population aimed at identifying men with a genetic predisposition (AIRC - Fondazione AIRC per la Ricerca sul Cancro, IG 2020 ID 25027). Germline DRG variants were identified in men with high-risk PCa or those aged &lt;50 scheduled for RARP. After informed consent, blood samples were collected, and data on age, stage, PSA, ISUP grade, and family history were recorded. Genetic analysis used a multigene panel, classifying VUS and PVs per ACMG/AMP and IARC guidelines. Primary outcome: VUS prevalence; secondary: correlations between VUS and pathological status, biochemical recurrence (BCR), and need for adjuvant therapy. Results: A total of 138 men who underwent RARP were enrolled. The median age was 64 years (IQR 57–68). ISUP grade was 1–2 in 54.0% of patients and 3–5 in 46.0%. Family history of PCa was present in 55%. Median PSA was 7.5 ng/mL (IQR 3.3–9.4). DRG variants were identified in 41 men (29.7%), of whom 34 (82.9%) had VUS and 7 (17.1%) had PVs (3 BRCA2, 1 BRCA1, 2 PALB2, 1 CHEK2). VUS carriers were younger at diagnosis (median 62 vs. 64 years). 25.8% of VUS carriers were node-positive, compared to 13.5% of those with negative DRG (p &gt; 0.05). BCR occurred in 24% of VUS patients vs. 18% of those without DRG variants at nearly 2.5 years of follow-up, but this difference was not statistically significant. No significant differences in ISUP grade or positive margin rates were observed. Conclusions: VUS germline mutations are common in PCa patients undergoing RARP. These mutations appear associated with worse outcomes. Study limitations include a single-center cohort, small sample size, and a predominantly European ancestry population.
Evaluating the efficacy and safety of pelvic lymph node dissection in high-risk prostate cancer patients undergoing radical prostatectomy: A systematic review and meta-analysis.
Authors: Qihao Wang, Jianjun Ye, Lei Zheng, Kai Chen, Qiang Wei, Yige Bao
Journal: Journal of Clinical Oncology (2025)

390 Background: Pelvic lymph node dissection (PLND) is currently considered the gold standard for lymph node staging in prostate cancer patients. However, there is a paucity high-quality evidence demonstrating an oncological prognostic benefit of PLND in high-risk prostate cancer (PCa) populations, as defined by D'Amico risk classification. Methods: We conducted a comprehensive systematic literature review utilizing MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL) and EMBASE databases. The search encompassed studies up to June 2024, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We identified original articles published in journals that reported survival analyses using Cox regression analysis and differences in hazard ratios (HRs) for the biochemical recurrence (BCR)-free survival (BRFS) (primary outcome) and metastasis-free survival (MFS), overall survival (OS) or cancer specific survival (CSS) (secondary outcomes). A meta-analysis of the effect of PLND on primary and secondary endpoints was performed using a random effects model. Results: Our analysis included seven studies, comprising one prospective and the rest retrospective. Pooled outcome data showed that PLND after radical prostatectomy did not independently predict BRFS (HR: 1.22; 95%CI: 0.99-1.50; p=0.006), MFS (HR: 1.21; 95%CI: 0.86-1.70; p=0.27), OS (HR: 0.91; 95%CI: 0.74-1.12; p=0.37), or CSS(HR: 1.02; 95%CI: 0.74-1.42; p=0.89) in high-risk prostate cancer patients. Heterogeneity was low to moderate. Conclusions: The available pooled analyses suggest that the therapeutic value of PLND is unclear. The high-risk PCa population should be carefully selected for lymph node dissection.
Characterization of genitourinary drug approvals by the FDA, 2020-2024.
Authors: David Joseph Benjamin, Arash Rezazadeh
Journal: Journal of Clinical Oncology (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
A phase 2 trial of neoadjuvant futibatinib plus durvalumab for cisplatin-ineligible patients with <i>FGFR</i> overexpressing muscle-invasive bladder cancer.
Authors: Yuanquan Yang, Rohit K. Jain, Shilpa Gupta, Irene Tsung, Dharmesh Gopalakrishnan, Jinesh S. Gheeya, Lai Wei, Swati Satturwar, Anil Parwani, Katharine A. Collier, Kamal S. Pohar, Debasish Sundi, Cheryl T. Lee, Zihai Li, Sameek Roychowdhury, Amir Mortazavi
Journal: Journal of Clinical Oncology (2025)

TPS899 Background: There is an unmet need to develop neoadjuvant therapies for cisplatin-ineligible patients (pts) with muscle-invasive bladder cancer (MIBC). Neoadjuvant immune checkpoint inhibition (ICI) has shown promising early results in this population; however, &gt; 2/3 pts did not achieve pathological complete response (pCR), a surrogate endpoint for improved survival. Fibroblast growth factor receptor inhibitor (FGFRi) may induce synergy with ICI through modulation of the tumor immune microenvironment. FGFR mRNA overexpression by RNA in situ hybridization (ISH) is an emerging biomarker that may predict responses to an FGFRi ± ICI. Futibatinib (FUTI) is an irreversible pan-FGFRi, and durvalumab (DURV) is an anti-PD-L1 antibody. Methods: This is a phase 2, single arm, multicenter study to evaluate the efficacy and safety of neoadjuvant FUTI + DURV before cystectomy. Pts with stage cT2 to cT4aN0M0, urothelial carcinoma predominant histology, cisplatin-ineligible by Galsky criteria, and FGFR1-3 mRNA expression ≥3+ by RNAscope ISH assay are eligible. Twenty-four pts will be treated with FUTI 20 mg PO daily and DURV 1500 mg IV on day 1 of every 28-day cycle for 3 cycles. The primary outcome is pCR (defined as ypT0N0). We hypothesize that FUTI + DURV will improve the pCR rate from 21% to 41%. This trial has 80% power to detect the alternative hypothesis while maintaining a one-sided α = 0.1. The study will begin with a safety lead-in period, during which 6 pts will be enrolled for dose-limiting toxicity (DLT) evaluations. After confirming safety (≤ 2 DLTs), another 18 pts will be enrolled. The study will be monitored for futility using a Bayesian Optimal Phase II design, including 2 interim analyses (12 and 18 pts). If there are ≥ 3 pCRs among the first 12 pts, we will continue enrollment. If there are ≥ 5 pCRs among the first 18 pts, the study will continue. When 24 evaluable pts are enrolled, we will reject the null hypothesis and conclude that the treatment is acceptable if there are ≥ 8 pCRs. The secondary endpoints include safety, pathologic downstaging rate, progression-free survival, and overall survival. Correlative studies will explore immune and molecular predictors of response and resistance in the tumor, blood, and urine. Clinical trial information: NCT06263153 .
Genome-scale metabolic reconstruction of urinary microbiome: Pathway for personalized medicine.
Authors: Betty Wang, Devika Nandwana, Mohit Sindhani, Christopher Weight, Nima Almassi, Vignesh Packiam, Alexander Kutikov, Daniel M. Geynisman, Pooja Ghatalia, Philip Abbosh, Laura Bukavina
Journal: Journal of Clinical Oncology (2025)

822 Background: The human microbiome significantly influences the efficacy and safety of various medications. To integrate microbial metabolism into precision medicine, it is crucial to develop strain- and molecule-specific computational models that can predict a patient's microbiome's ability to metabolize chemotherapy drugs. This study evaluates the potential of urine, pellet, and supernatant samples to identify microbial profiles and metabolizing genes in patients with bladder cancer. Methods: Catheterized urine, pellet, and supernatant samples from six patients (5 males and 1 female) with bladder cancer were analyzed to identify microbial species and strains, assess drug gene abundance, and predict drug metabolism. Whole-genome sequencing (WGS) was performed, and gene annotation was conducted using the PubSEED platform. Biosynthetic pathways were identified following the KEGG PATHWAY resource, and AGORA2 reconstruction was used for final metabolic reactions. Results: WGS revealed a diverse microbial community, with 1,024 species unique to urine, 386 unique to pellet, and 1,861 species common to both. The most prevalent species, Enterococcus faecalis and Staphylococcus epidermidis, accounted for over 60% of the microbial population in both urine and pellet samples. A detailed comparison of OTU abundance between paired urine and pellet samples showed significant variations in microbial composition, yet a strong correlation between the two sample types. The net metabolizing capacity of 13 chemotherapy-drug metabolites was assessed among the six patients. Mean flux calculations indicated highly variable metabolism of gemcitabine (median 773.57, IQR 380-1056), SN38 (irinotecan) (median 770.24, IQR 10.1-2234.5), and bile salt hydrolase (median 130.80, IQR 9.8-318.2). These findings highlight the microbiome's extensive role in influencing chemotherapy drug pharmacokinetics. Conclusions: This study demonstrates the potential of microbiome profiling in informing precision medicine, suggesting that microbiome modification could enhance chemotherapy drug pharmacokinetics and improve patient outcomes. Further research is needed to validate these findings and refine microbiome-based precision medicine in oncology.
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: Naoki Fujita, Shogo Hosogoe, Toshikazu Tanaka, Noritaka Ishii, Hiroyuki Ito, Takahiro Yoneyama, Chikara Ohyama, Shingo Hatakeyama
Journal: Journal of Clinical Oncology (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