ESMO E-Learning: Emerging Treatments for Managing mCRPC Patients
- To discuss increased insight into prostate cancer biology and a rationale for manipulating with blockade of underlining signaling pathway in the development of novel targeted treatments
- To review a mechanism of action and clinical data on emerging therapies in the management of patients with metastatic castration resistant prostate cancer (mCRPC)
- To provide an update on progress made in designing novel treatments for patients with mCRPC and critically discuss how to use them in the clinical context
|Title||Duration||Content||CME Points||CME Test|
|Emerging Treatments for Managing mCRPC Patients||12 min.||22 slides||1||Take Test|
The backbone of this E-Learning module is the elaboration on androgen receptor (AR) signalling as a therapeutic target and understanding of other mechanisms in prostate carcinogenesis that led to progress in the treatment of patients with metastatic castration resistant prostate cancer, rarely seen in the oncology field. Prof Johan de Bono, a world renowned expert, explains step by step the successful transition from chemistry design to the clinical use of abiraterone, sipuleucel-T, cabazitaxel, apharadin, and MDV3100.
The module starts with an observation from the past when hormonal treatment continued to have antitumour activity and observed high levels of intratumoural androgens despite castration that in fact indicated intracrine synthesis. It is now known that castration resistance is associated with AR Amplification, AR Mutations that increase AR (transcriptional) activity, increased AR (< 2x) expression (Ligand driven) in isogenic resistant prostate cancer cell lines, and AR is also reactivated in abiraterone and MDV3100 resistant prostate cancer. In addition oncogenic translocations/fusions driven by androgens plus oestrogen-response elements have been identified.
The fact that “hormone refractory” prostate cancer frequently remained driven by a ligand-activated androgen receptor, led academic researchers in UK to the chemical development of abiraterone. Later in the clinical development of the drug, it has been characterised as a major breakthrough in prostate cancer management.
Today there are multiple lines of treatment for advanced prostate cancer that improve overall survival (sipuleucel-T, docetaxel, abiraterone, cabazitaxel, MDV3100, alpharadin). However, optimal sequence of drugs administration now needs to be defined, as well as combination therapies. In addition, some drugs seem to express cross-resistance and it is likely that abiraterone will move into pre-chemotherapy arena.
The module states there are more than 20 different types of prostate cancers, and all with different “drivers”. Furthermore it touches a base of personalised oncology and a concept of clinical trials through patient selection based on sequencing.
A message from this E-Learning module could be that advanced prostate cancer is not hormone refractory, nor androgen independent; it remains nuclear steroid receptor driven even after abiraterone and MDV3100. The fact that hormone therapy works after chemotherapy is important since overall survival remains the only robust registration endpoint. At the end maximal androgen blockade is a misnomer. This module is an excellent update for all those interested in the use of these emerging therapies in patients with advanced prostate cancer.
The author is an employee of The Institute of Cancer Research which has a commercial interest in Abiraterone. Prof de Bono has served as a paid advisor for J&J, Medivation, Astellas and Sanofi.