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Novel Agents in the Management of Castration-Resistant Metastatic Prostate Cancer

Robert Dreicer, MD, MS
Published: Friday, Mar 04, 2011
The Prostate Cancer Clinical States model was first proposed by Scher and colleagues nearly 10 years ago. As this model has been refined, it provides a framework for thinking about prostate cancer from a clinical management perspective and in the context of conducting investigational studies for new drug development.

Historically, androgen-deprivation therapy (ADT) has been used as a first-line treatment for advanced prostate cancer, with a goal of achieving testosterone levels in the body nearly equivalent to the levels afforded by surgical castration (Figure 2).2 Based on Medicare data from the Surveillance, Epidemiology, and End Results (SEER) program, the use of ADT among Medicare beneficiaries was used in 44.8% of all prostate cancer cases diagnosed between 2000 and 2002; in 15% of patients, ADT was used as an adjuvant with radiation, and in 14% of patients, it was given as primary therapy.3

ADT initially induces remission or stabilization in most patients with locally advanced or metastatic prostate cancer, but within 18 to 24 months, nearly all will experience disease progression.4 Prior to the advent of prostate-specific antigen (PSA) testing, patients with known metastatic disease who developed disease-related symptoms (eg, pain, progressive fatigue, weight loss) were believed to be experiencing progression, which was verified using bone scanning and/or computed tomography (CT) imaging. Patients progressing on hormonal therapy were typically identified as androgen independent or hormone refractory. Median survival from the onset of progression for androgen-independent patients with metastatic disease was 10 to 12 months.4

In today’s PSA era, the identification of “progression” is typically a rising PSA in the setting of castrate levels of testosterone (<50 ng/dL). Recent evidence from hypothesis-generating studies has resulted in proposals to reduce the target castrate level of testosterone to ≤20 ng/dL, which has been associated with improved progression-free survival.5,6 However, a subset of patients treated with luteinizing hormone releasing hormone (LHRH) agonists, a therapy commonly used since the early 1970s, failed to achieve a target level of 50 ng/dL,6 and, of course, even patients who achieve this nadir eventually progress.

Management of patients with disease progression following ADT has typically involved an empiric effort to maintain patients at castrate levels of testosterone, though evidence to support this practice has been limited. Second-line hormonal therapies with antiandrogens or other agents such as ketoconazole, aminoglutethimide, and estrogenic compounds have been used. Although only relative minorities of patients respond and the response tends to be quite brief, patients occasionally will manifest a response that can be very durable.7

ANDROGEN RECEPTOR: PROSTATE CANCER’S HOLY GRAIL

Prostate cancer cells depend on androgens to survive and proliferate, which is the rationale behind androgen-ablative therapy.8 The most potent androgens are testosterone and dihydrotestosterone (DHT). In the initial development of prostate cancer and in progression of the disease, testosterone and DHT bind to and activate the androgen receptor (AR). DHT has a binding affinity for AR that is nearly 10 times that of testosterone. AR, a phosphoprotein, functions as a transcription factor to mediate the effects of these steroids on the cell cycle.9

Intraprostatic levels of testosterone and DHT (in situ and metastatic) remain elevated, despite achieving serum castrate levels with ADT.10 In addition, PSA—encoded by an androgen-responsive gene—is detectable in nearly all cases of Castration-Resistant Prostate Cancer (CRPC). It is clear that the AR-signaling pathway remains persistently activated despite androgen blockade.

In patients with CRPC, resumed progression is likely due to AR mutations, AR gene amplification, AR overexpression, modulation of AR via signaling pathways, alteration of coactivators, or a combination of molecular mechanisms.8,10 Some patients appear to have a hypersensitive AR phenotype that renders prostate cancer cells exquisitely sensitive to extremely low levels of testosterone and DHT.11

The development of newer and more effective methods of blocking AR synthesis may have therapeutic promise for patients with CRPC. Abiraterone acetate and MDV3100, two novel AR antagonists, are currently being evaluated in phase III studies. In preclinical and clinical studies, these drugs have shown promising activity against metastatic CRPC.

ABIRATERONE ACETATE

Abiraterone acetate is an important compound in late-stage development for CRPC and has been under investigation for more than 2 decades. It is an oral bioavailable prodrug of abiraterone, which selectively and irreversibly inhibits the activity of 17-hydroxylase/17,20-lyase (CYP17), an enzyme principally responsible for androgen and estrogen biosynthesis.12 CYP17 inhibition results in significantly lower levels of circulating dehydroepiandrosterone (DHEA) and androstenedione, a metabolite of DHEA that is synthesized into the more potent androgens testosterone and DHT.


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35th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® Clinical Vignette SeriesJan 31, 20192.0
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