Elsevier

European Urology

Volume 56, Issue 4, October 2009, Pages 594-605
European Urology

Platinum Priority – Collaborative Review – Prostate Cancer
Editorial by Joaquim Bellmunt, Jonathan E. Rosenberg and Toni K. Choueiri on pp. 606–608 of this issue
Castration-resistant Prostate Cancer: From New Pathophysiology to New Treatment Targets

https://doi.org/10.1016/j.eururo.2009.06.027Get rights and content

Abstract

Context

Castration-resistant prostate cancer (CRPC) refers to patients who no longer respond to surgical or medical castration. Standard treatment options are limited.

Objective

To review the concepts and rationale behind targeted agents currently in late-stage clinical testing for patients with CRPC.

Evidence acquisition

Novel targeted therapies in clinical trials were identified from registries. The MEDLINE database was searched for all relevant reports published from 1996 to October 2009. Bibliographies of the retrieved articles and major international meeting abstracts were hand-searched to identify additional studies.

Evidence synthesis

Advances in our understanding of the molecular mechanisms underlying prostate cancer (PCa) progression has translated into a variety of treatment approaches. Agents targeting androgen receptor (AR) activation and local steroidogenesis, angiogenesis, immunotherapy, apoptosis, chaperone proteins, the insulin-like growth factor (IGF) pathway, RANK-ligand, endothelin receptors, and the Src family kinases are entering or have recently completed accrual to phase 3 trials for patients with CRPC.

Conclusions

A number of new agents targeting mechanisms of PCa progression with early promising results are in clinical trials and have the potential to provide novel treatment options for CRPC in the near future.

Introduction

Prostate cancer (PCa) remains a significant medical burden in developed countries and a major cause of morbidity and mortality. In men, it is the most commonly diagnosed noncutaneous cancer and the second to third most common cause of cancer death in the western world [1]. Many patients with localised disease have an excellent long-term survival and high cure rates with standard approaches [2]. However, patients with high-risk, locally advanced, and metastatic disease have a poor prognosis; and although hormone therapy (HT) in the form of medical or surgical castration can induce significant long-term remissions, development of castration-resistant disease is inevitable. Castration-resistant prostate cancer (CRPC) has been used synonymously with androgen-independent PCa and hormone-refractory PCa but is the preferred term, as we now know that many men with CRPC respond to additional manipulations that ablate or block PCa growth stimulation by androgens. CRPC is clinically detected by a rise in prostate-specific antigen (PSA), typically defined as three consecutive rises over nadir in the context of castrate levels of serum testosterone and after antiandrogen withdrawal for at least 4 wk and despite secondary hormonal manipulations and/or radiologic progression [3], [4].

Systemic therapy for metastatic CRPC is remarkable for the relatively few options that have been developed. After failure of HT, treatments have been approved primarily for symptomatic benefit, such as mitoxantrone chemotherapy [5], radioactive isotopes [6], and the bisphosphonate zoledronic acid [7]. Despite multiple trials of cytotoxic chemotherapy in patients with metastatic CRPC, only docetaxel has been shown to improve overall survival (OS) [8], [9], with a median improvement in OS of 2.4 mo over mitoxantrone. In addition, an improvement in patient-reported pain and quality of life scores were also superior in docetaxel-treated patients and has now become a standard of care. Gains in this late-stage patient population may translate to greater benefits when applied to earlier states of PCa in the future to prevent or delay metastases and increase cure rates and OS. Indeed, a recent update of a study randomising patients with castration-sensitive disease to receive either the oral bisphosphonate clodronate or placebo has suggested that the secondary endpoint of OS was improved in those patients who received clodronate [10]. To this end, trials are ongoing with zoledronic acid in patients with metastatic castration-sensitive and high-risk localised disease (Table 1). Trials evaluating docetaxel given in an adjuvant or neoadjuvant fashion to patients with high-risk, clinically localised disease undergoing surgery or radiation therapy (RT) are also underway. Additionally, randomised studies testing the benefit of docetaxel in patients with PSA-recurrent or castration-naïve metastatic disease are ongoing (Table 1).

Over the past decade, there has been a significant increase in understanding of the biologic basis for PCa progression, fuelled in part from the development of high-throughput genomic, transcriptomic, and proteomic technologies. The mechanisms of androgen independence can be divided into those that are mediated by the androgen receptor (AR)—for example, through a hypersensitive, promiscuous, or amplified AR—and others that bypass it [11], [12]. Mechanisms common to all cancers underlying malignant proliferation, angiogenesis, metastases, and avoidance of immune surveillance are also implicated in PCa progression. From these advances, a large number of potential therapeutic targets have been identified. This article reviews the current concepts behind targeted therapy for CRPC with a focus on novel agents that are currently in late-stage clinical testing for patients with advanced PCa.

Section snippets

Androgen receptor signalling

It has long been recognized that after failure of castration therapy, second-line HTs can often be associated with clinical responses, initially presumed on the basis of extragonadal production of androgens [13]. An additional factor underlying such responses may also reside within PCa tissue itself. Several studies have demonstrated amplification and increased expression of AR in xenografts with hormone resistance and in PCa tissues from patients with CRPC [14], [15], [16]. In vitro and in

Vascular endothelial growth factor and receptor

In order for growth beyond a few millimetres and to be able to metastasize, malignant tumours must be able to recruit new vasculature in a process referred to as angiogenesis. Several mediators of angiogenesis have been identified, including vascular endothelial growth factor (VEGF), which signals through VEGF receptors (VEGFR) 1 and 2 to promote angiogenesis. Elevated VEGFR—notably VEGFR-2—has been associated with progression of PCa in the transgenic adenocarcinoma of mouse prostate (TRAMP)

Immunotherapy

The harnessing of the body’s immune system to illicit an antitumour effect and overcome immunologic tolerance of malignancies has been a long-sought-after oncologic therapeutic strategy. Active specific immunotherapy seeks to induce an immune-mediated antitumour effect by immunisation of a patient with tumour-specific antigens. Antigen-presenting cells such as dendritic cells are integral in the processing and presentation of antigens, via major histocompatibility complex (MHC) class I and

Apoptosis

Resistance to apoptosis, or programmed cell death, is another mechanism attributed to PCa progression and treatment resistance. The B-cell leukaemia/lymphoma 2 gene (BCL-2) is the prototype of a class of oncogenes that contributes to neoplastic progression by enhancing tumour cell survival through inhibition of apoptosis. Initially identified in follicular lymphoma as a result of the characteristic t14,18 translocation, BCL-2 is a mitochondrial membrane protein that functions to heterodimerize

Chaperone proteins

The heat shock protein-90 (HSP90) molecular chaperone complex is essential for AR stability and maturation and thus has been identified as a potential therapeutic target for CRPC. In addition, HSP90 acts as a chaperone to a number of other client proteins associated with malignant progression, including Akt, Raf-1, Her-2, and hypoxia-inducible factor 1α (HIF-1α) [53]. HSP90 is an ATP-dependent chaperone, and a number of specific inhibitors have been developed against its ATPase activity.

Insulin-like growth factor 1 and receptor

The insulin-like growth factor (IGF) axis is composed of two peptide growth factors (IGF-1 and IGF-2), two transmembrane receptors (IGF-IR and IGF-IIR), six IGF binding proteins (IGFBP-1 to IGFBP-6), and IGFBP proteases. IGFs are synthesized primarily in the liver and have effects on protein and carbohydrate metabolism but also regulate cellular processes of proliferation, differentiation, and apoptosis. These later attributes have resulted in the IGF axis being associated with a critical role

Bone targeting

Given the predilection of PCa to metastasize to bone, therapies directed towards the biologic underpinnings of bone progression are a rational treatment direction. Bisphosphonates, which inhibit bone the bone resorbing activity of osteoclasts by binding to the mineralised bone surface, are already an established treatment for patients with metastatic CRPC, and studies continue to define their use for earlier disease. Additional agents targeting bone metastases–related biologic targets are also

Conclusions

Over the past two decades, there has been an increased understanding of the biologic underpinnings of cancer in general and PCa specifically relating to androgen-independent progression, immune tolerance, factors affecting cell proliferation and survival, and mediators of metastases. Coupled with rational drug design and more sophisticated trial endpoints, a large number of therapeutic agents have entered into clinical trials over the past decade that promise to significantly change our

References (95)

  • A. Jemal et al.

    Cancer statistics, 2008

    CA Cancer J Clin

    (2008)
  • A.V. D’Amico et al.

    Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer

    JAMA

    (1998)
  • H.I. Scher et al.

    Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group

    J Clin Oncol

    (2008)
  • I.F. Tannock et al.

    Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points

    J Clin Oncol

    (1996)
  • F. Saad et al.

    A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma

    J Natl Cancer Inst

    (2002)
  • I.F. Tannock et al.

    Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer

    N Engl J Med

    (2004)
  • D.P. Petrylak et al.

    Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer

    N Engl J Med

    (2004)
  • Dearnaley DP, Mason MD, Parmar MK, Sanders K, Sydes MR. Survival benefit with oral sodium clodronate in metastatic but...
  • J.D. Debes et al.

    Mechanisms of androgen-refractory prostate cancer

    N Engl J Med

    (2004)
  • B.J. Feldman et al.

    The development of androgen-independent prostate cancer

    Nat Rev Cancer

    (2001)
  • S.D. Fossa et al.

    Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European Organization for Research and Treatment of Cancer Genitourinary Group

    J Clin Oncol

    (2001)
  • M.J. Linja et al.

    Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer

    Cancer Res

    (2001)
  • C.D. Chen et al.

    Molecular determinants of resistance to antiandrogen therapy

    Nat Med

    (2004)
  • J.L. Mohler et al.

    The androgen axis in recurrent prostate cancer

    Clin Cancer Res

    (2004)
  • R. Snoek et al.

    In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumors

    Clin Cancer Res

    (2009)
  • M.A. Titus et al.

    Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer

    Clin Cancer Res

    (2005)
  • M. Stanbrough et al.

    Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer

    Cancer Res

    (2006)
  • J.A. Locke et al.

    Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer

    Cancer Res

    (2008)
  • R. Hu et al.

    Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer

    Cancer Res

    (2009)
  • G. Attard et al.

    Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven

    J Clin Oncol

    (2008)
  • J.S. De Bono et al.

    Anti-tumor activity of abiraterone acetate (AA), a CYP17 inhibitor of androgen synthesis, in chemotherapy naive and docetaxel pre-treated castration resistant prostate cancer (CRPC)

    J Clin Oncol

    (2008)
  • H.I. Scher et al.

    Phase I/II study of MDV3100 in patients (pts) with progressive castration-resistant prostate cancer (CRPC)

    J Clin Oncol

    (2008)
  • W.J. Huss et al.

    Angiogenesis and prostate cancer: identification of a molecular progression switch

    Cancer Res

    (2001)
  • D.J. George et al.

    Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480

    Clin Cancer Res

    (2001)
  • R.K. Jain et al.

    Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model

    Cancer Res

    (2007)
  • J.C. Yang et al.

    A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer

    N Engl J Med

    (2003)
  • J. Picus et al.

    The use of bevacizumab (B) with docetaxel (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): initial results of CALGB 90006

    Proc Am Soc Clin Oncol

    (2003)
  • H.M. Verheul et al.

    Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model

    Clin Cancer Res

    (2007)
  • N. Isambert et al.

    A phase I dose escalation and pharmacokinetic (PK) study of intravenous aflibercept (VEGF Trap) plus docetaxel (D) in patients (pts) with advanced solid tumors: Preliminary results

    J Clin Oncol

    (2008)
  • R.J. Motzer et al.

    Sunitinib versus interferon alfa in metastatic renal-cell carcinoma

    N Engl J of Med

    (2007)
  • P.O. Periman et al.

    Sunitinib malate for metastatic castration resistant prostate cancer following docetaxel-based chemotherapy

    J Clin Oncol

    (2008)
  • E.J. Small et al.

    Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells

    J Clin Oncol

    (2000)
  • E.J. Small et al.

    Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer

    J Clin Oncol

    (2006)
  • C.S. Higano et al.

    Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer

    Cancer

    (2008)
  • L. Fong et al.

    Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment

    J Clin Oncol

    (2008)
  • D.R. Leach et al.

    Enhancement of antitumor immunity by CTLA-4 blockade

    Science

    (1996)
  • E.J. Small et al.

    A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer

    Clin Cancer Res

    (2007)
  • Cited by (138)

    • miRNAs and androgen deprivation therapy for prostate cancer

      2021, Biochimica et Biophysica Acta - Reviews on Cancer
    View all citing articles on Scopus
    View full text