Citations

129 Background: Few studies have explored the use of focal therapies to address select sites of resistant disease in men receiving 177-Lu-PSMA-617 for metastatic castrate resistant prostate cancer (mCRPC). Our institutional practice is to offer SBRT for patients with up to 5 sites of oligoprogression or non-responding lesions while undergoing 177Lu-PSMA-617 (every 6 weeks for 6 cycles total). This is determined by PSMA or choline PET imaging during the course of 177Lu-PSMA-617. Herein, we evaluated the safety of adding target SBRT during treatment with 177Lu-PSMA-617. Methods: This retrospective single institution analysis was conducted via systematic chart review to evaluate for adverse events during or after treatment. Grading of treatment-related adverse events was conducted using Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5). Results: Thirty-one patients receiving 177Lu-PSMA-617 with 51 sites of oligoprogressive or non-responding metastatic disease were treated with SBRT. The median number of sites treated was 1 (range 1-4). Most patients received SBRT immediately after cycle 6 (32%) or after cycle 3 or 4 (42%). Bone was the most commonly treated site of disease (90%) with the majority (54%) of bone sites being spine or sacrum, followed by lymph nodes (10%). Ultimately, 84% of patients completed all 6 cycles of 177Lu-PSMA-617 (range 4-6). The median follow-up time was 19.1 months (IQR 15.5-22.4) after 177Lu-PSMA-617 therapy start. A total of 2 patients experienced a pathologic fracture within the SBRT treatment field that could possibly be related to radiotherapy. One patient experienced a grade 2 neuropathy which may have been related to radiation therapy. Other potential adverse events are listed (Table). Conclusions: Our data demonstrates a low rate of significant toxicity with the use SBRT during treatment with 177Lu-PSMA-617. Further study is indicated to determine the oncologic efficacy and potential late side effects of this treatment strategy. Adverse events. Event All Grades Grade > 3 Any Adverse Event 104 2 Anemia 29 (94%) 0 Low Platelets 11 (35.5%) 1 (3.2%) Any Pathologic Fracture 7 (22.5%) 1 (3.2%) Possible SBRT-related Pathologic Fracture 2 (6.5%) 1 (3.2%) Bone Pain Flare 3 (9.6%) 0 Neuropathy 1 (3.2%) 0

341 Background: Specialist clinicians (oncologists, urologists, radiation oncologists) read through free text reports of prostate MRI and biopsy reports to risk stratify patients during initial consultation of localized PCa. This laborious and time-consuming process is repeated for each day during the clinic. Herein, we propose a hybrid stratification framework utilizing a combination of large language model (LLM) and rule-based programming to automate this process. Methods: This retrospective study included patients with localized PCa (2004-2024) presenting to care at Mayo Clinic with at least one positive prostate biopsy and MRI report available. The state-of-the-art LLM – GPT4 – was utilized using a structured zeroshot prompt to extract relevant phenotypic variables (clinical T stage, Gleason patterns, grade group, extent of specimen/cores involved, prostate size/volume) from unstructured MRI and biopsy reports. Using a rule-based algorithm, the extracted variables and PSA at PCa diagnosis were used to categorize each patient into one of the six NCCN risk categories (very low [VL], low [L], favorable intermediate [FInt], unfavorable intermediate [UFInt], high risk (HR), very high risk [VHR]). Prompts were iteratively developed using ~5% of the total dataset and validated on ~10% of the dataset. Final performance was assessed against a held-out expert annotated test dataset using evaluation metrics (accuracy, F1-score, precision, recall). Additionally, manual annotation was conducted by two independent novice reviewers to compare machine annotated and novice-human annotated risk categorization. Results: A total of 397 patients were included in the evaluation. The median age at diagnosis was 64.8 (IQR: 59.7-68.5); majority of the men were White (n: 366; 92%) and non-Hispanic (n: 371; 94%). The most prevalent risk category was UFint (n: 151; 38%) followed by FInt (n: 80; 20.2%), HR (n: 76; 19.1%), VHR (n: 64; 16.1%), L (21: 5.3%), and VL (n: 5; 1.3%). Novice reviewers achieved an accuracy of 79%, precision of 80%, recall of 82% and a F1-score of 0.81. The hybrid stratification framework using GPT4 achieved an accuracy of 89%, precision of 89%, recall of 88% and a F1-score of 0.88. Among 43 errors by GPT4 risk stratification, majority of the errors were due to miscategorization of clinical T-stage (n: 21; 49%) followed by erroneous number of positive cores (n: 13; 30%). However, additional evaluation showed that GPT4 achieved numerically higher performance (accuracy: 90%; precision: 91%; recall: 90%; F1: 0.90) compared to novice reviewers (accuracy: 77%; precision: 89%; recall: 77%; F1: 0.82) for ascertaining clinical T-stage. Conclusions: Large language models exhibited superior performance than novice clinicians for risk stratification in patients with localized PCa. As the next step, we intend to validate our framework for automated risk classification in a prospective manner.

184 Background: We update evidence on mHSPC when new evidence becomes available (PMID: 36862387). ARANOTE trial prompted us to assess the comparative efficacy of darolutamide (DARO) with other ARPi agents in mHSPC using the living network meta-analysis (LNMA). Methods: This LNMA is conducted using the living interactive evidence (LIvE) synthesis framework. Phase III trials assessing systemic treatments in mHSPC are included. Mixed treatment comparisons were made using a frequentist network meta-analysis. P-scores were computed to assess relative treatment rankings with higher values indicating potentially better efficacy. Results: This report of LNMA includes a total 11 trials (12628 patients; 12 unique treatment options) as of October 1 st , 2024. Overall results were consistent with prior updates. Analysis limited to the ARPi trials showed that inhigh volume, abiraterone acetate (AAP)+androgen deprivation therapy (ADT) (HR: 0.46; 95% CI: 0.40-0.53; rank 1), apalutamide (APA)+ADT (0.53; 0.41-0.68; rank 3), DARO+ADT (0.60; 0.44-0.81; rank 4) and enzalutamide (E)+ADT (0.48; 0.41-0.56; rank 2) significantly improved radiographic progression-free survival (rPFS) compared to ADT alone. No statistically significant differences were observed with DARO+ADT compared to AAP+ADT (1.30; 0.94-1.82), APA+ADT (1.14; 0.77-1.67) and E+ADT (1.24; 0.89-1.79). Inlow volume, AAP+ADT (0.48; 0.37-0.63; rank 4), APA+ADT (0.36; 0.22-0.58; rank 3), DARO+ADT (0.30; 0.15-0.60; rank 1) and E+ADT (0.32; 0.25-0.41; rank 2) significantly improved rPFS compared to ADT. E+ADT significantly improved rPFS compared to AAP+ADT (0.67; 0.47-0.96) in low volume. No statistically significant differences were observed with DARO+ADT compared to AAP+ADT (0.62; 0.30-1.30), APA+ADT (0.83; 0.36-1.92) and E+ADT (0.93; 0.45-1.94). In synchronous disease, AAP+ADT (0.58; 0.51-0.67; rank 4), APA+ADT (0.49; 0.39-0.62; rank 2), DARO+ADT (0.59; 0.44-0.79; rank 3) and E+ADT (0.42; 0.36-0.50; rank 1) significantly improved rPFS compared to ADT. E+ADT significantly improved rPFS compared to AAP+ADT (0.73; 0.59-0.89) in synchronous disease. In metachronous disease, DARO+ADT (0.34; 0.17-0.67; rank 1), APA+ADT (0.41; 0.22-0.77; rank 2) and E+ADT (0.44; 0.35-0.57; rank 3) significantly improved rPFS compared to ADT. No statistically significant differences were observed with DARO+ADT compared to APA+ADT (0.83; 0.33-2.08) and E+ADT (0.76; 0.37-1.57) in metachronous disease. The results were consistent for overall survival. Conclusions: Current evidence suggests no significant differences for darolutamide as compared to other ARPi agents. Enzalutamide may be preferred over AAP in low-volume or synchronous disease. Given similar efficacy, choice of ARPi requires careful consideration of patient-specific factors including cost, accessibility and toxicity.

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

AbstractBackgroundSince FDA approval in 2017, CAR‐T therapy has seen rapid clinical adoption. Shifting clinical trends have emerged with increasing utilization of CAR‐T therapies and a downward trend in HSCTs. Given the overlapping resources required for the manufacture and storage of these products, we sought to examine trends over a 6‐year period.MethodsThe apheresis patient database and Lab database were reviewed to compile a list of patients that underwent either CAR‐T or HSCT (autologous) collections, and/or received CAR‐T or autologous HSCT infusions between January 1, 2018 and December 12, 2023. This was further examined by year and disease group.ResultsThe total number of patients collecting for CAR‐T increased from 52 in 2018 to 150 in 2023 (slope = 21.97; p = .0013), accompanied by a decrease in the number of patients collecting for HSCT, from 425 in 2018 to 341 in 2023 (slope = −21.2; p = .0177). Neither total number (calculated as number of HSCT + CAR‐T) of patients collected (mean 476 + 20.4 per year), nor collection procedures (mean 972 ± 75.8 per year) changed significantly over the 6‐year period. The total number of CAR‐T infusions increased from 24 in 2018 to 111 in 2023 (slope = 17.7; p = .004), with a decrease in auto‐HSCT from 400 to 289 (slope = −28.7; p = .008). The overall number of infusions (calculated as number of HSCT + CAR‐T) did not change significantly (slope = −10.9; p = .13) over the 6‐year period.DiscussionOur findings confirm the increasing adoption of CAR‐T therapy occurring alongside a decreasing stem‐cell transplants, with stable overall resource utilization.

ZUMA-12 is a multicenter phase 2 study evaluating axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy as part of first-line treatment for high-risk large B-cell lymphoma (LBCL). In the primary efficacy analysis (n = 37; median follow-up, 15.9 months), axi-cel demonstrated a high rate of complete responses (CR; 78%) and a safety profile consistent with prior experience. Here, we assessed updated outcomes from ZUMA-12 in 40 treated patients after ≥3 years of follow-up. Eligible adults underwent leukapheresis, lymphodepleting chemotherapy, and axi-cel infusion (2 × 106 CAR T cells/kg). Investigator-assessed CR, objective response, survival, safety, and CAR T-cell expansion were assessed. The CR rate among response-evaluable patients (n = 37) increased after the primary analysis to 86% (95% confidence interval [CI], 71%-95%), with a 92% objective response rate. After a median follow-up of 47.0 months (range, 37.1-57.8 months), 36-month estimates (95% CI) of duration of response and event-free, progression-free, and overall survival were 81.8% (63.9%-91.4%), 73.0% (55.6%-84.4%), 75.1% (57.5%-86.2%), and 81.1% (64.4%-90.5%), respectively. In total, 4 patients had new malignancies, 2 occurring after the data cutoff of the primary analysis; none were axi-cel–related. Eight patients died on study, 2 of whom died from nonrelapse mortality causes. After long-term follow-up, axi-cel demonstrated a high durable response rate, with no new safety signals after the primary analysis, suggestive of an effective first-line therapy with curative intent in high-risk LBCL. Further assessments are needed to determine its benefit vs standard of care. This trial was registered at clinicaltrials.gov, as NCT03761056.

AbstractObjectiveLimited evidence guides the optimal timing of treatment after the detection of tumor growth during the observation of sporadic vestibular schwannoma (VS). The current work aimed to inform the timing of radiosurgical intervention based on an analysis of patient outcomes among those who ultimately failed stereotactic radiosurgery (SRS) and underwent salvage microsurgery.Study DesignA historical cohort study.SettingSeven centers across the United States and Norway.MethodsAdults with sporadic VS who underwent salvage microsurgery following failed primary SRS were included. The primary outcome of interest was the association between tumor size at the time of primary SRS and the ability to achieve gross total resection (GTR) and maintain postoperative House–Brackmann (HB) facial nerve grade I at the last follow‐up after salvage microsurgery.ResultsAmong 96 patients, the median (interquartile range [IQR]) cerebellopontine angle (CPA) tumor size at primary SRS was 14.5 mm (10.0‐19.0). Each 1‐mm increase in CPA tumor size at the time of primary SRS was associated with a 13% increased likelihood of near‐total/subtotal resection or most recent postoperative HB grade >I (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.05‐1.21, P = .001), with an optimal tumor size threshold to distinguish this outcome of 12 mm of CPA extension (c‐index 0.73). Similarly, for each 1‐mm increase in CPA tumor size at the time of primary SRS, a 9% increase in any postoperative complication with salvage microsurgery was observed (OR 1.09, 95% CI 1.02‐1.15, P = .009).ConclusionCorroborated by size threshold surveillance data informing the timing of primary microsurgical resection, the current study suggests that VS outcomes are optimized when primary radiosurgical intervention is undertaken on growing tumors when they harbor 10–15 mm of cerebellopontine angle extension or less.