John A. Fracchia

Enthusiasm continues in the medical community anxious for effective agents for men with metastatic castration-resistant prostate cancer (mCRPC). Most prostate cancer patients who develop metastatic disease are initially treated with readily available luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, with or without an anti-androgen. The rationale here is to decrease androgen levels and/or block androgen receptor (AR) binding. In patients whose disease becomes refractory to this front-line hormonal deprivation, the molecular mechanisms involved in androgen independence include androgen receptor gene amplification, AR mutations that allow stimulation by a variety of weak androgens, and AR activation by autocrine production of androgens from tumor cells. Patients with metastatic castration-resistant prostate cancer (mCRPC) who biochemically recur after androgendeprivation therapy with significant prostate-specific antigen (PSA) elevations and/or who develop radiographic or symptomatic metastases are then usually considered for cytotoxic chemotherapy. The only approved initial cytotoxic chemotherapeutic agent that has demonstrated improved survival for patients with mCRPC is docetaxel. For patients who fail docetaxel, cabazitaxel with prednisone is an approved second-line treatment. Similarly, another approved second-line treatment (albeit, hormonal) for patients who have failed docetaxel therapy is abiraterone acetate, which attacks the adrenal and extragonadal synthesis of androgen. The magnitude of this effect was not appreciated until it was recognized that the androgen receptor and ligand-dependent androgen receptor signaling remain active and upregulated in men with castrate levels of testosterone ( 50 ng/dL).1 Recognition of the importance of the signaling of the androgen receptor and its seemingly independent behavior in a milieu of little or no androgen is now appreciated.

Enthusiasm continues in the medical community anxious for effective agents for men with metastatic castration-resistant prostate cancer (mCRPC). Most prostate cancer patients who develop metastatic disease are initially treated with readily available luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, with or without an anti-androgen. The rationale here is to decrease androgen levels and/or block androgen receptor (AR) binding. In patients whose disease becomes refractory to this front-line hormonal deprivation, the molecular mechanisms involved in androgen independence include androgen receptor gene amplification, AR mutations that allow stimulation by a variety of weak androgens, and AR activation by autocrine production of androgens from tumor cells. Patients with metastatic castration-resistant prostate cancer (mCRPC) who biochemically recur after androgendeprivation therapy with significant prostate-specific antigen (PSA) elevations and/or who develop radiographic or symptomatic metastases are then usually considered for cytotoxic chemotherapy. The only approved initial cytotoxic chemotherapeutic agent that has demonstrated improved survival for patients with mCRPC is docetaxel. For patients who fail docetaxel, cabazitaxel with prednisone is an approved second-line treatment. Similarly, another approved second-line treatment (albeit, hormonal) for patients who have failed docetaxel therapy is abiraterone acetate, which attacks the adrenal and extragonadal synthesis of androgen. The magnitude of this effect was not appreciated until it was recognized that the androgen receptor and ligand-dependent androgen receptor signaling remain active and upregulated in men with castrate levels of testosterone ( 50 ng/dL).1 Recognition of the importance of the signaling of the androgen receptor and its seemingly independent behavior in a milieu of little or no androgen is now appreciated.

Enthusiasm continues in the medical community anxious for effective agents for men with metastatic castration-resistant prostate cancer (mCRPC). Most prostate cancer patients who develop metastatic disease are initially treated with readily available luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, with or without an anti-androgen. The rationale here is to decrease androgen levels and/or block androgen receptor (AR) binding. In patients whose disease becomes refractory to this front-line hormonal deprivation, the molecular mechanisms involved in androgen independence include androgen receptor gene amplification, AR mutations that allow stimulation by a variety of weak androgens, and AR activation by autocrine production of androgens from tumor cells. Patients with metastatic castration-resistant prostate cancer (mCRPC) who biochemically recur after androgendeprivation therapy with significant prostate-specific antigen (PSA) elevations and/or who develop radiographic or symptomatic metastases are then usually considered for cytotoxic chemotherapy. The only approved initial cytotoxic chemotherapeutic agent that has demonstrated improved survival for patients with mCRPC is docetaxel. For patients who fail docetaxel, cabazitaxel with prednisone is an approved second-line treatment. Similarly, another approved second-line treatment (albeit, hormonal) for patients who have failed docetaxel therapy is abiraterone acetate, which attacks the adrenal and extragonadal synthesis of androgen. The magnitude of this effect was not appreciated until it was recognized that the androgen receptor and ligand-dependent androgen receptor signaling remain active and upregulated in men with castrate levels of testosterone ( 50 ng/dL).1 Recognition of the importance of the signaling of the androgen receptor and its seemingly independent behavior in a milieu of little or no androgen is now appreciated.