Understanding the Mechanisms of Androgen Deprivation Resistance in Prostate Cancer at the Molecular Level

Abstract

Context

Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC).

Objective

To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC.

Evidence acquisition

PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included.

Evidence synthesis

This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression.

Conclusions

The mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC.

Patient summary

We looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor-compensatory, non–AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa.

Introduction

Prostate cancer (PCa) remains the second leading cause of death due to cancer in Western societies [1]. Usually PCa is diagnosed as localized disease, and its management includes surveillance or radical prostatectomy, radiation therapy, or even combination approaches such as hormonal therapy prior to prostatectomy. Few patients undergoing PCa screening present with metastatic disease, which is also present in ≥10% of unscreened populations at first presentation—usually in bone, the predominant site of advanced and lethal PCa [2]—highlighting critical differences between screened and unscreened populations.

Despite the obvious increase in overall survival of patients with PCa over the past decade, recent data indicate that improvement of survival among patients with metastatic PCa has not significantly contributed to this decline in mortality [3]. Patients with metastatic disease usually receive hormonal therapy that decreases the production of testosterone by the testes. However, after an initial response, which varies significantly among patients, the disease eventually progresses despite the low levels of testosterone in the systemic circulation (<20 ng/dl) [4]. This stage of disease is known as metastatic castration-resistant PCa (mCRPC); the average overall survival is 1.5 yr, with significant variability among patients with lymph node metastasis, bone metastasis, and metastasis in both lymph nodes and bone [3]. Docetaxel and cabazitaxel are the only chemotherapy regimens approved for this stage of the disease [5], [6]. Radium Ra 233 (Xofigo) injection was recently approved for the treatment of patients with castration-resistant PCa (CRPC), symptomatic bone metastases, and no known visceral metastatic disease [7].

Numerous studies during the last decade have highlighted the role of androgen receptor (AR) in the development of mCRPC, showing that despite systemic androgen depletion, AR signaling remains active and supports the survival and growth of PCa cells. Based on these results, two novel agents have been recently evaluated in clinical trials: abiraterone acetate (AA), an inhibitor of androgen synthesis, and enzalutamide, a potent antiandrogen.

AA is a CYP17A1 inhibitor blocking the production of androgens in the testes, adrenal glands, and tumor microenvironment by inhibiting both 17α-hydroxylase and 17,20 lyase activities of the CYP17A1 enzyme [8]. AA has been recently approved for chemotherapy-naive patients with mCRPC, improving overall survival by 4 mo [9].

Enzalutamide is a novel antagonist of AR, inhibiting nuclear translocation, chromatin binding, and interactions with AR coregulators [10]. Enzalutamide prolongs the survival of patients who failed chemotherapy [11], and more recent data suggest that in chemotherapy-naive mCRPC patients, enzalutamide increases overall and progression-free survival and delays the need for chemotherapy [12].

ARN-509, a next-generation antiandrogen, was found to be more effective than enzalutamide in CRPC preclinical models in terms of tumor growth [13]. According to a recent phase 1 clinical trial, ARN-509 is safe and well tolerated and displays dose-proportional pharmacokinetics demonstrating pharmacodynamic and antitumor activity across all dose levels examined [14].

Despite the significant advances in the targeting of AR that have been translated into survival improvement for patients with mCRPC, this stage of disease remains incurable and is associated with significant morbidity and mortality [15]. While the introduction of novel antiandrogens has provided survival benefits through tumor growth inhibition, two critical clinical concerns arise: (1) Which patients really benefit from these agents, and which biomarkers can be used to identify these patients? (2) What alternative approaches can be used if the disease progresses during treatment with these agents?

The aim of this review is to summarize the recent advances in the evaluation of the multiple levels of development of resistance to androgen deprivation and AR inhibition that occur before and after the introduction of novel antiandrogen axis agents. In PCa, the heterogeneity of the diversity of pathways involved demands a critical consideration of numerous possible explanations of these biological events.