tbuckley/cabot-search huggingface dataset:
Peri-operative treatment patterns in real-world muscle-invasive bladder cancer patients undergoing radical cystectomy in the era of adjuvant immunotherapy.
Authors: Patrick Squires, Ke Meng, Xiaohan Hu, Vladimir Turzhitsky, Yu-Han Kao, Zara Wermers, Jennifer Stuart, Chethan Ramamurthy, Connor Sweetnam, Haojie Li, Ronac Mamtani
Journal: Journal of Clinical Oncology (2025)

704 Background: Muscle-invasive bladder cancer (MIBC) has traditionally been managed with radical cystectomy (RC) and pelvic lymph node dissection combined with neoadjuvant (NAD) and/or adjuvant (AD) chemotherapy in eligible patients. In late 2021, adjuvant nivolumab, was approved in the US among patients with certain high-risk of recurrence (HRR) features. Contemporary peri-operative treatment utilization patterns in MIBC patients post-RC is lacking. This study aimed to characterize demographics, clinical features, treatment patterns, and surgical outcomes, in a contemporary cohort of MIBC patients undergoing RC in the post-immunotherapy era. Methods: The US Syapse Learning Health Network Enriched Bladder Cancer Cohort, comprised of patients from community-based practices with cancer registry data supplemented and validated by chart review, was used to identify adults with clinically diagnosed MIBC (T2-T4aN0M0, T1-T4aN1M0) undergoing RC from February 19, 2021 (6-months prior to nivolumab approval) to December 31, 2023, with a minimum 6-month follow-up post-RC (except in cases of patient death). Patients with history of other primary cancer, non-bladder systemic antineoplastic therapies, prior partial cystectomy, NAD radiation, or clinical trial participation were excluded. Real-world HRR following resection was defined using a combination of NAD agent receipt and pathological staging (PS) from RC: received NAD cisplatin-based therapy and pT2-T4a or pN+; or, if patient did not receive NAD cisplatin-based therapy, pT3-4a or pN+. Pathological complete response (pCR) was defined as pT0N0. Results: Of 138 eligible patients, mean age was 66 years, and the majority were male (82%), white (83%), current/former smokers (68%), presented as de novo MIBC (97%), and had urothelial histology (91%). Overall, 49% (67/138) of patients received RC without NAD or AD treatment. Around 46% (64/138) received NAD chemotherapy; of these, one-third achieved pCR (20/61 NAD chemotherapy-treated patients with complete PS data post-RC). The most prevalent NAD regimens were cisplatin + gemcitabine (58%; 37/64) and methotrexate + vinblastine + doxorubicin + cisplatin (30%; 19/64). Only 14% (20/138) of all patients received AD treatment, with 10% (14/138) receiving AD nivolumab. Half of patients had HRR following resection (63/125 patients with complete PS data post-RC). Among the HRR subgroup, 22% (14/63) received AD treatment, with 19% (12/63) receiving nivolumab. Conclusions: In this contemporary cohort of MIBC patients undergoing RC, nearly half received NAD treatment (mainly gemcitabine and cisplatin) while there was limited use of AD treatment. Since FDA approval, AD nivolumab use was 10% among all RC-treated MIBC patients and less than a fifth among HRR patients (nivolumab eligible).
PSA response to Lu177-PSMA-617 in patients experiencing xerostomia and ocular dryness in metastatic castration resistant prostate cancer.
Authors: Rebecca Hassoun, Mark Tann, Justin Sims, Ashleigh Auxier, Sandra K. Althouse, Tareq Salous, Jennifer King, Nabil Adra
Journal: Journal of Clinical Oncology (2025)

127 Background: Lu177-PSMA-617 (PSMA Lu177) therapy can cause dry mouth and/or eyes, as prostate specific membrane antigen (PSMA) is expressed in salivary and lacrimal glands. We evaluate the PSA response in pts with metastatic castration resistant prostate cancer (mCRPC) receiving PSMA-Lu177 who experienced dry mouth/eyes. Methods: The Indiana University Prostate Cancer database was queried for pts with mCRPC who were treated with PSMA Lu177. Adverse Events were documented throughout the course of treatment. PSA30 and PSA50 response were analyzed among subgroups of patients who had presence/absence of xerostomia and ocular dryness. Comparisons between the groups were based on the Chi Square test, or Fisher’s Exact test, if more appropriate. Results: 144 pts with mCRPC were treated with PSMA Lu177 between November 2022 and October 2024. Included pts received at least 2 doses. Median age was 74 (53, 91). 126 pts had metastatic disease in bone, 80 in pelvic lymph nodes, 27 lungs, 20 liver, and 5 brain. 58 pts had 1 prior ARPI, 86 pts had ≥2 prior ARPI. 28 pts had no prior taxane regimen, 116 had at least 1 prior taxane. 23 pts had prior PARP inhibitor. Median follow-up from start of PSMA Lu177 was 9.77 months (1.38-26.9). 62 (43.1%) pts experienced dry mouth, 15 (10.4%) experienced dry eyes, and 13 (9%) experienced both. 92 (63.9%) pts achieved PSA30 response, and 81 (56.3%) achieved PSA 50 response. Conclusions: Patients with mCRPC treated with PSMA Lu177 who reported dry mouth were more likely to experience PSA responses. Number and % of Pts Achieving PSA30 and PSA50 Response Characteristic (N) PSA30 response, N (%) PSA30 p-value PSA50 response, N (%) PSA50 p-value Dry mouth Present (N=62) Absent (N=82) 49 (79%)43 (52.4%) 0.0010 41 (66.1%)40 (48.8%) 0.0377 Dry eyes Present (N=15) Absent (N=129) 11 (73.3%)81 (62.8%) 0.4211 8 (53.3%)73 (56.6%) 0.8099 Dry eyes and/or dry mouth Present (N=64) Absent (N=80) 51 (79.7%)41 (51.3%) 0.0004 43 (67.2%)38 (47.5%) 0.0180
Additivity and the efficacy of immune checkpoint blockade-based combination regimens in urothelial cancer.
Authors: Noah Schlachter, Eric James Miller, Jonathan Forrest Anker, Matthew D. Galsky, Adam C Palmer
Journal: Journal of Clinical Oncology (2025)

779 Background: Immune checkpoint blockade (ICB)-based combination regimens have transformed the treatment landscape of advanced solid tumors including urothelial cancer. Understanding whether such combinations are synergistic, additive, or less than additive is crucial for (a) refining combination therapy in urothelial cancer, (b) dissecting the role of concurrent versus sequential treatment, and (c) identifying which cytotoxic agents combine most favorably with ICB. Here we analyzed phase III trials in advanced urothelial cancer to determine if the efficacy of combination therapies were predictable by additivity or exhibited non-additive effects. Methods: We analyzed progression-free survival (PFS) from phase III trials of ICB-containing regimens for advanced urothelial cancer (Table). PFS distributions of constituent drugs were used to calculate the predicted PFS of combination therapy under the null hypothesis of additive PFS times (Hwangbo et al, Nature Cancer, 2023). For KEYNOTE-361 and IMvigor130, which allowed investigator’s choice of cisplatin or carboplatin, separate predictions were made for cisplatin- and carboplatin-treated cohorts. The Cox Proportional Hazards model tested whether observed PFS significantly differed from additivity. Results: PFS of combination therapies in EV-302, CheckMate901, and DANUBE were statistically indistinguishable from additivity (Table). Trials using choice of cisplatin or carboplatin (KEYNOTE-361, IMvigor130) showed that ICB with cisplatin produced additive PFS, but ICB with carboplatin was significantly antagonistic (inferior to additive PFS; P = 0.00004). Conclusions: Recently approved regimens enfortumab vedotin + pembrolizumab, and nivolumab + gemcitabine-cisplatin, were as effective as predicted by additivity, demonstrating that combining individually effective agents without synergy can make effective regimens. In advanced urothelial cancer, PD-1 or PD-L1 inhibitors are antagonistic with carboplatin, but confer additive PFS benefits with cisplatin. Modeling the PFS of combination regimens from single agent data could have predicted the success of most contemporary phase III trials in advanced urothelial cancer. Trial Combination Predicted HR for PFS (95% CI) Observed HR for PFS (95% CI) P value EV-302 Enfortumab vedotin + Pembrolizumab 0.49 (0.44 - 0.55) 0.45 (0.38 - 0.54) 0.93 CheckMate901 Nivolumab + Gemcitabine-Cisplatin 0.69 (0.60 - 0.79) 0.72 (0.59 - 0.88) 0.78 DANUBE Durvalumab + Tremelimumab 0.87 (0.78 - 0.98) 0.88 (0.75 - 1.03) 0.92 KEYNOTE-361 Pembrolizumab + Chemotherapy 0.67 (0.59 - 0.77) 0.78 (0.65 - 0.93) 0.02 IMvigor130 Atezolizumab + Chemotherapy 0.61 (0.55 - 0.68) 0.82 (0.70 - 0.96) 0.0006 Pooled ICB + Gemcitabine-Cisplatin 0.65 (0.56 - 0.74) 0.71 (0.58 - 0.86) 0.78 Pooled ICB + Gemcitabine-Carboplatin 0.63 (0.57 - 0.70) 0.84 (0.73 - 0.97) 0.00004
Intravesical gemcitabine and docetaxel combined with intravenous tislelizumab as a durable strategy for high-risk non–muscle-invasive bladder cancer.
Authors: Xiaobao Chen, Jiang Wei, Ruoyun Xie, Huaiying Zheng
Journal: Journal of Clinical Oncology (2025)

703 Background: For decades, intravesical Bacillus Calmette-Guérin (BCG) has been the standard treatment for high-risk non-muscle-invasive bladder cancer (HR NMIBC). However, its poor tolerability and limited availability underscore the urgent need for more effective therapies. Intravesical sequential gemcitabine and docetaxel (GemDoce) has demonstrated efficacy in HR NMIBC, and immune checkpoint inhibitors (ICIs) have shown effectiveness as second-line therapy for patients with BCG-unresponsive NMIBC. Nevertheless, the combination of immunotherapy with intravesical GemDoce has not yet been reported. Methods: We retrospectively analyzed HR NMIBC patients, who received intravesical GemDoce combined with intravenous tislelizumab at Fujian Medical University Union Hospital from February 2023 to August 2024. Induction GemDoce was administered weekly for 6 weeks, then monthly maintenance. Tislelizumab started during the second GemDoce treatment and continued every 4 weeks. Inclusion required at least 6 weekly GemDoce after complete transurethral resection of bladder tumor (TURBT). Data including patient clinicopathologic features, treatment history, adverse events (AEs), and oncologic outcomes were retrospectively reviewed and analyzed. Results: 30 patients included in study, with a median number of 16 (range:6-22) GemDoce treatments and 12 (range:2-18) tislelizumab cycles. Median age was 70 (range:49-80) years. All patients had papillary disease with or without CIS, including 11 (36.7%) with HGTa and 19 (63.3%) with HGT1. CIS with HGTa was present in 2 (6.7%) patients. 5 (16.7%) patients were BCG-naïve HR NMIBC, while 25 (83.3%) patients were recurrent HR NMIBC. Most patients were male (90%, 27/30), and 56.7% (17/30) had a smoking history. Treatment was well tolerated with no discontinuations or dose reductions. In total, 12 (40%) patients reported AEs following treatment, all of which were grade 1-2. Median follow-up of 11.5 (range:2-18) months, no patients had recurrence, underwent RC, or died. Conclusions: These results suggest that intravesical GemDoce with intravenous tislelizumab is an effective and tolerable treatment option for patients with HR NMIBC. Further prospective study is warranted.
OMAHA-003: A phase 3 study of CYP11A1 inhibitor opevesostat versus next-generation hormonal agent (NHA) switch in metastatic castration-resistant prostate cancer (mCRPC) after NHA and taxane-based chemotherapy.
Authors: Evan Y. Yu, Yue Song, Chris Garratt, Christian Heinrich Poehlein, Charles Schloss, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2025)

TPS286 Background: The androgen receptor (AR) plays a pivotal role in prostate cancer pathogenesis, even after progression on androgen-directed therapies (ADT). In patients with mCRPC, activation of AR ligand binding domain (AR-LBD) somatic point mutations is a common mechanism of resistance to ADTs. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), which catalyzes the first and rate-limiting step of steroid biosynthesis. By inhibiting CYP11A1, opevesostat suppresses the production of all steroid hormones and their precursors that may promiscuously activate the AR signaling pathway. Opevesostat showed antitumor activity in patients with heavily pretreated mCRPC, and in those with AR-LBD mutations, in the phase 1/2 CYPIDES trial (Fizazi et al. NEJM Evid. 2024). The randomized, open-label, phase 3 OMAHA-003 study (NCT06136624) is evaluating the efficacy and safety of opevesostat versus NHA switch in patients with mCRPC who received NHA and taxane-based chemotherapy. Methods: Eligible patients havemCRPC (unselected for AR-LBD mutations) that progressed on ADT ≤6 months of screening and during/after treatment with 1 NHA or 1-2 taxane-based chemotherapies. Approximately 1200 patients (300 with, 900 without AR-LBD mutations) will be randomly assigned 1:1 to opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg QD) or enzalutamide 160 mg PO QD (if prior abiraterone) or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide). Primary endpoints are radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR) and overall survival in patients with AR-LBD mutation-positive and -negative disease, separately. Secondary endpoints include time to initiation of first subsequent anticancer therapy or death; objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR; and safety. Enrollment is ongoing. Clinical trial information: NCT06136624 .
Cabozantinib as subsequent therapy to an immune checkpoint-based therapy in renal cell carcinoma, phase 2 interventional study (AT ASIA, KCSG GU21-02).
Authors: Jae Lyun Lee, Sang Joon Shin, Inkeun Park, Woo Kyun Bae, Shinkyo Yoon, In-Ho Kim, Hong Jae Chon, Byoung Young Shim, Jin Young Kim, Jung Hoon Kim, Joo-Hwan Park, Il Hwan Kim, Miso Kim, Kwonoh Park, Hyo Jin Lee
Journal: Journal of Clinical Oncology (2025)

547 Background: Immune checkpoint inhibitors (ICIs) have significantly advanced the treatment of advanced renal cell carcinoma (aRCC). However, many patients develop disease progression, underscoring the need for effective second-line therapies. The optimal sequencing after ICI-based treatment remains under investigation. This phase II study evaluates the efficacy and safety of cabozantinib in patients with aRCC who progressed on first-line ICI combination therapies. Methods: This multicenter, prospective, phase II trial enrolled patients with advanced RCC who had progressed after receiving either nivolumab plus ipilimumab (Cohort 1) or a PD-1/PD-L1 inhibitor in combination with a VEGFR-TKI (e.g., pembrolizumab plus axitinib or pembrolizumab plus lenvatinib; Cohort 2). Non-clear cell histology was allowed in Cohort 2. Eligible patients were treated with cabozantinib at standard dosing. The primary endpoint was objective response rate (ORR) per RECIST 1.1 criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: From September 2021 to August 2024, 88 patients (Cohort 1, n=49; Cohort 2, n=39) were enrolled across 13 institutions. The baseline International Metastatic RCC Database Consortium (IMDC) risk categories were as follows: favorable (15.9%), intermediate (71.6%), and poor (12.5%). Prior nephrectomy was reported in 42.0% of patients, and non-clear cell histology accounted for 20.5% of Cohort 2. After a median follow-up of 18.3 months (95% CI, 11.3–25.3), the ORR was 47.7%. Partial responses were observed in 51.0% (95% CI, 40.1–61.5) of patients in Cohort 1 (ICI-ICI) and 43.6% (95% CI, 30.5–56.8) in Cohort 2 (ICI-VEGFR-TKI). Stable disease was achieved in 43.2% of patients overall. The median PFS was 7.9 months, with a PFS of 9.2 months (95% CI, 6.6–11.8) in Cohort 1 and 7.1 months (95% CI, 6.7–7.6) in Cohort 2. No significant difference in OS was observed between the cohorts, with a 12-month OS rate of 65.2%. Safety analysis revealed no novel adverse events beyond the known cabozantinib toxicity profile, with grade 3/4 hypertension, hand-foot syndrome, and fatigue being the most commonly reported events. Conclusions: Cabozantinib demonstrated substantial efficacy as a second-line treatment for advanced RCC following progression on ICI-based therapies, with a tolerable safety profile. These findings reinforce cabozantinib as an important treatment option for patients progressing after ICI regimens. Clinical trial information: NCT04714697 .
Transcriptional profiling of patients with metastatic hormone-sensitive prostate cancer to uncover specific signatures linked to the transition from androgen-dependent to androgen-independent phenotype.
Authors: Giovanna Pecoraro, Daniela Esposito, Stefania Belli, Fabrizio Di Costanzo, Fortuna Migliaccio, Francesca Messina, Felice Pepe, Silvia Varricchio, Marco Caruso, Sarah Scagliarini, Sabrina Rossetti, Felice Crocetto, Vincenza Conteduca, Francesca Sanguedolce, Umberto Malapelle, Ciro Imbimbo, Alberto Servetto, Roberto Bianco, Luigi Formisano
Journal: Journal of Clinical Oncology (2025)

227 Background: Metastatic hormone-sensitive prostate cancers (mHSPC) are generally sensitive to androgen deprivation therapy (ADT). However, resistance often occurs, leading to disease progression. Understanding the transcriptomic changes underpinning the shift to antiandrogen resistance is crucial for identification of novel therapeutic vulnerabilities. Methods: Sixty patients with mHSPC undergoing ADT plus androgen receptor pathway inhibitors (ARPI) were enrolled. We defined non-responder (NR) patients (13/60) with biochemical/ radiological progression within 6 months of treatment and responder (R) (47/60) as those with stable disease or partial/complete response and eventually disease progression after 6 months. Total RNA was extracted from archived Formalin-Fixed Paraffin-Embedded (FFPE) basal prostate biopsies tissue samples using Maxwell RSC RNA FFPE Kit, and RNA was profiled using NanoString Tumor Signaling 360 Panel. Results: To identify gene signatures associated with response to ADT + ARPI, we analyzed differentially expressed genes between NR and R patients, through Rosalind platform Gene Set Analysis. Notably, NR patients exhibited significant upregulation of genes linked to cell cycle progression and DNA replication. The mitotic kinases AURKB and PLK1 were the most markedly upregulated genes in NR versus R samples (p=0.02 and p=0.01, respectively), suggesting enhanced cell cycle progression despite antiandrogen therapy. Coherent with these results, hyper-expression of KIF23 and CDC20 in NR vs R samples further confirmed aberrant cell cycle progression. Importantly, NR biopsies also exhibited increased expression of metastasis-promoting genes, such as HGF (p= 6.53 e-3 ), which may influence therapy response. Kaplan-Meier survival analysis reinforced the clinical significance of these findings, revealing that patients with hyper-expression of AURKB, KIF23, or CDC20, had shorter progression-free survival (PFS) compared to those with lower expression levels (p=0.0037, p=0.0007 and p=0.0289, respectively). These results underscore the potential of these molecular markers as predictive tools for resistance to ADT + ARPI and as potential targets for future therapeutic interventions. Conclusions: This study provides new insights into the transcriptomic landscape of mHSPC and identifies key gene signatures responsible for resistance to standard-of-care. Validation in larger cohorts is essential to confirm the predictive value of these genes and to identify patients eligible for novel combinatory treatments aimed at delaying this critical phenomenon.
Results from the prior treatment cohort of a phase I/II study of nivolumab and axitinib in patients with advanced renal cell carcinoma.
Authors: Matthew R. Zibelman, Yasser Ged, Michael A Carducci, Ana M. Molina, Rahul Ravilla, Rachel Basiura, Courtney Lambert, Madeline Wargins, Erika Jerome, Eli Mikkelsen, Karthik Devarajan, Karen J Ruth, Rutika Kokate, Fern Anari, Pooja Ghatalia, Daniel M. Geynisman, Elizabeth R. Plimack
Journal: Journal of Clinical Oncology (2025)

548 Background: Combination tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We report updated analysis of a multi-center, investigator-initiated (IIT), phase I/II study of axitinib (axi) with nivolumab (nivo) in the previously treated patient cohort. Methods: The study investigated the combination of axi/nivo in an initial dose finding phase I portion and a phase II portion including 2 parallel arms: treatment naïve mRCC patients and mRCC patients previously treated with TKIs or IO/IO combination (NCT03172754). We are presenting final results from the previously treated cohort. Included patients had pathology with any clear cell component, ECOG performance status of 0-1, no known or symptomatic brain metastases, and no history of autoimmune disease. The recommended phase 2 dose of axi was 5 mg BID and patients were treated for up to 2 years then could stop one or both therapies. The primary endpoint of the phase II portion was objective response rate (ORR) per investigator assessment. Results: Twenty-six patients were accrued to the previously treated arm, all evaluable for efficacy and toxicity. The median age was 62 yrs (range: 42-81), 80.8% were male and 88.5% were white. Twenty pts had 1 prior line of therapy (18 TKI alone), 6 pts had 2 or more prior lines of Tx. Two pts had prior nivo with ipilimumab. Median follow-up was 47.2 months. The ORR was 30.8% (all PRs) and 57.7% achieved stable disease. The primary PD rate was 11.5%. Median OS was 48.4 months and median PFS was 13.0 months. Six pts (23.1%) completed two years of Tx on trial and elected to stop one or both drugs (2 elected to stay on axi alone). Five pts remain progression-free and have received no subsequent therapy with a median progression-free interval of 23.2 months. None had received prior IO. Adverse event (AE) data was similar to published data for IO/TKI combinations. There was one Gr4 TRAE of elevated lipase and 12 pts (46%) experienced a Gr3 TRAE. One pt (4%) discontinued the study due to TRAEs. Conclusions: Final results from the previously treated cohort of this IIT of axi/nivo for pts with mRCC demonstrated an ORR of 30.8% and a DCR of 88.5% with no unexpected AEs. Though there were no CRs, disease control rate and median OS were encouraging in this previously treated population. This is the only reported IO/TKI trial that allowed for stopping of all Tx at 2 years, with 6 pts (23.1%) meeting this milestone, 5 of whom (19% of all pts) remain progression-free for a median period close to 2 years. Clinical trial information: NCT03172754 .