# KEYNOTE-199: pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer

Source: https://onco.cc/key-papers/paper-antonarakis-keynote-199-pembrolizumab-jco-2020/  
OnCo record `paper-antonarakis-keynote-199-pembrolizumab-jco-2020` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Checkpoint immunotherapy transformed several cancers and did almost nothing here. In 258 men with advanced prostate cancer, about 1 in 20 had a response, and whether the tumour expressed PD-L1 made no difference.

## Summary

Emmanuel Antonarakis, Johann de Bono and the KEYNOTE-199 investigators gave pembrolizumab 200 mg every three weeks to 258 men with metastatic castration-resistant prostate cancer who had already had docetaxel and at least one targeted endocrine therapy, in three parallel cohorts: measurable PD-L1-positive disease, measurable PD-L1-negative disease, and bone-predominant disease irrespective of PD-L1.

The response rates, 5 percent and 3 percent in the two measurable cohorts, are the clearest statement available of why prostate cancer is called an immunologically cold tumour, and they sit consistently with the genomics: a median tumour mutational burden of 2.6 mutations per megabase and only 4 percent mismatch repair deficiency (paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019). The responses that did occur were durable, which is why the field keeps returning to the question with combinations rather than abandoning it.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Also known as: KEYNOTE-199; Antonarakis 2020 pembrolizumab prostate
- Tags: prostate-evidence
- Journal: Journal of Clinical Oncology
- Year: 2020
- DOI: 10.1200/jco.19.01638
- Authors: Antonarakis ES, Piulats JM, Gross-Goupil M, et al.
- Findings: Objective response rate 5 percent (95 percent confidence interval 2 to 11) in cohort 1 (measurable, PD-L1-positive, 133 patients) and 3 percent (less than 1 to 11) in cohort 2 (measurable, PD-L1-negative, 66 patients).; Median duration of response was not reached in cohort 1 (range 1.9 to at least 21.8 months) and was 10.6 months in cohort 2 (range 4.4 to 16.8 months).; Disease control rate 10 percent in cohort 1, 9 percent in cohort 2 and 22 percent in cohort 3 (bone-predominant disease, 59 patients).; Median overall survival 9.5 months in cohort 1, 7.9 months in cohort 2 and 14.1 months in cohort 3.; Treatment-related adverse events occurred in 60 percent of patients, were grade 3 to 5 in 15 percent and led to treatment discontinuation in 5 percent.
- What it means: The measured size of the immunotherapy problem in prostate cancer: a response rate in the low single figures, no signal from PD-L1 expression, and durable benefit in a small subgroup nobody can yet identify prospectively. Any claim that immunotherapy is coming to prostate cancer has to explain this trial.
- Caveats: Single-arm phase 2 with no control, in a heavily pre-treated population, so the survival figures reflect prognosis as much as treatment.; PD-L1 positivity did not separate responders from non-responders, so it is not a usable biomarker here.; Mismatch repair status, which does predict response to checkpoint blockade in prostate cancer as elsewhere, was not the selection criterion; the responders in cohort 3 in particular remain unexplained.

## Sources

- J Clin Oncol 2020: https://doi.org/10.1200/jco.19.01638
- PubMed: https://pubmed.ncbi.nlm.nih.gov/31774688/
- ClinicalTrials.gov NCT02787005: https://clinicaltrials.gov/study/NCT02787005

## Connected records

- key papers: [Cabozantinib plus atezolizumab in metastatic prostate cancer (CONTACT-02): final analyses from a phase 3, open-label, randomised trial](https://onco.cc/key-papers/paper-nct04446117-lancet-oncol-2025/), [Pembrolizumab Plus Docetaxel and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort B Study](https://onco.cc/key-papers/paper-nct02861573-eur-urol-2022/), [Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours](https://onco.cc/key-papers/paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019/), [Sipuleucel-T immunotherapy for castration-resistant prostate cancer](https://onco.cc/key-papers/paper-kantoff-n-engl-j-med/)
- roadmaps: [Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch](https://onco.cc/roadmaps/prostate-roadmap/)
- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- fronts: [Immunotherapy](https://onco.cc/fronts/immunotherapy/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- drugs: [Docetaxel](https://onco.cc/drugs/docetaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- companies: [Merck & Co. (MSD)](https://onco.cc/companies/merck/)
- terms: [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)
- people: [Johann de Bono](https://onco.cc/people/johann-de-bono/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/), [No one can predict who responds to immunotherapy](https://onco.cc/bottlenecks/b-immunotherapy-response/)
- journals: [Journal of Clinical Oncology](https://onco.cc/journals/jco/)

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