Article

Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy

The authors' affiliations are listed in the Appendix.
New England Journal of Medicine (Impact Factor: 54.42). 12/2012; 368(2). DOI: 10.1056/NEJMoa1209096
Source: PubMed

ABSTRACT Background Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy. Methods In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival. Results The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone-prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the efficacy boundary. Abiraterone-prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone-prednisone. Conclusions Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer. (Funded by Janssen Research and Development, formerly Cougar Biotechnology; ClinicalTrials.gov number, NCT00887198 .).

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    • "Significantly, AR expression is increased in CRPC and most AR-stimulated genes are highly expressed, indicating that AR transcriptional activity has been substantially restored (Yuan et al., 2014). The recent clinical success of abiraterone (CYP17A1 inhibitor that further suppresses androgen synthesis) and enzalutamide (AR antagonist ) has confirmed that AR, stimulated by residual androgens, is a driver of tumor growth in CRPC (de Bono et al., 2011; Ryan et al., 2013; Scher et al., 2012). However, patients treated with these agents still generally relapse within 1–2 years, and high levels of AR and of AR-regulated genes in many of these relapsed tumors indicate that AR activity has again been restored. "
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    ABSTRACT: Lysine-Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4) but has a coactivator function on some genes through mechanisms that are unclear. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR-regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show that LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and that it has a distinct AR-linked coactivator function mediated by demethylation of other substrates. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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    • "The introduction of new treatment options for patients who have metastatic castration-resistant prostate cancer (mCRPC) during the past decade has provided several effective new therapeutic strategies, including two different taxanes, a systemic alpha particle–emitting radionuclide, as well as two novel endocrine drugs and a vaccine [1] [2] [3] [4] [5] [6] [7] [8]. Because docetaxel had been shown to prolong survival [1] [2], first cabazitaxel [3] and more recently two new drugs— blocking androgen synthesis through CYP17 inhibition and the androgen receptor (AR), respectively—have been shown to further improve survival in mCRPC patients both before and after chemotherapy [5] [6] [7] [8]. Abiraterone acetate, a selective CYP17A1 inhibitor, blocks the synthesis of androgenic steroids, causing effective systemic and intratumoural suppression of androgen production [9]. "
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    ABSTRACT: Background The degree of antitumour activity of enzalutamide following disease progression on docetaxel and abiraterone remains controversial. Objective To examine the effect of enzalutamide in patients progressing following taxane-based chemotherapy and abiraterone. Design, setting, and participants Metastatic castration-resistant prostate cancer patients entering one of four European compassionate use programmes of enzalutamide. Outcome measurements and statistical analysis The primary end point was overall survival (OS). Secondary end points were association between OS and posttreatment prostate-specific antigen (PSA) kinetics, patient characteristics, and progression-free survival, respectively. Kaplan-Meier survival analysis and Cox proportional hazard analysis were performed. Results and limitations We identified 137 patients who prior to enzalutamide had progressed following a median of eight cycles of docetaxel and seven courses of abiraterone. The median time on enzalutamide was 3.2 mo; median OS from the time patients started enzalutamide was 8.3 mo (95% confidence interval, 6.8–9.8). Only 45 (38%) and 22 (18%) patients had PSA declines (unconfirmed) >30% and 50%, respectively. Patients who had more than 30% or 50% falls in PSA had improved survival compared with patients who had no such PSA fall (11.4 mo vs 7.1 mo; p = 0.001 and 12.6 vs 7.4 mo; p = 0.007, respectively). Poor performance status and low haemoglobin was negatively associated with OS. Conclusions Median OS on enzalutamide following disease progression on taxane-based chemotherapy and abiraterone was modest, but patients who experience a PSA decline >30% or 50%, respectively, with enzalutamide in this setting had longer survival. Patient summary Enzalutamide produces modest prostate-specific antigen (PSA) responses in patients progressing following chemotherapy and abiraterone. Despite a modest PSA response, survival may still be improved.
    European Urology 08/2014; DOI:10.1016/j.eururo.2014.07.028 · 12.48 Impact Factor
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    • "In December 2012, Abiraterone in combination with prednisone received FDA approval for treatment of mCRPC in chemotherapy naïve patients as well. In a phase III randomized controlled trial (COU-AA-302) [34], 1088 patients with mCRPC who had not received chemotherapy were assigned either to abiraterone and prednisone (N = 546) or placebo plus prednisone (N = 542). The primary endpoints were radiographic progression free survival (rPFS) and overall survival (OS). "
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    ABSTRACT: Recently, the standard of care for metastatic Castration Resistant Prostate Cancer (mCRPC) has changed considerably. Persistent androgen receptor (AR) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer. Androgen receptor gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells, making them extremely sensitive to low levels of circulating androgens. Additionally, prostate cancer cells are able to maintain dihydrotestosterone (DHT) concentration in excess of serum concentrations to support tumor growth. For many years ketoconazole was the only CYP17 inhibitor that was used to treat mCRPC. However, significant toxicities limit its use. Newly approved chemotherapeutic agents such as Abiraterone (an oral selective inhibitor of CYP17A), which blocks androgen biosynthesis both within and outside the prostate cancer cells), and enzalutamide (blocks AR signaling) have improved overall survival. There are also ongoing phase III trials for Orteronel (TAK- 700), ARN- 509 and Galeterone (TOK-001), which targets androgen signaling. In this review, we will present the rationale for the newly approved hormonal treatments, their indications and complications, and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents. Finally, we will talk about the potential upcoming hormonal treatments for mCRPC.
    BMC Urology 07/2014; 14(1):55. DOI:10.1186/1471-2490-14-55 · 1.94 Impact Factor
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