KEYNOTE-199: Pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC).

Bono, Johann S. de; Goh, Jeffrey C.; Ojamaa, Kristiina; Rodriguez, J.M. Piulats; Drake, Charles G.; Hoimes, Christopher J.; Wu, Haiyan; Poehlein, Christian; Antonarakis, Emmanuel S.

doi:10.1200/jco.2018.36.15_suppl.5007

Cited by 83 publications

(63 citation statements)

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“…The current PC-related medical literature describes a few PD-1 axis checkpoint inhibitor therapy successes with some highly promising results with pembrolizumab monotherapy. [1][2][3][4][5]7,11,12 The recent approval of pembrolizumab for MSI-H solid neoplasms is the only current indication for ICI therapy in PC. Despite these encouraging results, additional immune-related targets are needed.…”

Section: Discussionmentioning

confidence: 99%

“…A pembrolizumab monotherapy study of 23 heavily pretreated PC with at least 1% positivity for PD‐L1 immunohistochemistry in tumor or stroma cells demonstrated an overall response rate of 13% . A subsequent pembrolizumab monotherapy study of 258 docetaxel‐refractory metastatic CRPC demonstrated a disease control rate of 26% …”

Section: Introductionmentioning

confidence: 99%

“…11 A subsequent pembrolizumab monotherapy study of 258 docetaxel-refractory metastatic CRPC demonstrated a disease control rate of 26%. 12 Our knowledge of the immune microenvironment of PC is limited.…”

Section: Introductionmentioning

confidence: 99%

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Identification of targets for prostate cancer immunotherapy

et al. 2019

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Background We performed profiling of the immune microenvironment of castration‐resistant (CRPC) and castration‐sensitive (CSPC) prostate cancer (PC) in order to identify novel targets for immunotherapy. Methods PD‐L1 and CD3/CD8 immunohistochemistry, PD‐L1/2 fluorescent in situ hybridization, tumor mutation burden, microsatellite instability, and RNA‐seq of 395 immune‐related genes were performed in 19 CRPC and CSPC. Targeted genomic sequencing and fusion analysis were performed in 17 of these specimens. Results CD276, PVR, and NECTIN2 were highly expressed in PC. Comparison of CRPC versus CSPC and primary versus metastatic tissue revealed the differential expression of immunostimulatory, immunosuppressive, and epithelial‐to‐mesenchymal transition (EMT)‐related genes. Unsupervised clustering of differentially expressed genes yielded two final clusters best segregated by CRPC and CSPC status. Conclusion CD276 and the alternative checkpoint inhibition PVR/NECTIN2/CD226/TIGIT pathway emerged as relevant to PC checkpoint inhibition target development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of targets for prostate cancer immunotherapy

et al. 2019

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“…In cluster A, we observed a high TMB which has been associated in other tumor types with a high sensitivity to immune check-point inhibitors 9,11,12 . Clinical trials using pembrolizumab in selected mCRPC patients are underway (KEYNOTE-028, KEYNOTE-199) 36,37 . Interestingly, in both cluster B and cluster D, we identified patients that do not have the defining biallelic CDK12 or BRCA2 (somatic) mutation.…”

Section: Discussionmentioning

confidence: 99%

The genomic landscape of metastatic castration-resistant prostate cancers using whole genome sequencing reveals multiple distinct genotypes with potential clinical impact

Dessel

Riet

Smits

et al. 2019

Preprint

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43Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. 44With the recent development of novel treatments, accurate stratification strategies are needed. Here 45 we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 46 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight 47 distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite 48 instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and 49 BRCA2 aberrations, a tandem duplication genotype associated with CDK12 -/and a chromothripsis-50 enriched subgroup. Our data suggests that stratification on WGS characteristics may improve 51 identification of MSI, CDK12 -/and HRD patients. From WGS and ChIP-seq data, we show the 52 potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight 53 the central role of AR signaling in tumor progression. These data underline the potential value of 54 using WGS to accurately stratify mCRPC patients into clinically actionable subgroups. 55 157This analysis did not reveal systematic biases due to pre-treatment in aberrations, such as TMB, 158 kataegis, chromothripsis, ETS fusions, or somatically altered genes ( Supplementary table 3). 159 Methods 657 Patient cohort and study procedures 658 b * * c i j k l m Cluster A Cluster B Cluster C Cluster D Cluster E Cluster F Cluster G Cluster H

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“…Indeed, the PD‐1 inhibitor pembrolizumab was recently approved for any solid metastatic tumours with microsatellite instability or MMR deficiency. Most prostate cancers have a low mutation rate, and there is a very low response rate to checkpoint inhibition in unselected patients . However, hypermutated MMR‐deficient prostate cancers can have strong responses ; for example, in a recent large pan‐cancer clinical sequencing initiative, a 55‐year‐old patient with a pathogenic germline MUTYH mutation and enzalutamide‐resistant mCRPC was identified.…”

Section: Efficacy Of Immune Checkpoint Inhibitors In Mmr‐deficient Prmentioning

confidence: 99%

DNA repair defects in prostate cancer: impact for screening, prognostication and treatment

Warner

Yip

et al. 2018

BJU International

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Failure of effective DNA damage repair is a hallmark of cancer, but was previously underappreciated as a driver of aggressive prostate cancer. However, recent international sequencing efforts have revealed that both germline and somatic alterations within the homologous recombination and mismatch repair pathways are relatively common in lethal metastatic disease. BRCA2 gene alterations are particularly prevalent and are linked to poor prognosis as well as poor responses to systemic therapy for castrationresistant prostate cancer, although there is conflicting support for the latter. Defective DNA repair contributes to tumour heterogeneity, evolution and progression, but there are high hopes that management of this aggressive subset will be transformed by biomarker-driven use of poly-ADP ribose polymerase (PARP) inhibitors and platinum-based chemotherapy. In this review, we detail the relationship between DNA repair defects and prostate cancer, highlighting the prevalence of mutations in key genes and their controversial association with clinical outcomes.

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KEYNOTE-199: Pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC).

Cited by 83 publications

References 0 publications

Identification of targets for prostate cancer immunotherapy

Identification of targets for prostate cancer immunotherapy

The genomic landscape of metastatic castration-resistant prostate cancers using whole genome sequencing reveals multiple distinct genotypes with potential clinical impact

DNA repair defects in prostate cancer: impact for screening, prognostication and treatment

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