Refers to article:
Enzalutamide in Castration-resistant Prostate Cancer Patients Progressing After Docetaxel and Abiraterone
Accepted 21 June 2013
January 2014 (Vol. 65, Issue 1, pages 30 - 36)
A better understanding of castration-resistant prostate cancer (CRPC) biology over the past 10 yr has led to the addition of multiple agents to the therapeutic armamentarium for metastatic CRPC . In docetaxel-treated patients, two androgen pathway inhibitors have demonstrated an improvement in overall survival (OS): the CYP17 inhibitor abiraterone and the androgen receptor (AR) inhibitor enzalutamide  and . A second-generation taxane, cabazitaxel , and a bone-targeting radiopharmaceutical, radium-223 , also led to an improved OS in docetaxel-treated patients. The reduction in the risk of death achieved with these four agents in the post-docetaxel setting is in the 30% range. Abiraterone has also been studied in chemotherapy-naïve CRPC patients with a clear demonstration that progression-free survival is meaningfully improved . Along with abiraterone, radium-223 and sipuleucel-T  have also demonstrated survival benefits in docetaxel-naïve patients, raising the question of how these agents should be used to optimise their administration. Transition from one treatment to the next is usually based on a combination of clinical, biochemical, and radiologic measures and of course on US Food and Drug Administration and European Medicines Agency–guided indications, but a growing body of evidence suggests that this approach should no longer be followed in clinical practice.
In the current issue of European Urology, Schrader et al. provide data showing that enzalutamide therapy has limited activity in patients progressing after abiraterone . In this small retrospective study (n
Mechanisms of resistance to both enzalutamide and abiraterone are currently under study. Both agents target the same pathway, although at different steps. A recent preclinical study suggested that resistance to abiraterone may occur through induction of AR as well as AR splice variants that confer ligand-independent AR transactivation . Generation of AR splice variants lacking the ligand-binding domain has also been reported as a putative mechanism of resistance to enzalutamide . Cross-resistance might also involve steroidogenesis activation, as a recent study showed increased testosterone concentration in the bone marrow of patients treated with enzalutamide . Similar data were observed with abiraterone in some preclinical models of abiraterone-resistant CRPC . This selection of tumour cells with activation of steroidogenesis in response to enzalutamide treatment indicates that steroid production may provide a growth advantage and could be a contributing mechanism for resistance. The lack of significant anticancer activity of abiraterone and prednisolone following enzalutamide progression indicates, however, that increased steroidogenesis alone is unlikely to be the sole mechanism of resistance to enzalutamide. Another study showed that testosterone and dihydrotestosterone concentrations in bone marrow aspirates from CRPC patients treated with abiraterone remained low at progression . Concomitant treatment with enzalutamide and abiraterone might be more clinically useful than the sequential use of abiraterone followed by enzalutamide or vice versa to reverse drug resistance; this hypothesis is currently under investigation in clinical trials. An alternative mechanism of resistance is the ligandless activation of AR by oncogenic pathways such as the phosphatidylinositol 3-kinases (PI3K)–AKT signalling pathway. Several studies have demonstrated a crosstalk between the AR pathway and PI3K signalling in prostate cancer (PCa) models. Phase 1/2 trials assessing the combination of either abiraterone or enzalutamide with a PI3K/AKT/target of rapamycin inhibitor are now ongoing.
Because (partial) cross-resistance between taxanes and AR-directed agents have also been suggested by preclinical and clinical data showing that taxanes may also interfere with AR itself, it is critical that all these agents be appropriately selected for each patient. Ideally, these therapies should be offered based on individual biological or radiologic predictive factors. The characterisation of potential driving genomic alterations in CRPC may provide the opportunity for a better understanding of mechanisms of resistance to targeted therapies in CRPC. Whole-exome sequencing of large PCa cohorts report recurrent mutations; copy number alterations in several of the same genes and pathways (AR, MYC, PTEN, SPOP, MLL2); and translocations involving the genes of the ETS family of transcription factors, such as ERG and ETV1. Other aberrant, mutually exclusive gene alterations such as AKT,PIK3CA and BRAF mutations or FGFR fusions have also been reported at lower frequency. The whole genomic landscape of CRPC, with transcriptomics and metabolomics information, could be used to develop a biology-based personalised approach for patient with CRPC. Some academic centres are currently conducting biopsy-based molecular analyses, including the molecular profiling of tumours before and after therapy, to decipher the mechanisms of acquired resistance. With the evolving landscape of therapies and the extensive molecular and biologic characterisation of PCa, it is time for the development of clinical trials testing personalised treatment for CRPC.
Conflicts of interest
Dr. Loriot holds consultancies from Sanofi and grants from Sanofi and Astellas. Dr. Fizazi has received funding from Sanofi.
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Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris Sud, Villejuif, France Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris Sud, Villejuif, France
Corresponding author. Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris Sud, 114 rue Edouard Vaillant, 94800 Villejuif, France. Tel. +33 1 42 11 43 17; Fax: +33 1 42 115 211.
© 2013 Published by Elsevier B.V.