Tumor mutational burden as a predictive biomarker for immune checkpoint inhibitor versus taxane chemotherapy benefit in metastatic castration-resistant prostate cancer: A real-world biomarker study.
Authors: Sayegh Nicolas , Graf Ryon , Fisher Virginia , Weberpals Janick , Huang Richard S.P. , Lin Douglas I. , Gjoerup Ole , Raskina Kira , Severson Eric Allan , Haberberger James , Ross Jeffrey S. , Alexander Brian Michael , Levy Mia Alyce , Oxnard Geoffrey R. , Agarwal Neeraj 
Published: February 2022

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Background: The most useful biomarkers for clinical decision-making identify patients likely to have improved outcomes on one treatment vs. another. To date, no study has compared the treatment class-specific outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) on Immune Checkpoint Inhibitor (ICPI) vs. taxane chemotherapy by tumor mutational burden (TMB, mutations/megabase). Methods: Association of genomic data with clinical variables and outcomes in cohort of patients with mCRPC treated January 2011- April 2021. Longitudinal de-identified clinical data from ̃280 U.S. academic or community-based cancer clinics were derived from electronic health records, curated via technology-enabled abstraction by Flatiron Health and linked to genomic testing by Foundation Medicine (FoundationOne or FoundationOne CDx assays). 45 patients (14 with TMB ≥ 10, 31 TMB < 10) received single-agent anti-PD1 axis ICPI, 696 (30 with TMB ≥ 10, 666 TMB < 10) received single-agent taxanes, at discretion of physician without randomization. For time to next therapy (TTNT) and overall survival (OS) assessments, imbalances between treatment groups were adjusted with propensity weighting. Results: Overall cohort: Median age: 70 (IQR: 64 – 76), median PSA: 79.4 (IQR: 19.0 – 254), 108 (18.8%) were ECOG 2+, 644 (86.9%) had received prior systemic treatments for mCRPC. Patients receiving ICPI vs. taxanes had comparable pre-therapy age, PSA, hemoglobin, alkaline phosphatase, prior second generation novel hormonal therapy use, and prior opioid use, but higher TMB (median 3.5, IQR: 1.7 – 15 vs. median 2.5, IQR 1.3 – 3.8, p < 0.001), higher ECOG scores (0, 1, 2+ respectively 13.9%, 55.6%, 30.6% vs. 29.4%, 52.6%, 18.8%, p = 0.057), and greater prior taxane use (73.3% vs. 53.7%, p = 0.01). Among patients with evaluable PSA response, no difference was observed on taxanes by TMB level. No patients had PSA decline ≥ 50% on ICPI if TMB < 10, 4 of 9 with TMB ≥ 10 had PSA decline ≥ 50%. TMB < 10 receiving ICPI vs. taxanes had worse TTNT (median 2.4 vs. 4.1 months; HR: 2.7, 95%CI: 1.7 – 4.0, p < 0.001) and numerically worse OS (median 4.2 vs. 6.0 months, HR: 1.08; 95%CI: 0.68– 1.7, p = 0.73). In contrast, for TMB ≥ 10 ICPI vs. taxane use was associated with more favorable TTNT (median 8.0 vs. 2.4 months; HR: 0.37, 95%CI: 0.15 – 0.87, p = 0.022) and OS (median 19.9 vs. 4.2 months; HR: 0.23, 95%CI: 0.10 – 0.57, p = 0.0085). Among all 741 patients, 44 had TMB ≥ 10, 22 had high microsatellite instability (MSI-H), 20 had both. Treatment interactions with TMB ≥ 10 (TTNT: p < 0.001, OS: p = 0.021) were stronger than MSI-H (TTNT: p = 0.0038, OS: p = 0.080). Conclusions: The results suggest ICPI may be a viable alternative to taxane chemotherapy for patients with mCRPC with TMB ≥ 10, adding validity to existing FDA approved platform and pan-tumor TMB score cutoff of 10.