Continued targeting of androgen receptor signalling: a rational and efficacious therapeutic strategy in metastatic castration-resistant prostate cancer

Abstract

Prostate cancer represents the most common cancer in men, leading to 11% of all male cancer-related deaths [1]. For the last few decades patients with metastatic prostate cancer with a rising prostatespecific antigen (PSA) while on treatment with luteinising hormone-releasing hormone (LHRH) analogues, have been classified as “hormone refractory”, to define the development of resistance to surgical or medical castration and in general to hormonal treatments [2]. Following this, prostate cancer therapy has been limited to first-line taxotere-based chemotherapy or secondary hormonal manipulations. Two prospective randomised trials have shown that docetaxel prolongs life by 2−3 months compared with mitoxantrone and improves the quality of life and symptom control in patients who have progressed on androgen deprivation therapy (ADT) [3,4]. The alternative unsatisfactory options comprised diethylstilbestrol, anti-androgens, low-dose steroids and ketoconazole, all characterised by a short-lasting (4 months) response in approximately 20−30% of patients and no proven impact on overall survival (OS) [5]. Over the past decade, a strong body of laboratory and clinical evidence has completely changed our understanding and the therapeutic approach to advanced prostate cancer, which remains hormonedriven, despite progression in medical or surgical castration. It is for this reason that nowadays the correct term used to describe this condition is “castration-resistant prostate cancer” (CRPC) and is no longer called “hormone-refractory prostate cancer”, as it was before [6,7]. This misconception was based on the clinical experience of a poor response to secondary hormonal manipulations following progression in ADT. To support this concept it was hypothesised that prostate cancer might be composed of a heterogeneous population of cancer cells, some of which are androgen-independent and therefore more likely to survive and dominate in the context of an androgen-deprived tumour environment [8]. However, more recent laboratory research has revealed that following the selective pressure of androgen deprivation, in the majority of prostate cancer cells there is overexpression of the androgen receptor (AR) [9] and increased expression of enzymes responsible for the intratumoural synthesis of androgens [10]. The centrality of AR-signalling in the proliferation and survival of prostate cancer cells is indirectly demonstrated by the increased expression of androgenregulated genes such as PSA concomitantly with disease progression [11]. Furthermore, clinical data from novel AR-targeting agents have shown that the effective targeting of AR signalling following the castration-resistant status results in a biochemical and radiological response suggesting that reactivation of AR signalling is the biological event underlying progression, despite castration levels of testosterone. Abiraterone acetate, a novel potent selective inhibitor of CYP17, a key enzyme along the biosynthesis of androgens and oestrogens, has demonstrated significant tumour activity (PSA decline 50% in 50– 60% of both chemotherapy-naive and chemotherapyrefractory metastatic CRPC patients and radiological response) [12–16]. Notably, most of the patients enrolled were progressing after treatment with secondary hormonal manipulations. The same scenario was also shown in Phase II trials investigating the treatment activity of a novel anti-androgen, MDV3100, in metastatic CRPC patients [17]. These very promising preliminary data prompted further analysis in Phase III trials in preand postdocetaxel settings to test the effect on OS in patients treated with abiraterone and MDV3100. The results of the Phase III randomised placebo-controlled trial evaluating abiraterone acetate in comparison with placebo, both combined with prednisone, were presented at the ESMO (European Society of Medical Oncology)