The Role of Histology-Agnostic Drugs in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Abstract

Precision medicine has opened up a new era in the development of anti-cancer agents that is focused on identifying biomarkers predictive of treatment response regardless of tumor histology. Since 2017, the Food and Drug Administration has approved six drugs with histology-agnostic indications: pembrolizumab (both for tumors with the mismatch-repair deficiency (dMMR)/high microsatellite instability (MSI-H) phenotype and for those with the high tumor mutational burden (TMB-H) phenotype), dostarlimab (for dMMR tumors), larotrectinib and entrectinib (for tumors harboring neurotrophic tyrosine receptor kinase (NTRK) fusions), and the combination of dabrafenib plus trametinib (for BRAF V600E-mutated tumors). The genomic alterations targeted by these antineoplastic agents are rare in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, only a small number of mCRPC patients were enrolled in the clinical trials that led to the approval of the above-mentioned drugs. Therefore, we critically reviewed the literature on the efficacy of histology-agnostic drugs in mCRPC patients. Although the available evidence derives from retrospective studies and case reports, our results confirmed the efficacy of pembrolizumab in dMMR/MSI-H mCRPC. In contrast, few data are available for dostarlimab, larotrectinib, entrectinib, and dabrafenib-trametinib in this subset of patients. Large, multi-institutional registries aimed at collecting real-world data are needed to better comprehend the role of tissue-agnostic drugs in mCRPC patients.

Androgen Metabolism and Response in Prostate Cancer Anti-Androgen Therapy Resistance

“…ADT therapy can promote tumor dormancy, prolong the survival of patients, and improve the quality of life, but it can rarely cure prostate cancer, and most tumors will recur [ 110 , 111 ]. Tumor resistance to ADT is cumulative: with the change of lineage, some tumor cells will eventually lose AR expression and develop into small cell carcinoma; this type of tumor is called neuroendocrine prostate cancer (NEPC), and this type of cancer cells express neuroendocrine markers, mostly induced by treatment, and a small part is primary, and does not respond to ARSI et al [ 112 ]. Developing new treatments for this type of cancer is an urgent problem for basic research.…”

Androgen Receptor Signaling Inhibition in Advanced Castration Resistance Prostate Cancer: What Is Expected for the Near Future?

“…The identification of different mCRPC phenotypes may prove to be clinically relevant. Aside from the agnostic FDA approval of pembrolizumab [ 148 ] and dostarlimab for MSI-H or dMMR/TMB-H [ 149 ] and for dMMR tumors [ 150 ], respectively, there are clinical trials ongoing testing immune checkpoint inhibitors (ICIs) in selected patients with mCRPC. In the KEYNOTE-199 trial, pembrolizumab in PD-L1 positive mCRPC previously treated with docetaxel and endocrine therapy showed a disease control rate (DCR) of 10% and a median OS of 9.5 months [ 151 ].…”

Immunotherapy for Prostate Cancer: A Current Systematic Review and Patient Centric Perspectives

“…Both of these are immune checkpoint inhibitors that target the PD-1/PD-L1 pathways; these are approved among the subset of patients with DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI-H), or high mutational burden (TMB-H). Notably, the FDA has approved six drugs since 2017 which have histology-agnostic indications of interest in metastatic castration-resistant PC [ 24 ]. These include pembrolizumab (tumors with dMMR/high MSI), dostarlimab (dMMR tumors), entrectinib and lartotrectinib (tumors with neurotrophic tyrosine receptor kinase fusions), and trametinib combined with dabrafenib (tumors with BRAF V600E mutations) [ 24 ].…”

“…Notably, the FDA has approved six drugs since 2017 which have histology-agnostic indications of interest in metastatic castration-resistant PC [ 24 ]. These include pembrolizumab (tumors with dMMR/high MSI), dostarlimab (dMMR tumors), entrectinib and lartotrectinib (tumors with neurotrophic tyrosine receptor kinase fusions), and trametinib combined with dabrafenib (tumors with BRAF V600E mutations) [ 24 ].…”