e17059 Background: It is unclear if patients with different HRR gene-mutated mCRPC derive consistent benefit from treatment with PARPi and API combination. Approval labels for PARPi+API are inconsistent across regulatory bodies in the US (Food and Drug Administration, FDA) and Europe (European Medical Agency, EMA), adding to confusion among practicing clinicians. Therefore, we aimed to assess the differential efficacy of PARP+API therapy by different genes using up-to-date trial evidence. Methods: We maintain a living meta-analysis on mCRPC treatments that is updated when new data becomes available. Here, we report data from phase III randomized control trials (RCTs) assessing PARPi+API in 1L mCRPC. The outcomes of interest included radiographic progression-free survival (rPFS) and overall survival (OS). Hazard ratios (HR) for rPFS and OS by different genes were summarized using random effects meta-analysis via inverse variance approach. Results: We have screened 27376 references since the inception of this living review. Here, we report data from three trials (15 references) with a total of 1618 patients. Frequently reported HRR gene mutations in the included trials were BRCA2 (35%), ATM (21%), CDK12 (12.2%), CHEK2 (12.2%), BRCA1 (4.6%), and PALB2 (3.4%). In terms of rPFS, statistical benefit was observed in BRCA (0.28; 95% CI: 0.13-0.59) and CDK12 (0.58; 95% CI: 0.35-0.95) subgroups, whereas no statistically significant benefit was seen in PALB2 (0.53; 95% CI: 0.21-1.32), ATM (0.93; 95% CI, 0.57-1.53), and CHEK2 (0.92; 95% CI: 0.53-1.61) subgroups. For OS, benefit was observed in BRCA (0.47; 95%CI: 0.31-0.71) subgroup. While not statistically significant, a signal of meaningful OS benefit was observed in PALB2 (0.33; 95%CI: 0.10-1.16) but no OS benefit was observed in ATM (0.97; 95% CI: 0.57-1.67), CDK12 (0.80; 95% CI: 0.36-1.78), and CHEK2 (0.81; 95% CI: 0.37-1.75) subgroups. Conclusions: Current results show that mCRPC patients with BRCA and CDK12 alterations had delayed disease progression with PARPi+API as 1L therapy. BRCA mutations are also associated with improved OS, while patients with CHEK2 and ATM derived no significant benefit with PARPi+API combination. [Table: see text]
639 Background: Immunotherapy combined with chemotherapy (IO/C) as the first-line management of locally advanced or metastatic urothelial carcinoma (LA/mUC) has been investigated in multiple trials with conflicting outcomes. Therefore, we conducted a meta-analysis of available trials to compare objective response rates (ORR) of this combination regimen, both in overall and in cisplatin-ineligible populations. Methods: EMABSE and MEDLINE were searched from 2000 through July 20 th , 2023, to identify phase II and III clinical trials assessing IO, C or both in LA/mUC. Main outcome of interest was objective response rates (ORR) as defined in the included trials. An inverse variance random-effects meta-analysis was performed to estimate pooled ORR using the restricted maximum likelihood estimation method. Subgroup differences were assessed among IO/C, IO alone, and C alone. The threshold for statistical significance was established at 0.1. Results: Of 5975 citations identified, a total of 26 trials with a total of 4,628 participants were included in this systematic review. In the overall group, the ORR in IO/C trials (5 trials, 1,236 patients) was 44.70% (95% CI: 21.88%- 70.0%). In IO trials (7 trials, 2,189 patients), ORR was 23.68% (19.55%- 28.36%) and in C trials (26 trials, 4,628 patients) was 43.46% (37.43%-49.68%]). In the cisplatin-ineligible group, the ORR in IO/C trials (2 trials, 240 patients) was 60.06% (33.38%-81.86%), in IO trials (6 trials, 1,103 patients) was 26.15% (23.01%; 29.56%), and in C trials (8 trials, 767 patients) was 42.45% (35.67%-49.52%). In terms of subgroup differences, the difference in ORR was statistically significant between IO/C and IO trials (p= 0.0844) and between IO and chemotherapy trials (p< 0.0001) in the overall population. Similarly, we found a statistically significant difference in ORR between IO/C and IO (p= 0.0108) and between IO and chemotherapy trials (p< 0.0001) in the cisplatin-ineligible population. No statistically significant differences were observed between IO/C and C alone. Conclusions: First-line IO/C may achieve a better objective response compared to IO alone in patients diagnosed with locally advanced/metastatic UC. Although, there appears to be a trend of greater benefit with IO/C compared to C alone, the difference was not statistically significant. The results will be updated as soon data from new trials (CheckMate 901 and EV 302) becomes available which could offer new insights. [Table: see text]
ABSTRACT Objective Data extraction from the published literature is the most laborious step in conducting living systematic reviews (LSRs). We aim to build a generalizable, automated data extraction workflow leveraging large language models (LLMs) that mimics the real-world two-reviewer process. Materials and Methods A dataset of 10 clinical trials (22 publications) from a published LSR was used, focusing on 23 variables related to trial, population, and outcomes data. The dataset was split into prompt development (n=5) and held-out test sets (n=17). GPT-4-turbo and Claude-3-Opus were used for data extraction. Responses from the two LLMs were compared for concordance. In instances with discordance, original responses from each LLM were provided to the other LLM for cross-critique. Evaluation metrics, including accuracy, were used to assess performance against the manually curated gold standard. Results In the prompt development set, 110 (96%) responses were concordant, achieving an accuracy of 0.99 against the gold standard. In the test set, 342 (87%) responses were concordant. The accuracy of the concordant responses was 0.94. The accuracy of the discordant responses was 0.41 for GPT-4-turbo and 0.50 for Claude-3-Opus. Of the 49 discordant responses, 25 (51%) became concordant after cross-critique, with an increase in accuracy to 0.76. Discussion Concordant responses by the LLMs are likely to be accurate. In instances of discordant responses, cross-critique can further increase the accuracy. Conclusion Large language models, when simulated in a collaborative, two-reviewer workflow, can extract data with reasonable performance, enabling truly ‘living’ systematic reviews.
193 Background: We maintain a network meta-analysis for the treatment of mCSPC using a living interactive evidence (LIvE) synthesis framework. Recently, the STAMPEDE trial presented evidence regarding a new triplet regimen (enzalutamide-abiraterone-androgen deprivation therapy [E+AAP+ADT]). Hence, in this report we provide the most-up-to-date evidence to inform the choice of optimal therapy in mCSPC patients. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with androgen pathway inhibitors (API), docetaxel (D), or both in patients with mCSPC were included. Mixed treatment comparisons for overall-survival (OS) and progression-free survival (PFS) were made across randomized comparisons using a frequentist network-meta-analysis. Additionally, subgroup data from three trials (ENZAMET, TITAN, ARCHES) by the receipt of docetaxel were abstracted to evaluate the comparative effectiveness of different triplet regimens. Treatment effects were expressed as hazard ratio (HR) and 95% confidence intervals (CI). Relative treatment rankings were evaluated using P-scores and assessed in congruency with the pairwise estimates. Results: This report includes 10 clinical trials (30 references) and over 11500 patients updated as of 1 st October 2022. Using randomized data in overall patient population, AAP+D+ADT (rank 1; HR: 0.50; 95% CI: 0.35-0.72) and E+AAP+ADT (rank 4; HR: 0.76; 0.62-0.93) significantly improved PFS compared to D+ADT (rank 7) but not when compared to E+ADT (rank 2) and APA+ADT (rank 3). Similarly, darolutamide (DARO)+D+ADT (rank 1; HR: 0.68; 0.57-0.81), AAP+D+ADT (rank 2; HR: 0.75; 0.59-0.95) significantly improved OS when compared to D+ADT (rank 7). Efficacy by volume of disease and timing of metastatic presentation was consistent with prior update. Using subgroup data by the receipt of docetaxel, a total of five triplet regimens (DARO+D+ADT, AAP+D+ADT, E+D+ADT, apalutamide (APA)+D+ADT, and E+AAP+ADT) were evaluable for comparisons. E+D+ADT (rank 3) improved PFS compared to D+ADT (rank 9; HR: 0.52; 0.41-0.66) and E+AAP+ADT (rank 6; HR: 0.70; 0.52-0.94). Compared to AAP+ADT (rank 7), E+D+ADT (HR: 0.64; 0.49-0.84) and AAP+D+ADT (rank 2; 0.62; 0.42-0.91) significant improved PFS. However, no significant differences were observed among E+D+ADT, AAP+D+ADT, and APA+D+ADT. Similarly, DARO+D+ADT (rank 1) improved OS compared to APA+D+ADT (HR: 0.47; 0.24-0.93). Conclusions: Current evidence favors the use of emerging triplet regimens over docetaxel doublet but not API doublets in overall population. Among different triplets, E+AAP+ADT may not delay progression compared to docetaxel triplets. Hence, access to treatment, toxicity, disease volume and timing of metastases should be carefully considered in mCSPC patients.
454 Background: Limited data exist on outcomes in mRCC patients with major venous involvement (MVI). Assessment of impact of a given variable on prognosis in cancer patients is challenging given competing causes of death (PMID: 25417239). This analysis aims to estimate cancer prognosis in mRCC patients with MVI, considering death from competing causes. Methods: Data from the Surveillance Epidemiology and End Results (SEER) database (2010-2020) were analyzed for survival and mortality in mRCC patients with MVI. 5-year (y) overall survival (OS) and 5-y probability of cancer death were calculated using the actuarial method in SEER*Stat 8.4.4, reported as percentages with 95% confidence intervals (CI). Results were based on the site of MVI (renal vein, inferior vena cava [IVC]) and stratified by age (<65, >65 years), gender (male, female), and race/ethnicity (Non-Hispanic [NH] White, NH Black, NH Asian/Pacific Islander [API], Hispanic). Results: A total of 89047 mRCC patients were included in our analysis of whom 10785 (12%) had major venous involvement (MVI). Overall, patients who experienced MVI had worse prognosis as compared to those who did not have MVI (5-y OS: 53.2% vs 84.4% and 5-y cancer death: 38.6% vs 8.2% respectively). Among cohort with MVI, prognosis was poor with IVC involvement as compared to involvement of renal vein (5-y OS: 36% vs 57%; 5-y cancer death: 56% vs 35% respectively). Patients who had the worst prognosis with MVI included older adults (>65 y) (5-y OS: 47.8%; 5-y cancer death: 40.8%) and NH Black (5-y OS: 41.5%; 5-y cancer death: 49.8%) (Table). Conclusions: Prognosis in mRCC with MVI, especially with IVC involvement, was poor, particularly for older adults (>65 y) and NH Black patients. Further research is needed for better prognostication and risk stratification to improve outcomes for high-risk patients. Subgroup No MVI MVI N 5-year OS (%), 95% CI 5-year Cancer death (%), 95% CI N 5-year OS (%), 95% CI 5-year Cancer death (%), 95% CI Overall population 78,262 84.4 (84.1-84.7) 8.2 (8.0-8.4) 10,785 53.2 (52.0-54.3) 38.6 (37.5-39.7) Age <65 y 49,217 89.0 (88.6-89.2) 6.5 (6.3-6.8) 5,897 57.5 (56.0-59.0) 36.8 (35.4-38.3) >65 y 29,045 77.0 (76.1-77.2) 10.9 (10.5-11.4) 4,888 47.8 (46.0-49.5) 40.8 (39.2-42.4) Gender Male 49,221 83.0 (82.7-83.5) 8.9 (8.6-9.2) 7,503 53.2 (51.8-54.6) 38.3 (37.0-39.6) Female 29,041 86.5 (86.0-86.9) 7.0 (6.7-7.4) 3,282 53.0 (51.0-55.0) 39.4 (37.4-41.3) Race/ethnicity NH White 49,520 84.0 (83.7-84.4) 8.3 (8.0-8.5) 7,182 53.5 (52.1-54.8) 38.0 (36.7-39.3) NH Black 8,878 82.0 (81.0-82.9) 8.1 (7.5-8.8) 685 41.5 (37.1-45.9) 49.8 (45.4-54.1) NH API 4,747 86.0 (85.1-87.4) 8.5 (7.6-9.4) 713 52.9 (48.2-57.3) 39.9 (35.5-44.1) Hispanic (All Races) 13,826 86.5 (85.8-87.2) 7.9 (7.4-8.4) 2,014 56.2 (53.4-58.8) 36.7 (34.1-39.2) N: number of cases; OS: overall survival; CI: confidence interval; NH: Non-Hispanic; API: Asian/Pacific Islander; MVI: major venous involvement.
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