Targeting the N-Terminal Domain of the Androgen Receptor: A New Approach for the Treatment of Advanced Prostate Cancer.

: Despite the recent approval and widespread use of abiraterone acetate and enzalutamide for the treatment of castration-resistant prostate cancer (CRPC), this disease still poses significant management challenges because of various tumor escape mechanisms, including those that allow androgen receptor (AR) signaling to remain active. These AR-related resistance mechanisms include AR gene amplification or overexpression, constitutively active ligand-independent AR splice variants, and gain-of-function mutations involving the AR ligand-binding domain (LBD), among others. Therefore, the development of AR-targeted therapies that function independently of the LBD represents an unmet medical need and has the potential to overcome many of these resistance mechanisms. This article discusses N-terminal domain (NTD) inhibition as a novel concept in the field of AR-directed therapies for prostate cancer. AR NTD-targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR-mediated transcriptional activity, and as a result, may affect a broader AR population including mutational and splice variant ARs. Indeed, the first clinical trial of an AR NTD inhibitor is now underway. IMPLICATIONS FOR PRACTICE: Because of emerging resistance mechanisms that involve the ligand-binding domain of the androgen receptor (AR), there is currently no effective treatment addressing tumor escape mechanisms related to current AR-targeted therapies. Many patients still demonstrate limited clinical response to current hormonal agents, and castration-resistant prostate cancer remains a lethal disease. Intense research efforts are under way to develop therapies to target resistance mechanisms, including those directed at other parts of the AR molecule. A novel small-molecule agent, EPI-506, represents a new pharmaceutical class, AR N-terminal domain inhibitors, and shows preclinical promise to overcome many known resistance mechanisms related to novel hormonal therapies.

Cumulative summation graphs are a useful tool for monitoring positive surgical margin rates in robot-assisted radical prostatectomy.

OBJECTIVE: • To explore the usefulness of cumulative summation (CUSUM) graphs for monitoring positive surgical margin (PSM) rates during a surgeon's transition from open to robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: • Data were prospectively collected from patients undergoing RARP by a single surgeon. • Preoperatively all patients were either low or moderate risk under the D'Amico classification system. • A CUSUM graph was charted retrospectively to analyse the PSM rate in patients undergoing RARP for pathological stage T2 (pT2) disease. • Acceptable and unacceptable PSM rates were set at 10% and 15% respectively. RESULTS: • From a cohort of 226 patients, 158 patients with pT2 disease were selected. The mean (range) age of these patients was 59.2 (39-73) years, the median (range) Gleason score was 6 (4-9), the mean (range) PSA was 6.43 (0.52-17.5) ng/mL and the mean (range) prostate volume was 44 (18-120) cm(3). In all, 21 patients had PSMs (13%). • CUSUM graphs were produced and clearly demonstrated the change in PSM rate over time. CONCLUSION: • CUSUM graphs are a novel and useful visual representation of the learning curve for surgeons. • PSM rates in patients with pT2 disease are a good outcome to monitor using CUSUM graphs as they are binary and lack the confounding factors associated with other outcomes such as continence and erectile dysfunction. • We advocate the use of CUSUM graphs as a method of quality assurance with the introduction of a robotics programme.