ICIs Demonstrate Longer TTNT and OS Over Taxane Treatment in mCRPC

Investigators report that immune checkpoint inhibitors (ICIs) were had longer time-to-next therapy (TTNT) and longer overall survival (OS) than taxanes in patients with metastatic castration-resistant prostate cancer (mCRPC) when a patient’s tumor mutational burden (TMB) was 10 mt/Mb or greater but not when TMB was less than 10 mt/Mb, according to a nonrandomized study published in Journal of the American Medical Association (JAMA) Network Open.²

Fewer patients with TMB of less than 10 mutationsper megabase (mt/Mb) receiving ICI had worse TTNT compared with patients receiving taxanes. The median TTNT for these patients was 2.4 months (range, 1.1-3.2) months vs 4.1 months (range, 2.2-6.3), respectively (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 was associated with more favorable TTNT compared with the use of taxanes. The median TTNT was 8.0 months (range, 3.4-unknown) vs 2.4 months (range, 2.4-7.3), respectively (HR, 0.37, 95% CI, 0.15-0.87; P = .02). The median (OS was 19.9 months (range, 8.06-unknown) vs 4.2 months (range, 2.69 – 6.12), respectively (HR, 0.23; 95% CI, 0.10-0.57; P = .001).

The study enrolled 741 men with a median age of 70 (range, 64-76) with mCRPC to receive comprehensive genomic profiling and were treated with ICI or single-agent taxane therapy. A total of 45 patients (6.1%) received ICI therapy and 696 patients (93.9%) received taxane therapy.

In a comparative effectiveness analysis of clinical variables and outcomes, investigators used prospectively defined biomarker-stratified genomic data from a deidentified clinicogenomic database. Data included men with previously treated mCRPC receiving ICI or single-agent taxane chemotherapy from January 2011 to April 2021.

Patients had a baseline median pretreatment prostate specific antigen (PSA) level of 79.4 (19.0-254) ng/mL. A total of 108 patients (18.8%) had tumors with ECOG performance status scores of 2 or greater, and 644 patients (86.9%) had received prior systemic treatments for mCRPC. Investigators notedno significant differences in age, pretherapy PSA levels, ECOG performance status score, practice setting (community vs academic), prior neoadjuvant hormonal therapy use, prior prescribed opioid use, and biopsy site between patients who received ICIs vs those who received taxanes.However, patients who received ICIs had a higher median TMB compared with those receiving taxanes (3.5 mt/Mb (1.7-15.0) vs 2.5 mt/Mb (1.3-3.8), respectively; P < .001).

Investigators explored the association between TMB and microsatellite instability (MSI). Of all 741 patients, 2 (<1%) had MSI- high (MSI-H) and TMB of fewer than 10 mt/Mb, 20 (2.7%) had MSI-H and TMB of 10 mt/Mb or greater, 24 (3.2%) had microsatellite stability (MSS) and TMB of 10 mt/Mb or greater, 601 (81%) had MSS and TMB of fewer than 10 mt/Mb, and 94 (12.7%) had TMB of fewer than 10 mt/Mb and had unknown or indeterminate microsatellite status.Patients who were MSI-H receiving ICIs had a favorable TTNT vs those receiving taxanes (HR, 0.38; 95% CI, 0.15-0.94; P = .04), but there was no significant difference in OS (HR, 0.44; 95% CI, 0.15-1.27; P = .13). Patients with TMB of 10 mt/Mb or greater receiving ICIs had better OS and TTNT with weaker treatment interactions.

In patients who received ICIs, the most common treatment received was pembrolizumab (Keytruda; 75.6%), nivolumab (Opdivo; 20%), and atezolizumab (Tecentriq; 4.4%). Patients who received taxanes were treated with docetaxel (50.9%) and cabazitaxel (Jevtana; 49.1%). Biospy sites were evaluated in the prostate (41.7%), the lymph nodes (16.5%), the liver (13.1%), and in other sites (28.7%) in all patients.

These 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.

_REFERENCES:

_{1. Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. J Clin Oncol. 2020;38(5):395-405. doi:10.1200/JCO.19.01638}

_{2. Graf RP, Fisher V, Weberpals J, et al. comparative effectiveness of immune checkpoint inhibitors vs chemotherapy by tumor mutational burden in metastatic castration-resistant prostate cancer. JAMA Netw Open. 2022;5(3):e225394. Published March 1, 2022. doi:10.1001/jamanetworkopen.2022.5394}