Apalutamide Submitted for FDA Approval in Prostate Cancer

Excerpt:

“Janssen Biotech has submitted a new drug application to the FDA for apalutamide (ARN-509) for the treatment of non-metastatic castration-resistant prostate cancer (CRPC), the manufacturer of the next-generation oral androgen receptor inhibitor announced today.

“Apalutamide inhibits the action of testosterone in prostate cancer cells and prevents androgen from binding to the androgen receptor. Currently, there are no FDA-approved treatments for patients with nonmetastatic CRPC, Janssen noted in a press release.”

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Second-Generation AR-Targeting Agent Explored in High-Risk Prostate Cancer

Excerpt:

“Researchers are hoping the results of a late-stage efficacy and safety study of apalutamide (ARN-509) in patients with high-risk, localized, or locally advanced prostate cancer who are receiving primary radiation therapy will demonstrate an improvement in metastasis-free survival, according to global principal investigator, Howard M. Sandler, MD.

“ ‘The patient population that we’re studying are men who are at risk of dying of prostate cancer,’ Sandler, chair of the Department of Radiation Oncology at Cedars-Sinai Medical Center in Los Angeles, told OncologyLive. ‘If we can provide better upfront disease control, we’re hoping to reduce the number of men who enter into the castrate-resistant prostate cancer stage.’ “

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OncoBriefs: Delayed Tx for Prostate Ca, New Antiandrogen

“Prostate cancer mortality has declined by more than 60% compared with historical data for a cohort of conservatively managed patients followed for more than 20 years, a retrospective analysis showed.

“The findings will be reported in detail at the 50th anniversary meeting of the American Society of Clinical Oncology, which begins here May 30. Other ASCO-related prostate cancer data included in this edition of OncoBriefs come from studies of physical activity to counteract adverse effects of androgen-deprivation therapy (ADT) and preliminary clinical results from a trial of an investigational second-generation androgen inhibitor.”

Editor’s note: This article gives a good overview of some important prostate cancer news that will be discussed this weekend at the American Society of Clinical Oncology (ASCO) Annual Meeting. In addition to lower mortality and the benefits of physical activity for men treated with ADT, the article discusses promising results for a drug called ARN-509, which may benefit patients with metastatic castration-resistant prostate cancer.


Scientists Discover Why Combo Treatment Works for People with High-Risk Prostate Cancer


The vast majority of high-risk prostate cancer cases are caused by abnormally high activity of a protein called the androgen receptor. Present in many prostate cells, androgen receptors detect androgen hormones (including testosterone), and in response, turn on or off genes. Genes that are regulated by androgen hormones are critical for the development of the prostate and maintenance of its function. But when the androgen receptor is overly active, which can occur via several different processes in the aging prostate, it can activate genes that can lead to uncontrolled proliferation of prostate cells. This contributes to the development of aggressive prostate cancer. Continue reading…


Phase I Study of ARN-509, a Novel Antiandrogen, in the Treatment of CRPC

“Purpose: ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ARN-509 in men with metastatic CRPC…Conclusion: ARN-509 was safe and well tolerated, displayed dose-proportional pharmacokinetics, and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data.”


Phase I Study of ARN-509, a Novel Antiandrogen, in the Treatment of Castration-Resistant Prostate Cancer

“Purpose: ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ARN-509 in men with metastatic CRPC…Conclusion: ARN-509 was safe and well tolerated, displayed dose-proportional pharmacokinetics, and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data.”


Emerging Molecularly Targeted Therapies in Castration Refractory Prostate Cancer

“Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.”


A Clinically Relevant Androgen Receptor Mutation Confers Resistance to 2nd Generation Anti-Androgens Enzalutamide and ARN-509

“Despite the impressive clinical activity of 2nd generation anti-androgens enzalutamide and ARN-509 in prostate cancer patients, acquired resistance invariably emerges. To identify the molecular mechanisms underlying acquired resistance, we developed and characterized cell lines resistant to ARN-509 and enzalutamide. In a subset of cell lines, ARN-509 and enzalutamide exhibit agonist activity, due to a missense mutation (F876L) in the ligand binding domain of the androgen receptor (AR). AR F876L is sufficient to confer resistance to ARN-509 and enzalutamide in in vitro and in vivo models of CRPC.”


Identification of Antiandrogen Resistance Mutation Leads to Design of Molecules That Could Overcome Resistance


Researchers recently identified a genetic mutation that results in resistance to the drug enzalutamide (Xtandi) and to other second-generation antiandrogen receptor drugs. The discovery has already led to the design of new compounds that could overcome this type of resistance in prostate cancer patients. Those compounds are in preclinical studies. Continue reading…