Elsevier

Cancer Treatment Reviews

Volume 41, Issue 10, December 2015, Pages 884-892
Cancer Treatment Reviews

Laboratory-Clinic Interface
Understanding and overcoming the mechanisms of primary and acquired resistance to abiraterone and enzalutamide in castration resistant prostate cancer

https://doi.org/10.1016/j.ctrv.2015.08.002Get rights and content

Highlights

  • Enzalutamide and abiraterone prolong OS, but resistance is a major clinical problem.

  • Mechanisms of de novo or acquired resistance can be AR-dependent or AR-independent.

  • To prevent or overcome resistance, many new agents are currently being tested.

  • The addition of these drugs may improve synergically the efficacy of hormonal therapy.

Abstract

In recent years, in castration resistant prostate cancer (CRPC), several new drugs have been approved that prolong overall survival, including enzalutamide and abiraterone, two new-generation hormonal therapies.

Despite the demonstrated benefit of these agents, not all patients with CRPC are responsive to treatment, the gain in median progression-free survival with these therapies compared to standard of care is, rather disappointingly, still less than six months and the appearance of acquired resistance is almost universal. Approximately one third of patients treated with abiraterone and 25% of those treated with enzalutamide show primary resistance to these agents. Even if the mechanisms of resistance to these agents are not fully defined, many hypotheses are emerging, including systemic and intratumoral androgen biosynthesis up-regulation, androgen receptor (AR) gene mutations and amplifications, alteration of pathways involved in cross-talk with AR signaling, glucocorticoid receptor overexpression, neuroendocrine differentiation, immune system deregulation and others.

The aim of this paper is to review currently available data about mechanisms of resistance to abiraterone and enzalutamide, and to discuss how these mechanisms could be potentially overcome through novel therapeutic agents.

Introduction

With nearly 220,000 new cases expected in the USA in 2015, prostate cancer (PC) represents the most frequent type of cancer in men, accounting for almost 26% of new cancer cases [1]. Despite most of the new patients are diagnosed in early stage, approximately 4% of the cases at baseline are in advanced stage and some patients treated initially with radical surgery will subsequently relapse.

Since the seminal work of Huggins and Hodges [2], androgen deprivation therapy (ADT), either surgical or biochemical, has been the mainstay of treatment for relapsed and metastatic PC patients, due to the driving role of androgen receptor (AR) in the development of these tumors.

Despite the initial high response rates, many patients become castrate-resistant within 3 years from the start of ADT and, consequently, there is a growing interest in testing new agents and strategies to overcome acquired resistance.

Recently it has been shown that, in castration resistant PC (CRPC) patients, even small concentrations of extra-gonadal androgens persisting despite ADT could activate the AR pathway and that PC cells could synthesize their own androgens [3]. Following these observations, a renewed interest on the AR signaling pathway was generated, and a second generation of hormonal therapies has been developed.

Abiraterone acetate is an oral drug that selectively and irreversibly inhibits the CYP17A1 microsomal enzyme, leading to the inhibition of testosterone biosynthesis in adrenal glands, in testis and in PC cells. Enzalutamide is an oral AR antagonist with an 8-fold higher affinity for its target than bicalutamide, preventing also AR nuclear translocation and DNA binding.

In CRPC, patients pretreated with docetaxel, two phase III trials, COU-AA-301 and AFFIRM, showed an improvement in overall survival (OS) with abiraterone (median OS 14.8 vs 10.9 months; hazard ratio [HR] 0.65, 95% CI, 0.54–0.77; p < 0.001) [4] and enzalutamide (median OS 18.4 vs 13.6 months; HR 0.63, 95% CI, 0.53–0.75; p < 0.001) [5], respectively. More recently, the COU-AA-302 study confirmed the efficacy of abiraterone in asymptomatic and mildly symptomatic chemotherapy-naive metastatic CRPC patients in terms of OS (median OS 34.7 vs 30.3 months; HR: 0.81, 95% CI, 0.70–0.93; p = 0.0033) [6].

In the PREVAIL study, enzalutamide showed a statistically significant 29% reduction in the risk of death (HR 0.70, 95% CI, 0.59–0.83; p = 0.0001) and an 81% reduction in the risk of radiographic progression compared to placebo (HR 0.19; CI 95%, 0.15–0.23; p < 0.0001) [7].

Based on these data, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) granted approval for abiraterone for the treatment of both docetaxel-naive and docetaxel-pretreated CRPC patients and for enzalutamide in the post-docetaxel setting.

Despite the inhibitory properties of these agents, PC cells, even after initial response, become resistant and cause clinical disease progression, posing the question how to deal with acquired resistance. In this paper we will review the putative mechanisms of primary and acquired resistance to new hormonal agents and some potential new strategies to overcome it.

Section snippets

Physiological androgen synthesis

In adult men, testosterone (T) and 5-α-dihydrotestosterone (DHT), mainly produced in the testes, with only 5–10% being synthesized from the adrenal glands, are the commonest forms of endogenous androgens and the major physiological AR ligands. Other steroid hormones, also produced by the adrenal glands, such as androstenedione and dehydroepiandrosterone (DHEA), can bind the AR.

In peripheral tissues, weak adrenal androgens such as DHEA-sulfate (DHEA-S) can be reduced to T, even if this

The androgen receptor

The AR gene is located on chromosome Xq11–12 and accounts for eight exons. AR is a 110-kDa nuclear protein that contains 918 acid residues and binds a specific hormone response element (HRE) known as androgen response element (ARE). AR is formed by different domains: the N-terminal domain (NTD), the DNA-binding domain (DBD), the hinge region and the ligand-binding domain (LBD) [9].

Once activated, AR binds AREs as a dimer. There are two different AREs: the inverted repeat AREs, that bind and

The adaptive response to androgen deprivation

Recently, a significant shift in the understanding of natural history of PC has occurred and it is currently known that castration resistance does not necessarily results in resistance to hormonal agents. In fact, despite the dramatic decrease of serum T induced by ADT, CRPC remains driven by AR signaling, being able to overexpress androgen dependent genes [13].

Multiple mechanisms have been identified to explain this phenomenon, including AR gene mutation [14], AR gene overexpression [15], AR

The mechanisms of resistance to abiraterone or enzalutamide

Despite the demonstrated benefits of both abiraterone and enzalutamide, some CRPC patients are primary resistant and do not respond to treatment, the gain in progression-free survival and OS obtained with these therapies is clinically relevant but limited, and the appearance of acquired resistance is the rule for all treated patients.

Although primary resistance has been defined by some authors as the absence of PSA reduction [25], a commonly accepted definition of primary resistance is a

Discussion

In the 1990s dedicated studies on AR in CRPC revealed escape mechanisms from androgen blockade through either mutation or amplification of AR [14]. Additionally, these resistance mechanisms corroborate the hypothesis that androgen-signaling remains biologically relevant despite castrate levels of testosterone and these observations guided the research and development of a new generation of androgen synthesis inhibitors and AR antagonists [4], [5].

However, primary and acquired resistance to new

Conclusion

Although during the past decade specific molecular alterations have been identified in the so called “oncogene addicted” tumors that led to the development of specific and effective targeted therapies that induce tumor shrinkage in most of the treated cases as well as significantly extend progression-free survival, the responses to these agents is limited by the onset of acquired resistance. A deeper understanding of resistance mechanisms to these drugs is essential to maximize their efficacy

Conflict of interest

None.

References (78)

  • R.L. Siegel et al.

    Cancer statistics, 2015

    CA Cancer J Clin

    (2015)
  • C. Huggins et al.

    Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate

    CA Cancer J Clin

    (1972)
  • J.L. Mohler et al.

    The androgen axis in recurrent prostate cancer

    Clin Cancer Res

    (2004)
  • J.S. de Bono et al.

    Abiraterone and increased survival in metastatic prostate cancer

    N Engl J Med

    (2011)
  • H.I. Scher et al.

    Increased survival with enzalutamide in prostate cancer after chemotherapy

    N Engl J Med

    (2012)
  • T.M. Beer et al.

    Enzalutamide in metastatic prostate cancer before chemotherapy

    N Engl J Med

    (2014)
  • C.T. Baumann et al.

    Intracellular localization and trafficking of steroid receptors

    Cell Biochem Biophys

    (1999)
  • H.Y. Wong et al.

    Phosphorylation of androgen receptor isoforms

    Biochem J

    (2004)
  • C.A. Heinlein et al.

    Role of chaperones in nuclear translocation and transactivation of steroid receptors

    Endocrine

    (2001)
  • H.V. Heemers et al.

    Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex

    Endocr Rev

    (2007)
  • J.L. Mohler

    Castration-recurrent prostate cancer is not androgen-independent

    Adv Exp Med Biol

    (2008)
  • C.D. Chen et al.

    Molecular determinants of resistance to antiandrogen therapy

    Nat Med

    (2004)
  • M. Stanbrough et al.

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

    Cancer Res

    (2006)
  • R. Hu et al.

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

    Cancer Res

    (2009)
  • C. Cai et al.

    Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy

    Endocr Relat Cancer

    (2011)
  • J. Geller et al.

    Effects of castration compared with total androgen blockade on tissue dihydrotestosterone (DHT) concentration in benign prostatic hyperplasia (BPH)

    Urol Res

    (1987)
  • A. Mizokami et al.

    The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor

    Cancer Res

    (2004)
  • T. Nishiyama et al.

    The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer

    Clin Cancer Res

    (2004)
  • S.T. Page et al.

    Persistent intraprostatic androgen concentrations after medical castration in healthy men

    J Clin Endocrinol Metab

    (2006)
  • E.A. Mostaghel et al.

    Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer

    Cancer Res

    (2007)
  • J.A. Locke et al.

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

    Cancer Res

    (2008)
  • R.B. Montgomery et al.

    Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth

    Cancer Res

    (2008)
  • O. Caffo et al.

    Potential value of rapid prostate-specific antigen decline in identifying primary resistance to abiraterone acetate and enzalutamide

    Future Oncol

    (2014)
  • K. Fizazi et al.

    Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5

    J Clin Oncol

    (2015)
  • E.A. Mostaghel et al.

    Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants

    Clin Cancer Res

    (2011)
  • N. Sharifi et al.

    “Getting from here to there” – mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer

    J Investig Med

    (2010)
  • R. Li et al.

    Abiraterone inhibits 3beta-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer

    Clin Cancer Res

    (2012)
  • C. Liu et al.

    Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer

    Cancer Res

    (2015)
  • M.E. Taplin et al.

    Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer

    N Engl J Med

    (1995)
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