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.

Keywords: BRAF V600E; MSI-H; NTRK; TMB-H; dMMR; histology-agnostic; prostate cancer.

Figure 1

In normal cells, the MMR system guarantees DNA fidelity by detecting (MSH2/MSH6 complex) and repairing (MLH1/PMS2 complex) genetic mismatches that occurred during DNA replication. In contrast, dMMR/MSI-H tumor cells are not able to repair DNA mismatches in microsatellites and, consequently, are characterized by an accumulation of genomic alterations, which result in a higher quantity of neoantigens. This immunogenic phenotype is generated by a higher genomic mutational burden and provides dMMR/MSI-H tumors with an increased susceptibility to the reactivation of the anti-cancer response when treated with immune checkpoint inhibitors. “Created with BioRender.com”.

Figure 2

TMB-H tumors are characterized by higher levels of production of tumor-specific mutant epitopes that may function as neoantigens identified as “non-self” by the immune system. Hyper-mutated tumors (bottom) are more responsive than hypo-mutated tumors (top) to immune checkpoint inhibitors. “Created with BioRender.com”.

Figure 3

The interaction between ligands and TRK receptors generates TRK receptor dimerization, activating crosstalk between multiple intracellular signaling pathways involving PI3K and mitogen-activated protein kinase pathways. Abbreviations: protein kinase B (AKT); diacylglycerol (DAG); extracellular signal-regulated kinase (ERK-1); GRB2-associated binding protein-1 (GAB-1); growth factor receptor-bound protein-2 (GRB-2); inositol trisphosphate (IP-3); mitogen-activated protein kinase kinase (MEK); mammalian target of rapamycin (m-TOR); nuclear factor kinase-β (NF-Kβ); 3-phosphoinositide-dependent protein kinase-1 (PDK-1); protein kinase C (PKC); phospholipase C-γ (PLC-γ); rapidly accelerated fibrosarcoma (RAF); rat sarcoma virus (RAS); Son of sevenless (SOS). “Created with BioRender.com”.

Figure 4

The RAS/RAF/MEK/ERK pathway is an essential molecular pathway among all MAPK signal transduction pathways and plays a crucial role in several cellular processes, including proliferation, differentiation, apoptosis, and stress responses. Abbreviations: ETS-like-1 (ELK-1); extracellular signal-regulated kinase (ERK); mitogen-activated protein kinase (MEK); rapidly accelerated fibrosarcoma (RAF); rat sarcoma virus (RAS). “Created with BioRender.com”.