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A real-world experience of pembrolizumab monotherapy in microsatellite instability-high and/or tumor mutation burden-high metastatic castration-resistant prostate cancer: outcome analysis

Prostate Cancer and Prostatic Diseases (2024)Cite this article

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Abstract

Background

The efficacy of pembrolizumab monotherapy in metastatic castration-resistant prostate cancer patients (mCRPC) when stratified by MSI-H and/or TMB-H is poorly defined. Additionally, outcomes based on sequencing source (i.e., tissue or liquid biopsy) have not been well described. We sought to assess outcomes of pembrolizumab monotherapy in patients with mCRPC and compare efficacy based on MSI-H and/or TMB-H when identified by tissue or liquid biopsy.

Methods

A retrospective analysis was performed of mCRPC patients treated at Mayo Clinic with pembrolizumab monotherapy between 2018 and 2023. Objective response rates (ORR), median progression-free survival (mPFS), and overall survival (mOS), were determined by RECIST v1.1 criteria.

Results

Twenty-two patients with mCRPC received pembrolizumab monotherapy for at least 3 cycles for a MSI-H or TMB-H indication. All patients had next generation sequencing (NGS) performed via tissue (n = 11) or liquid (n = 10) biopsy source. The ORR was 50% (27.3% complete response and 22.7% had partial response). The mPFS for TMB 10-14.9 mut/Mb (n = 4), TMB 15–24.9 mut/Mb (n = 6), and TMB ≥ 25 mut/Mb (n = 10) was 2.1, not reached (NR), and NR, respectively (p = 0.0003). The mOS for these same groups was 5.1 months, 20.5 months, and not reached, respectively. Among patients with TMB-H without co-occurring MSI-H or CDK12 (n = 6), none experienced a response and only one patient had stable disease compared to patients with MSI-H (n = 12) for whom the ORR was 75%. Immunotherapy responsive alterations such as ATRX and PTCH1 mutations were frequently noticed among patients who had complete response (CR).

Conclusions

Our hypothesis-generating study suggests that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12.

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Fig. 1: Efficacy of pembrolizumab in patients with mCRPC.
Fig. 2: Patients PSA response to pembrolizumab.
Fig. 3: Survival of patients receiving pembrolizumab.

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Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA

    Osama Mosalem, Winston Tan, Roxana S. Dronca & Adam M. Kase

  2. Division of Hematology and Oncology, Department of Internal Medicine, Mayo Clinic, Phoenix, AZ, 85054, USA

    Alan H. Bryce

  3. Department of Medical Oncology, Mayo Clinic, Rochester, MN, 55902, USA

    Daniel S. Childs, Lance C. Pagliaro & Jacob J. Orme

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Contributions

Protocol / project development: OM, AK. Data collection or management: OM, AK. Data analysis: OM, AK. Manuscript writing / editing: OM, AK, JO, WT. Other (Interpretation of data and revision): OM, WT, AB, RD, DC, LP, JO, AK.

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Correspondence to Adam M. Kase.

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Competing interests

LCP; research support from Exelixis. DSC; Honoria from Targeted Oncology, IntrinsiQ MJH Life Sciences, International Centers for Precision Oncology Foundation. Consulting or advisory for Janssen Biotech and Novartis.

Ethics approval

Institutional review board approval IRB: 19-009479. The study was performed in accordance with the Declaration of Helsinki.

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Mosalem, O., Tan, W., Bryce, A.H. et al. A real-world experience of pembrolizumab monotherapy in microsatellite instability-high and/or tumor mutation burden-high metastatic castration-resistant prostate cancer: outcome analysis. Prostate Cancer Prostatic Dis (2024). https://doi.org/10.1038/s41391-024-00799-y

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