Novel targeted therapeutics for metastatic castration-resistant prostate cancer

Abstract

Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard of care for these patients and is associated with a modest prolongation of survival, there is an urgent need for novel treatment strategies for metastatic prostate cancer. In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. This review discusses some of the key therapeutic agents that have emerged for the treatment of metastatic castration-resistant prostate cancer in the last 5 years, with an emphasis on both molecular targets and clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists, receptor activator of nuclear factor κB (RANK) ligand inhibitors, vitamin D analogues, cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents.

Introduction

Prostate cancer is the most common malignancy in men worldwide. In the United States, there were an estimated 186,300 new diagnoses of prostate cancer and 28,700 prostate cancer deaths in 2008, representing 25% of new cancer cases and 10% of male cancer deaths [1]. This makes prostate cancer the second leading cause of cancer death in men. While the disease can potentially be cured when localized, metastatic prostate cancer remains incurable.

Treatment of localized prostate cancer is usually centered around surgery and/or radiation therapy. However, even after definitive local therapy, approximately 30–50% of patients will have a local or distant recurrence [2], [3]. Patients with metastatic prostate cancer have a median survival of 3–7 years, and most men die of it [2]. Treatment for metastatic disease involves surgical castration or hormonal manipulation using gonadotropin-releasing hormone (GnRH) agonists, antiandrogens, or both. Although the majority of these patients initially respond to androgen deprivation therapy, all eventually progress to a state of castration-resistant prostate cancer (CRPC). Treatment options for these men are limited. Secondary hormonal manipulations, such as ketoconazole, are often used but these produce short-lived responses and do not improve survival [4]. Other acceptable approaches in these men include watchful waiting until the development of symptoms, or the initiation of cytotoxic chemotherapy. In this regard, the chemotherapeutic agent docetaxel has been shown to improve overall survival in patients with CRPC, but only by a median of 2.9 months (median survival 19.2 months versus 16.3 months using mitoxantrone, P = .004) [5], [6]. Novel therapies for this patient population are urgently needed.

Since the approval of docetaxel by the Food and Drug Administration (FDA) in 2004, no new anti-cancer therapies have entered the market for the treatment of metastatic CRPC. On the other hand, the number of agents for CRPC in various stages of clinical development is higher than ever before. This has been made possible due to our accelerated understanding of the biological and molecular mechanisms underpinning prostate cancer growth and spread, which has fueled an expansion in research on new therapeutic approaches. This review will highlight novel targeted therapies that have emerged for CRPC in the last 5 years, focusing on the mechanism of action and developmental status of some key clinical compounds that have reached phase II and III clinical trials (Table 1). Advances in chemotherapeutic drugs, hormonal agents, and bisphosphonates will not be discussed herein.