Archana Anantharaman

Targeting the androgen receptor in metastatic castrate-resistant prostate cancer: A review.

Despite recent advances in the treatment of advanced prostate cancer (PCa), metastatic castrate-resistant PCa remains incurable at this time. The androgen receptor (AR) plays a key role in the development and progression of PCa, continuing to be active in most patients even after the development of castration resistance. Here, we aim to more closely review the mechanisms by which AR signaling is maintained, including AR overexpression/overamplification, intracrine androgen synthesis, AR mutations, and the development of AR splice variants. We also review therapies targeting each of these mechanisms. We also discuss the potential role of AR-CAG repeats and AR splice variants as potential biomarkers of response to hormonal manipulation therapies.

A Stepping Stone Toward Personalized Oncology: Genomic Analysis of Circulating Tumor Cells to Guide Management of Metastatic Castration-resistant Prostate Cancer.

With the advent of novel, life-prolonging hormonal and chemotherapies, the treatment of metastatic castrationresistant prostate cancer (mCRPC) has dramatically changed in recent years. Abiraterone acetate and enzalutamide both target the androgen receptor (AR) and block downstream androgen-mediated signaling in cancer cells, whereas cabazitaxel—a novel taxane chemotherapeutic— works much like docetaxel to impair microtubule function in cancer cells. In addition, a number of other hormonal agents (ARN-509, galeterone, ODM-201) are under investigation for the treatment of mCRPC [1]. In an era of evergrowing therapeutic options, a major challenge facing clinicians is determining which agent is most appropriate for an individual patient. Predictive biomarkers can address this need and provide information specific to an individual patient. In recent years, the detection and analysis of circulating tumor cells (CTCs) has been shown to have clinical utility in prostate cancer, both as a marker for overall prognosis [2] and as a surrogate end point for clinical trials [3]. Yet, until recently, most studies focused primarily on the enumeration of CTCs and did not use the molecular and genotypic information contained within these cells to inform clinical decision making. Advances in CTC-capture technology, along with improvements in the reliable analysis of small inputs of DNA and RNA, have allowed researchers to understand more qualitative information from an individual patient’s CTCs. These advances in CTCmolecular and genetic analysis were recently shown to have promise for understanding treatment resistance to novel AR-targeting therapies [4]. To understand how CTCs can provide important clinical information about the AR-signaling axis, it is important to note that most prostate cancers develop resistance to androgen deprivation therapy through the development of genetic changes, such as AR amplification, AR mutation, or intracrine androgen synthesis [5–7], which allow for maintenance of AR signaling in the castrate environment. One resistance mechanism under active investigation is alternativeAR splicing [8]. In thismechanism, a change in the processing of the full-length AR messenger RNA leads to the development of a constitutively active splice-variant AR protein that lacks the androgen binding domain but retains the ability to bind to the cell’s DNA to promote cell growth and survival (Fig. 1). A recent study [4] showed that detection of a specific AR splice variant, termed AR-V7, in CTCs of men with mCRPC was highly predictive of resistance to both abiraterone acetate and enzalutamide. Men with AR-V7– positive CTCs did not have prostate-specific antigen (PSA) responses to either of these hormonal agents and had shorter progression-free survival (PFS) and overall survival (OS) comparedwithmenwhodid not have detectable AR-V7. This finding suggested that the presence of AR-V7 in CTCsmay be a useful predictive biomarker to guide the choice of whether to use hormonal agents in this population. A major question that arose from this work is whether the presence of AR-V7 is simply a marker of an aggressive disease process and overall poor prognosis. To answer this question, in this month’s issue of European Urology, Onstenk et al evaluated the association of AR-V7 inmCRPC CTCswith response to the taxane chemotherapeutic cabazitaxel [9]. E U RO P E AN URO L OG Y 6 8 ( 2 0 1 5 ) 9 4 6 – 9 4 8

High-Dose Abiraterone Acetate in Men With Castration Resistant Prostate Cancer

Micro‐Abstract Abiraterone acetate with prednisone prolongs progression‐free and overall survival in men with advanced prostate cancer, but most eventually acquire resistance to treatment. In this study we evaluated the clinical benefit of increasing the dose of abiraterone acetate in patients who develop acquired resistance to standard‐dose therapy while exploring the pharmacokinetics and pharmacodynamics of resistance. Background: Abiraterone acetate (AA) inhibits androgen biosynthesis and prolongs survival in men with metastatic castration‐resistant prostate cancer (mCRPC) when combined with prednisone (P). Resistance to therapy remains incompletely understood. In this open‐label, single‐arm, multicenter phase II study we investigated the clinical benefit of increasing the dose of AA at the time of resistance to standard‐dose therapy. Patients and Methods: Eligible patients had progressive mCRPC and started AA 1000 mg daily and P 5 mg twice daily. Patients who achieved any prostate‐specific antigen (PSA) decline after 12 weeks of therapy continued AA with P until PSA or radiographic progression. At progression, AA was increased to 1000 mg twice daily with unchanged P dosing. Patients were monitored for response to therapy for a minimum of 12 weeks or until PSA or radiographic progression. The primary end point was PSA decline of at least 30% after 12 weeks of therapy at the increased dose of AA. Results: Forty‐one patients were enrolled from March 2013 through March 2014. Thirteen men experienced disease progression during standard‐dose therapy and were subsequently treated with AA 1000 mg twice per day. Therapy was well tolerated. No PSA declines ≥ 30% nor radiographic responses were observed after 12 weeks of dose‐escalated therapy. Higher baseline dehydroepiandrosterone levels, lower circulating tumor cell burden, and higher pharmacokinetic levels of abiraterone and abiraterone metabolites were associated with response to standard‐dose therapy. Conclusion: Increasing the dose of abiraterone at the time of resistance has limited clinical utility and cannot be recommended. Lower baseline circulating androgen levels and interpatient pharmacokinetic variance appear to be associated with primary resistance to AA with P.

Tackling non-metastatic castration-resistant prostate cancer: special considerations in treatment

ABSTRACT Introduction: Prostate cancer (PCa) is currently the second most common cancer affecting men worldwide. Metastatic castration-resistant prostate cancer (mCRPC) is the incurable form of PCa, carrying the poorest prognosis, and can develop from non-metastatic CRPC (M0 CRPC). CRPC is defined as progression of the disease with castrate level testosterone levels, achieved with primary androgen deprivation therapy (ADT). M0 CRPC is a highly heterogeneous disease process lacking clear standard of care therapies. Areas covered: In this review, a broad literature search was undertaken to explore data available for therapeutic options and guidelines in the management of M0 CRPC. Expert commentary: While there are compelling data for various therapeutics for the treatment of M0 CRPC, no clear standard of care is apparent at this time. Furthermore, technological advances in imaging may have a significant impact on this future of this disease state.