tbuckley/cabot-search huggingface dataset:
Assessing the mid-term impact of enhanced prostate cancer screening in Caucasian men with germline DNA repair pathogenic variants.
Authors: Massimo Lazzeri, Vittorio Fasulo, Nicolò Maria Buffi, Paolo Casale, Rodolfo Hurle, Alberto Saita, Marco Paciotti, Alessio Finocchiaro, Muhannad Aljoulani, Rosanna Asselta, Giulia Soldà, Ilaria De Simone, Piergiuseppe Colombo, Miriam Cieri, Federica Maura, Pietro Cavalli, Giovanni Lughezzani
Journal: Journal of Clinical Oncology (2024)

278 Background: Family history is a major prostate cancer (PCa) risk factor. Pathogenic gene variants (e.g., BRCA1/BRCA2) greatly increase PCa risk (2.5 to 8.6-fold for &lt;65-year-olds) and affect outcomes. This study assesses an enhanced screening protocol's effectiveness and participant compliance. It combines PHI for familial cases and multiparametric MRI for those with pathogenic DNA repair gene (DRG) variants. Methods: This non-profit charity-funded study (AIRC - Fondazione AIRC project IG 2020 ID 25027) evaluates targeted screening for men at higher genetic risk of PCa due to PVs in a specific gene region (DRG). Conducted at a tertiary Hospital with collaboration from departments of Oncology, Breast Unit, Urology, Pathology, Radiology, Laboratory and Medical Genetics. It includes men aged 35-69 with documented deleterious DRG mutations who consent to planned screening. Exclusion criteria are prior prostate surgery, prostate cancer diagnosis, MRI contraindications, or variants of unknown significance (VUS). Results: Between 2020 and 2023, a total of 90 patients participated in this study. Their median age was 51.5 years (IQR 46.0-60.2). The median total PSA level was 0.9 (IQR 0.5-1.63), and the median PHI was 17 (IQR 12.3-23.8). Notably, 20.1% of patients had a family history of breast/ovarian cancer, while 79.9% had a family history of PCA. Most participants hailed from Northern Italy (69.4%). PVs were identified as follows: BRCA2 (55.7%), BRCA1 (17.8%), ATM (4.44%), PMS2 (3.33%), BRCA (3.33%), MSH2 (2.22%), TMPRSS2-ERG (2.22%), BRIP1 (1.11%), MLH1 (1.11%), MSH6 (1.11%), BRCA3 (1.11%), and 6.67% of patients reported mutations without specific details. In terms of screening compliance, 36 patients completed 1 visit, 31 completed 2 visits, 1 completed 3 visits, and 22 scheduled their first follow-up. Regarding PHI levels, 62.8% had PHI levels below 20, 33.5% fell in the 20-40 range, and 3.70% exceeded 40. For patients with PSA levels below 3 and PHI above 20 (n=17), only one exhibited a positive mpMRI result and is scheduled for a biopsy. Conversely, among patients with PSA levels above 3 and PHI below 20 (n=2), one underwent mpMRI, which yielded a negative result. Among the patients who underwent mpMRI, six underwent biopsy, and all resulted negatives. Conclusions: In summary, this study achieved high participant compliance with the screening method and underscores the importance of using PHI and multiparametric MRI, especially in those with genetic predispositions. These tools hold potential for enhancing prostate cancer detection accuracy and merit further exploration for early diagnosis in at-risk populations.
A phase I, open-label, dose-finding study of fatty acid synthase (FASN) inhibitor TVB-2640 administered in combination with enzalutamide (Enza) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pier Vitale Nuzzo, Caroline Fidalgo Ribeiro, Silvia Rodrigues, Escarleth Fernandez, Ana M. Molina, Jones Nauseef, Cora N. Sternberg, Scott T. Tagawa, Massimo Loda, David M. Nanus
Journal: Journal of Clinical Oncology (2024)

TPS248 Background: Recent studies have shown that targeting lipid synthesis is a novel therapeutic strategy to overcome androgen resistance in mCRPC. TVB-2640 is a first-in-class FASN inhibitor, a key enzyme in de novo lipogenesis that is overexpressed and androgen-regulated in CRPC. FASN promotes the synthesis of palmitate that can be elongated and desaturated to produce saturated fatty acids (SFAs) and monounsaturated FA (MUFAs) that can support membrane synthesis and energy production, protect against free radicals and chemotherapeutics, and regulate post-translational modifications of major oncogenic pathways. Our preliminary in vitro and in vivo data show that TVB-2640 co-administered with enza to CRPC cells significantly reduced cell growth, increased apoptosis, and promoted cell cycle arrest, as well as down-regulating full-length androgen receptor (AR) and its splice variant, AR-V7. Methods: This is an open-label, single-arm, Phase I dose-escalation study that enrolls pts with mCRPC who are candidates to receive enza. The primary objective is to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of TVB-2640 in combination with enza. Secondary objectives include safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. Exploratory objectives include the effects of FASN inhibition on metabolites, genetics, and lipids in human blood and tumor tissue, to identify potential predictive and prognostic markers of response. Pts with a confirmed histological or cytological diagnosis of PC, evidence of metastatic PC on imaging (bone scan and/or CT/MRI scan), serum testosterone &lt;50 ng/dl, who had progressed on androgen-depletion therapy (ADT), with documented progressive metastatic castration-resistant prostate cancer (mCRPC) based on Prostate Cancer Working Group 3 (PCWG3) criteria a are eligible. Enrolled pts will receive enza at a daily dose of 160 mg for 36 days to reach a steady state, followed by the addition of oral TVB-2640 starting at 100 mg/daily. The dose escalation will follow the Bayesian optimal interval (BOIN) design with additional dose levels of 150 mg, 200 mg, 250 mg, and 300 mg daily. The maximum sample size for this study is 30 pts, with a target dose-limiting toxicity (DLT) rate of 25% or less and a maximum of 15 pts at any given dose level. This is the first clinical trial to evaluate the targeting of the AR pathway through inhibition of lipid synthesis as a new approach to treating mCRPC. Enrollment of Cohort 1 began in August 2023. Clinical trial information: NCT05743621 .
Efficacy and safety between first-line therapies in metastatic castration-resistant prostate cancer in combination in the PARPi and ARSI era: A systematic review and network meta-analysis.
Authors: Xuanjun Guo, Yixin Li, Mengying Wang, Hexiang Peng, Huangda Guo, Tianjiao Hou, Hanyu Zhang, Jin Jiang, Tao Sheng, Yu Fan, Tao Wu, Zhisong He
Journal: Journal of Clinical Oncology (2024)

146 Background: The treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) has evolved tremendously, while little is known about the efficacy and safety comparison between current first-line mCRPC systemic therapies in the overall patient population and in the context of clinically relevant subgroups. Methods: We conducted a systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs). Multiple databases (PubMed, Embase, and Cochrane Library), ClinicalTrials.gov, and major congress abstracts were searched in the first-line treatment of mCRPC. The primary efficacy outcomes were radiographic progression-free survival (rPFS) and overall survival (OS). The safety outcomes were adverse events (AEs), serious AEs (sAEs), and grade ≥3 AEs. Two separate pairwise meta-analyses were conducted since there were no common arms between therapies with and without docetaxel (Doc) when considering OS and safety outcomes, while only trials without Doc assessed rPFS. Moreover, we performed subgroup analyses according to treatment regimens and homologous recombination repair (HRR) gene alteration status. Results: The analysis included data from 35 clinical trials (38 references) published as of June 6, 2023, comprising a total of 24,400 patients. For the non-Doc group, analysis of treatment ranking revealed that PARPi doublet, especially talazoparib plus enzalutamide, had the highest likelihood of improving rPFS and OS compared with ARSI doublet, ARSI monotherapy, and immunotherapy, mainly in the HRR-deficient patients while raising some concerns about safety profiles. Regarding therapies based on Doc, most Doc doublet regimens demonstrated subtle improvement in OS compared to Doc monotherapy with tolerable toxicity. Conclusions: This systematic review and meta-analysis provided a comprehensive analysis of the therapeutic effects and safety profiles of various first-line mCRPC systemic therapies. Our findings may provide decision-making guidance to clinicians and help inform mCRPC patients-centered treatment regimens. In an era of PARPi combination with ARSI, unfortunately, because of the lack of common arm delivery of Doc, we cannot estimate the relative value of Doc versus non-Doc as first-line mCRPC therapies.
Preliminary data from a dose-escalation phase 1 study with HP518, an AR PROTAC degrader: Safety, tolerability, pharmacokinetics (PK), and first assessment of anti-tumor activity in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Arun Azad, Howard Gurney, Craig Underhill, Lisa Horvath, Mark Voskoboynik, Xinghai Li, Ivan King, Lisa Shao, Yiyun Dai, Frank Perabo
Journal: Journal of Clinical Oncology (2024)

124 Background: HP518 is an oral proteolysis targeting chimera (PROTAC) protein degrader that target androgen receptor (AR) mutations for the treatment of mCRPC. To evaluate the safety, PK, and anti-tumor activity of HP518, and select a recommended phase 2 dose (RP2D), we conducted a first-in-human, Phase 1, open-label, multicenter, non-randomized, dose escalation study in pts with mCRPC. We report results of the ongoing Phase 1 study at five Australian sites. Methods: Pts with mCRPC with disease progression on at least 1 novel hormonal agent (NHA) and ≤ 1 line of chemotherapy received HP518 QD orally in sequential cohorts (25, 50, 100, 200, and 300, 400, 500 mg per day, Bayesian N-CRM design). Primary objectives were to assess HP518 safety and select the RP2D. Secondary objectives included evaluating the PK of HP518, PSA50 response and radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria. Exploratory objectives were to evaluate AR expression in CTCs before and after 12 weeks of treatment and conduct genomic profiling using cfDNA. Results: As of 08Sep2023, a total of 22 pts were enrolled, with current one-daily dosing of 500 mg HP518. Overall, HP518 was well tolerated, with cumulative 10 SAE (1 related/9 unrelated). No DLT was observed. There were 13 Grade ≥3 treatment-emergent adverse events (TEAEs) in 6 pts treated up to 500 mg; no grade ≥4 TEAEs. The most common TEAE in all cohorts was grade 1 or 2 vomiting and nausea which were well managed with prophylactic anti-emetics. Preliminary PK results were obtained from 18 pts dosed with 25 mg to 500 mg per day. Following multiple oral doses of HP518, median peak plasma concentrations were observed at 3 -12 hours post-dose. Over the 5-fold dose range (100 to 500 mg), the increase in Cmax and AUC0-last was approximately dose proportional on day 1. Steady state was reached between day 56 and day 84. Among 16 pts who finished the DLT period, a PSA50 response was seen in 3 pts. 2 pts had confirmed partial responses per RECIST criteria, with 8 pts remaining on treatment. 2 pts received HP518 for ≥24 weeks including 1 pt with a durable PSA50 response for 52 weeks, who also showed PR. Notably, this patient harbored an F877L, E873_F879del AR ligand-binding domain (LBD) mutations. Conclusions: HP518, a novel AR PROTAC degrader, demonstrates in this Phase 1a dose-escalation study, an acceptable safety/tolerability profile and a signal of efficacy in an unselected mCRPC patient population. The presence of AR LBD mutations may predict benefit from HP518, and merits further investigation in pts with mCRPC. Clinical trial information: NCT05252364 .
Individual-level social determinants of health and allostatic load/chronic toxic stress in men with prostate cancer.
Authors: Nickolas Stabellini, Jennifer Cullen, Marcio S Bittencourt, Justin Moore, Neal L Weintraub, Biplab Datta, Steven S. Coughlin, John Shanahan, Alberto J. Montero, Avirup Guha
Journal: Journal of Clinical Oncology (2024)

263 Background: Allostatic load (AL)/chronic toxic stress is linked to a higher risk of adverse cancer-specific and cardiac events in prostate cancer (PC) patients especially non-Hispanic Blacks (NHBs). We hypothesize that NHBs experience more adverse social determinants of health (SDOH) that increases this AL. Methods: We included men≥18 years diagnosed with PC (2010-2022). Individual-level SDOH with 19 covariates across 4 domains was obtained. Pre-PC diagnosis AL was calculated as an ordinal measure (0-11). Components and cutoffs for the AL score: Each measure above the cutoff add 1 point to AL. Systolic blood pressure (BP) ≥140 mmHg, diastolic BP ≥90 mmHg, heart rate &gt;100 bpm, total cholesterol (chol) ≥240 mg/dl, high-density lipoprotein chol ≤50 mg/dl, triglycerides ≥150 mg/dl, glycated hemoglobin ≥6.5, body mass index ≥30 kg/m2, glucose ≥110 mg/dl, C-reactive protein &gt;3 mg/L and interleukin-6 &gt;1.8 pg/ml. A gradient-boosting Machine Learning model ranked AL predictors using SHAP scores (SS). Cubic splined from logistic regressions defined SDOH adversity cutoffs. Results: Among 4,258 patients (886 NHB), the median age was 69 (IQR 63-77). Most were former smokers (44.2%), and the median Charlson comorbidity score was 4 (IQR 2-7). In NHBs, the SDOH variables among the top 5 overall predictors of AL were annual income (SS=0.10), neighborhood murder index (SS=0.07), neighborhood median income (SS=0.06), and neighborhood car theft index (SS=0.05). Considering all the SDOH features analyzed, NHBs faced adversity in 12 of 19 SDOH features (63%; Table). Conclusions: SDOH related to the neighborhood, built environment, and economic stability, are crucial predictors of pre-PC diagnosis AL in NHBs. [Table: see text]
Randomized trial of transperineal versus transrectal prostate biopsy to prevent infection complications.
Authors: Jim C. Hu, Andrew Vickers, Mohamad E. Allaf, Behfar Ehdaie, Andrew J Cohen, Benjamin T Ristau, David Green, Misop Han, Michael Rezaee, Christian P. Pavlovich, Jeffrey S. Montgomery, Keith Kowalczyk, Ashley Ross, Shilajit Kundu, Hiten D Patel, Gerald J Wang, John N Graham, Melissa Assel, Anthony J Schaeffer, Edward M. Schaeffer
Journal: Journal of Clinical Oncology (2024)

261 Background: Transrectal prostate biopsy is the predominant approach to prostate cancer detection in the U.S. and worldwide. The transperineal approach is traditionally preformed under general anesthesia. Recent advances enable prostate biopsy to be performed through the skin of the perineum (transperineal) under local anesthesia. There are potential advantages to this clean, percutaneous approach over the inherently contaminated transrectal approach. However, comparative evidence is limited. Methods: In a multicenter, randomized trial, we used two-stage consent and assigned participants with suspicion for prostate cancer to undergo transperineal biopsy without antibiotic prophylaxis vs. transrectal biopsy with targeted prophylaxis. The primary outcome was post-biopsy infection, with secondary outcomes of urinary retention, significant bleeding, cancer detection, and a numerical rating scale (0-10) for biopsy-related pain and discomfort during 7-days post-biopsy. Results: Six-hundred fifty-eight participants underwent randomization, and 567 (86%) of participants were included in the intent to treat analysis. Seventy-nine men declined to participate. There were zero transperineal versus 4 (1.4%) transrectal biopsy infections (adjusted difference -1.4%; 95% confidence interval -3.2, 0.3; P=0.059). Rates of other complications were very low and similar by approach. Importantly, detection of clinically significant cancer was similar (53% transperineal vs. 50% transrectal, adjusted difference 2.0%; 95% CI -6.0, 10; p=0.6). Participants undergoing transperineal biopsy experienced worse periprocedural pain (0.6 adjusted difference [0-10 scale] 95% CI 0.2, 0.9; P=0.002), but the effect was small and resolved by 7-days. Conclusions: Office-based transperineal biopsy is tolerable, does not compromise cancer detection and likely reduces the risk of infection without antibiotic prophylaxis, thereby improving antibiotic stewardship. Altogether, our findings support office based transperineal prostate biopsy without antibiotic prophylaxis as the new standard of care for prostate cancer detection with per patient and population-based antibiotic stewardship and healthcare cost benefits. Finally, two-stage consent facilitates accrual for surgical randomized trials, as evidenced by the relatively low rate of participants declining and withdrawing from the trial. Clinical trial information: NCT04815876 .
Post hoc analysis of rPFS and OS from the TALAPRO-2 (TP-2) study: Genomic subgroups based on likelihood of <i>BRCA</i> or HRR gene alteration status.
Authors: Neal D. Shore, Neeraj Agarwal, Arun Azad, Joan Carles, Andre P. Fay, Nobuaki Matsubara, Ugo De Giorgi, Jae Young Joung, Peter C.C. Fong, Eric Voog, Robert J Jones, Curtis Dunshee, Stefanie Zschaebitz, Jan Oldenburg, Xun Lin, Cynthia G. Healy, Nicola Di Santo, Douglas Laird, Fabian Zohren, Karim Fizazi
Journal: Journal of Clinical Oncology (2024)

136 Background: Prior to randomization in TP-2, patients (pts) (N=805; all-comers) were prospectively assessed for HRR gene alterations in tumor tissue and/or ctDNA using FoundationOne CDx and/or FoundationOne Liquid CDx. In the all-comers cohort, talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment for pts with mCRPC significantly improved rPFS vs ENZA (HR 0.63; 95% CI 0.51–0.78). To investigate if ITT results for TP-2 all-comers were driven by unidentified biomarker-positive pts, we assessed the correlation between rPFS/OS outcomes and pt BRCA or HRR alteration status. Methods: Within each analysis by BRCA or HRR alteration status, three exploratory subgroups based on the likelihood of BRCA/HRR alterations were defined using all available FoundationOne records from prospective and retrospective exploratory testing. BRCA1/2 mutated ( BRCAm; 10% ITT) or HRR mutated (HRRm; 33% ITT): pts were identified via a positive test result in either ctDNA and/or tumor tissue testing. Undetermined BRCAm (38% ITT) or undetermined HRRm (28% ITT): pts with one negative BRCAm/HRRm test result not confirmed by the other test, or for whom the results of both tests were indeterminate. Non- BRCAm (51% ITT) or non-HRRm (39% ITT): pts with negative BRCAm or HRRm status confirmed by both ctDNA and tumor tissue testing. Results: A benefit in rPFS was demonstrated in the non- BRCAm and non-HRRm subgroups (Table) with a non- BRCAm median rPFS of 33.1 vs 22.1 months favoring TALA + ENZA (HR 0.71; 95% CI 0.52–0.96). A trend towards improved OS was also observed in the non- BRCAm and non-HRRm subgroups. OS data in the undetermined HRRm (36%) and undetermined BRCAm (39%) groups were least mature. For both rPFS and OS for undetermined BRCAm and undetermined HRRm, HRs were higher than those for BRCAm, non- BRCAm, HRRm, or non-HRRm; the reasons for this are unclear. Conclusions: The statistically significant rPFS improvement in the TP-2 all-comer ITT population did not seem to be attributable to pts with undetected BRCA/HRR alterations. There was evidence of rPFS benefit in the non- BRCAm and non-HRRm subgroups in favor of TALA + ENZA. While the OS data are still maturing, there is a clear benefit for pts with BRCAm and no detrimental impact for pts negative for BRCAm or HRRm by both tumor and ctDNA. Clinical trial information: NCT03395197 . [Table: see text]
Treatment options and outcome of patients with metastatic renal cell carcinoma with brain or bone metastases: Real world evidence from a German retrospective multi-center analysis.
Authors: Pia Paffenholz, Philipp Ivanyi, Jozefina Casuscelli, Ramona Stelmach, Melis Guer, Katrin Schlack, Christopher Darr, Emily Rinderknecht, Thomas Hilser, Luka Flegar, Melanie Klee, Daniel Seidl, Analena Handke, Tim Nestler, Angelika Mattigk, Marinela Augustin, Sameh Hijazi, Marc Rehlinghaus, Axel Heidenreich, Viktor Gruenwald
Journal: Journal of Clinical Oncology (2024)

387 Background: Brain (BM) and bone metastases (BOM) in renal cell carcinoma (RCC) are associated with poor outcome. We evaluated real-world treatment paradigms of RCC patients with BM and BOM. Methods: We retrospectively analyzed RCC patients with BM and/or BOM treated at 18 German tertiary cancer centres from 2003 to 2023. Adverse events (AE) were reported according to CTCAE 5.0, objective response rate (ORR) according to local standard. Overall survival (OS) was calculated from start of treatment to progression or death, respectively and determined by KM plots. Results: We included 453 patients with a median age of 64 years (IQR 56-71). 93% of all patients had BOM, 15% BM and 8% both. Most patients (79%) had clear cell RCC, 7% of all patients had sarcomatoid differentiation. 82% of patients had an ECOG PS of 0/1. IMDC risk was favorable/intermediate/poor in 20/56/24%. 64% received prior nephrectomy. Patients with BOM received first-line IO-combinations in 61% (IO-IO: 38%, TKI-IO: 62%), TKI-monotherapy in 39%, while patients with BM received IO-combinations in 68% (IO-IO: 37%, TKI-IO: 63%) and TKI in 32%. IO-based first-line therapy increased from 2003 to 2023. AE of all grades occurred in 87% and 69% during IO-based therapy or TKI monotherapy, and CTCAE grade ≥ 3 in 42% or 25%. Best ORR and survival outcomes with median follow-up of 23 months (IQR 9-42) are described in table 1. 56% and 58% of all patients with BOM and BM received second-line treatment, with Cabozantinib (34%; 34%) and Nivolumab (17%, 23%) being the most common treatment options. In the subgroup of RCC with sarcomatoid features (n=36), 34 patients had BOM and 7 had BM, of which were treated with IO-combinations in 88% (BOM; IO-IO: 41%, TKI-IO: 59%) or 66% (BM; IO-IO: 50%, TKI-IO: 50%) and TKI-monotherapy in 12% (BOM) or 34% (BM) of all patients. Response rates (ORR/SD/PD) were 48%/28%/24% for IO-based therapy and 0%/50%/50% for TKI-monotherapy in RCC with sarcomatoid features, mOS was 41 months (95% CI 16.7-65.3). Conclusions: RCC patients with BOM and BM are increasingly treated with IO-combinations but lead to higher rates of AE grade ≥ 3. In patients with BOM, IO-TKI revealed higher ORR compared to IO-IO combination, but not in patients with BM. However, the small sample size and retrospective design are major limitations of our analysis. Prospective studies evaluating treatment options for BOM and BM in patients with RCC is critical. [Table: see text]