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- Title
Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer.
- Authors
Graf, Ryon P.; Fisher, Virginia; Weberpals, Janick; Gjoerup, Ole; Tierno, Marni B.; Huang, Richard S. P.; Sayegh, Nicolas; Lin, Douglas I.; Raskina, Kira; Schrock, Alexa B.; Severson, Eric; Haberberger, James F.; Ross, Jeffrey S.; Creeden, James; Levy, Mia A.; Alexander, Brian M.; Oxnard, Geoffrey R.; Agarwal, Neeraj
- Abstract
Key Points: Question: What is the comparative effectiveness of single-agent immune checkpoint inhibitors (ICIs) vs taxane chemotherapy in populations of patients with metastatic castration-resistant prostate cancer (mCRPC) defined by levels of tumor mutational burden (TMB)? Findings: In this comparative effectiveness study of 741 patients with mCRPC, patients with TMB of 10 mutations per megabase (mt/Mb) or greater had significantly longer time to next treatment and overall survival with ICIs vs taxanes. Meaning: These findings suggest that in scenarios where taxane use is considered, ICIs are a viable alternate treatment option for patients with mCRPC and TMB of 10 mt/Mb or greater. This comparative effectiveness study assesses outcomes among patients with metastatic castration-resistant prostate cancer receiving immune checkpoint inhibitors (ICIs) vs taxane chemotherapy, stratified by tumor mutational burden (TMB). Importance: The most useful biomarkers for clinical decision-making identify patients likely to have improved outcomes with one treatment vs another. Objective: To evaluate treatment class-specific outcomes of patients receiving immune checkpoint inhibitor (ICI) vs taxane chemotherapy by tumor mutational burden (TMB). Design, Setting, and Participants: This comparative effectiveness analysis of clinical variables and outcomes used prospectively defined biomarker-stratified genomic data from a deidentified clinicogenomic database. Data included men with previously treated metastatic castration-resistant prostate cancer (mCRPC) receiving ICI or single-agent taxane chemotherapy from January 2011 to April 2021 at approximately 280 US academic or community-based cancer clinics (approximately 800 sites of care). Data were analyzed from July to August 2021. Exposures: Single-agent ICI or single-agent taxanes. Treatments were assigned at discretion of physician and patient without randomization. Imbalances of known factors between treatment groups were adjusted with propensity weighting. Main Outcomes and Measures: Prostate-specific antigen (PSA) response, time to next therapy (TTNT), and overall survival (OS). Results: A total of 741 men (median [IQR], 70 [64-76] years) with mCRPC received comprehensive genomic profiling and were treated with ICI or single-agent taxane therapy. At baseline, the median (IQR) PSA level was 79.4 (19.0-254) ng/mL, 108 men (18.8%) had Eastern Cooperative Oncology Group Performance Status scores of 2 or greater, and 644 men (86.9%) had received prior systemic treatments for mCRPC. A total of 45 patients (6.1%) received ICI therapy and 696 patients (93.9%) received taxane therapy. Among patients with TMB of fewer than 10 mutations per megabase (mt/Mb) receiving ICI, compared with those receiving taxanes, had worse TTNT (median [IQR], 2.4 [1.1-3.2] months vs 4.1 [2.2-6.3] months; hazard ratio [HR], 2.65; 95% CI, 1.78-3.95; P <.001). In contrast, for patients with TMB of 10 mt/Mb or greater, use of ICIs, compared with use taxanes, was associated with more favorable TTNT (median [IQR], 8.0 [3.4 to unknown] months vs 2.4 [2.4-7.3] months; HR, 0.37, 95% CI, 0.15-0.87; P =.02) and OS (median 19.9 [8.06 to unknown] months vs 4.2 [2.69 – 6.12] months; HR, 0.23; 95% CI, 0.10-0.57; P =.001). Among all 741 patients, 44 (5.9%) had TMB of 10 mt/Mb or greater, 22 (3.0%) had high microsatellite instability, and 20 (2.7%) had both. Treatment interactions with TMB of 10 mt/Mb or greater (TTNT: HR, 0.10; 95% CI, 0.32-0.31; P <.001; OS: HR, 0.25; 95% CI, 0.076-0.81; P =.02) were stronger than high microsatellite instability alone (TTNT: HR, 0.12; 95% CI, 0.03-0.51; P =.004; OS: HR, 0.38; 95% CI, 0.13-1.12; P =.08). Conclusions and Relevance: In this comparative effectiveness study, ICIs were more effective than taxanes in patients with mCRPC when TMB was 10 mt/Mb or greater but not when TMB was fewer than 10 mt/Mb. The results add validity to the existing TMB cutoff of 10 mt/Mb for ICI use in later lines of therapy, and suggest that ICIs may be a viable alternative to taxane chemotherapy for patients with mCRPC with high TMB.
- Subjects
THERAPEUTIC use of antineoplastic agents; DRUG efficacy; IMMUNE checkpoint inhibitors; CANCER chemotherapy; METASTASIS; CANCER patients; COMPARATIVE studies; TUMOR markers; PROSTATE tumors; IMMUNOTHERAPY; THERAPEUTICS; EVALUATION
- Publication
JAMA Network Open, 2022, Vol 5, Issue 3, pe225394
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2022.5394