Abstract and Introduction
Historically, patients diagnosed with castration-resistant prostate cancer (CRPC) have had poor survival rates. In recent years there have been significant advances in the treatment of CRPC. In addition to cytotoxic chemotherapy, treating physicians and their patients now have the option of several new agents that target not only androgen- and cytotoxic-mediated pathways, but also the patient's own immune system. In this review, we discuss the existing US FDA-approved therapies, a wide range of experimental treatments that are currently in development, and also palliative options for patients with symptoms secondary to metastatic disease. We also discuss the progression-free survival, overall survival, PSA levels and other end points used in clinical trials in order to evaluate and compare novel therapeutic options for CRPC. Currently, docetaxel and sipuleucel-T are the first line treatment options for patients with CRPC; approved second-line treatments for first line treatment failure are limited to cabazitaxel and abiraterone acetate. Recently, a few experimental agents, MDV3100 and radium-223, have demonstrated efficacy in improving overall survival in patients who had previously failed chemotherapy. These agents, and possibly others introduced in this review, are positioned to change the treatment landscape for CRPC.
Prostate cancer is the most commonly diagnosed malignancy among men in the USA, and is the second most common cause of cancer mortality in that group. It is estimated that one in six American men will receive a diagnosis of prostate cancer at some point in their lives, at an average age of 68 years. In 2010, there were 217,730 newly diagnosed cases and 32,050 deaths from prostate cancer in the USA alone.
Localized prostate cancer is potentially curable with the use of one or a combination of modalities including brachytherapy, cryotherapy, external beam radiation therapy (RT), hormone therapy and/or radical prostatectomy (RP).[3,4] Although less than 5% of patients initially present with metastatic disease, up to 40% of men diagnosed with localized prostate cancer go on to develop metastatic disease after undergoing local therapy with curative intent.
Metastases from prostate cancer are most often seen in the bone. These are predominantly osteoblastic, and occur in more than 80% of men with metastatic prostate cancer.[6,7] Bone metastases can cause substantial pain, increased risk of fractures and eventual neurologic sequelae. Once the disease metastasizes, it is considered incurable and all further treatments are palliative. Medical or surgical castration (i.e., androgen deprivation therapy [ADT]) can be utilized in these patients to reduce tumor burden, alleviate symptoms and prolong overall survival.
Localized and regional prostate cancer can be treated primarily with RP or RT. Patients receiving these therapies have 10-year survival rates ranging from 85 to 95%.[10–12] The management of advanced and metastatic disease, however, is more difficult and requires systemic treatment with either hormonal (i.e., androgen deprivation) therapy or chemotherapy. Since androgens are the main regulators of prostate cancer growth, the rationale for ADT is that tumor cells deprived of key hormonal growth regulators will either undergo apoptosis or survive in an arrested state in the G1 phase of the cell cycle. The median duration of response to ADT is approximately 18–24 months, after which most patients progress to a more aggressive form of disease termed castration (hormone)-resistant prostate cancer (CRPC).[15,16] CRPC, unlike early prostate cancer, is an aggressive disease that progresses despite castrate levels of testosterone (≤50 ng/ml). It is diagnosed by one or more of the following:
Continuous rise in serum levels of prostate-specific antigen (PSA);
Progression of pre-existing disease;
The appearance of new metastases.
There are numerous proposed explanations as to why CRPC develops. These have largely been discovered through gene expression studies examining the various states of tumor growth. Some hypotheses include alterations in the androgen response signaling pathway that enable constitutive activation of the hormone response pathway, re-expression of a subset of androgen-responsive genes that were initially downregulated after ADT, and androgen receptor (AR) gene amplification, which occurs in up to 50% of circulating tumor cells in patients with CRPC.[13,18]
The outlook for patients with CRPC is quite grim. Several investigators have reported that, without treatment, median survival time ranges from 9.1 to 21.7 months.[19–24] CRPC is now the second most common cause of male cancer-related mortality. However, recent discoveries pertaining to the biology and pathophysiology of the disease over the last two decades have enabled the development of new therapeutic modalities with the hope of improving those statistics. In recent years, a select few chemotherapy, hormonal, immunotherapy and palliative agents have gained US FDA approval for use in patients with CRPC. Additionally, many experimental anticancer drugs are in development, and there are numerous ongoing clinical trials seeking to elucidate optimal treatment regimens using existing modalities that maximize survival time while minimizing side effects.
This article seeks to review the current treatment options (Figure 1), including those indicated for palliative care, and to comment on the status of experimental treatment options for patients with CRPC. It also seeks to compare the survival rates, advantages, disadvantages and adverse reactions experienced by patients undergoing each of the different therapies.
Current treatment algorithm for castration-resistant prostate cancer. CRPC: Castration-resistant prostate cancer; RT: Radiation therapy.
Expert Rev Anticancer Ther. 2012;12(7):951-964. © 2012 Expert Reviews Ltd.