Management of Castration-Resistant Prostate Cancer in 2011

Introduction

It is estimated that one in six men will be diagnosed with prostate cancer at some time during their lifetime, with a predicted 217730 new diagnoses and 32050 deaths attributable to prostate cancer in the United States in 2010. The wide application of prostate-specific antigen (PSA) screening has resulted in a shift toward patients being diagnosed with earlier stage disease and a decrease in the presence of metastases at diagnosis. However, a significant number of patients still present with advanced disease and up to 40% of patients treated with primary radical prostatectomy or radiation therapy with curative intent will experience disease progression. For a large proportion of these patients, hormonal therapy in the form of medical or surgical castration (ie, androgen deprivation therapy, ADT) can improve survival. However, despite being treated with ADT, cancer cells can develop into a castration-resistant disease state. There are a number of mechanisms that contribute to the development of castration-resistant prostate cancer (CRPC), including reactivation of androgen receptors (AR) despite castrate levels of circulating androgens, as well as the development of neuroendocrine differentiation and transformation to an AR-negative, truly hormone refractory neuroendocrine prostate cancer. Cancer cells usually develop resistance around 1–3 years after the start of systemic therapy, and those patients who suffer from CRPC have an average survival of approximately 30 months. The poor quality of life and prognosis of these patients have invigorated research with the goal of understanding the principal biology behind prostate cancer progression and identifying novel therapeutic agents. In this article, we will first focus on novel CRPC biomarkers as well as first- and second-line therapeutic approaches to CRPC.

Abstract

INTRODUCTION

Despite stage migration with the advent of prostate-specific antigen (PSA) screening, many patients still present with metastatic prostate cancer or experience disease progression following aggressive primary therapy. Androgen deprivation therapy is the initial therapy for metastatic prostate cancer. Although highly effective, all men eventually experience disease progression to a castrate-resistant status. Those patients who suffer from castration-resistant prostate cancer (CRPC) have a median survival of approximately 1–3 years. Treatment for CRPC has primarily been chemotherapy-based; however, in the last few years there have been several new therapeutic developments.

OBJECTIVES

In this review, we explore both first- and second-line therapies for CRPC.

METHODS

A Medline search was conducted using the keywords prostate cancer and castration resistant. Original articles, review articles, and editorials were critically reviewed and summarized.

RESULTS

Treatments that will be discussed include docetaxel-based combinations, new cytotoxic agents, src inhibitors, immunotherapy vaccines, and novel targets. When discussing these therapeutic strategies, we must consider how the trials are evaluated. We will discuss PSA, circulating tumor cells, progression-free survival, overall survival, and other endpoints for evaluating response. Docetaxel and sipuleucel-T are currently the best first-line treatment options for CRPC and cabazitaxel seems to be the best option for patients who fail docetaxel and sipuleucel-T. Among the first-line treatment options for patients with CRPC, the data supporting docetaxel are at this time stronger than those for sipuleucel-T.

CONCLUSIONS

Patients suffering from CRPC have very poor survival, underscoring the unmet need for novel therapeutics. Although many agents appear promising, well-designed randomized phase III trials are necessary to establish their impact on survival and quality of life. Promising new therapies include hormonal manipulations such as abiraterone and MDV3100 as well as anti-prostate specific membrane antigen treatments.

Keywords

castration-resistant prostate cancer, prostate-specific antigen, docetaxel, cytotoxic agents, first-line therapy, second-line therapy