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Second-Generation Androgen Receptor Antagonists as Hormonal Therapeutics for Three Forms of Prostate Cancer.

ABSTRACT: Enzalutamide is the first second-generation nonsteroidal androgen receptor (AR) antagonist with a strong binding affinity to AR. Most significantly, enzalutamide can prolong not only overall survival time and metastatic free survival time for patients with lethal castration-resistant prostate cancer (CRPC), but also castration-resistant free survival time for patients with castration-sensitive prostate cancer (CSPC). Enzalutamide has thus been approved by the US Food and Drug Administration (FDA) for the treatment of both metastatic (in 2012) and non-metastatic (in 2018) CRPC, as well as CSPC (2019). This is an inspiring drug discovery story created by an amazing interdisciplinary collaboration. Equally important, the successful clinical use of enzalutamide proves the notion that the second-generation AR antagonists can serve as hormonal therapeutics for three forms of advanced prostate cancer. This has been further verified by the recent FDA approval of the other two second-generation AR antagonists, apalutamide and darolutamide, for the treatment of prostate cancer. This review focuses on the rational design and discovery of these three second-generation AR antagonists, and then highlights their syntheses, clinical studies, and use. Strategies to overcome the resistance to the second-generation AR antagonists are also reviewed.

SUBMITTER: Rajaram P

PROVIDER: S-EPMC7287767 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Second-Generation Androgen Receptor Antagonists as Hormonal Therapeutics for Three Forms of Prostate Cancer.

Rajaram Pravien P Rivera Alyssa A Muthima Kevin K Olveda Nicholas N Muchalski Hubert H Chen Qiao-Hong QH

Molecules (Basel, Switzerland) 20200524 10

Enzalutamide is the first second-generation nonsteroidal androgen receptor (AR) antagonist with a strong binding affinity to AR. Most significantly, enzalutamide can prolong not only overall survival time and metastatic free survival time for patients with lethal castration-resistant prostate cancer (CRPC), but also castration-resistant free survival time for patients with castration-sensitive prostate cancer (CSPC). Enzalutamide has thus been approved by the US Food and Drug Administration (FDA ...[more]

PMID: 32456317

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Project description:BackgroundNonmetastatic castration-resistant prostate cancer (nmCRPC) is defined as a rising prostate-specific antigen concentration, despite castrate levels of testosterone with ongoing androgen-deprivation therapy or orchiectomy, and no detectable metastases by conventional imaging. Patients with nmCRPC progress to metastatic disease and are at risk of developing cancer-related symptoms and morbidity, eventually dying of their disease. While patients with nmCRPC are generally asymptomatic from their disease, they are often older and have chronic comorbidities that require long-term concomitant medication. Therefore, careful consideration of the benefit-risk profile of potential treatments is required.MethodsIn this review, we will discuss the rationale for early treatment of patients with nmCRPC to delay metastatic progression and prolong survival, as well as the factors influencing this treatment decision. We will focus on oral pharmacotherapy with the second-generation androgen receptor inhibitors, apalutamide, enzalutamide, and darolutamide, and the importance of balancing the clinical benefit they offer with potential adverse events and the consequential impact on quality of life, physical capacity, and cognitive function.Results and conclusionsWhile the definition of nmCRPC is well established, the advent of next-generation imaging techniques capable of detecting hitherto undetectable oligometastatic disease in patients with nmCRPC has fostered debate on the criteria that inform the management of these patients. However, despite these developments, published consensus statements have maintained that the absence of metastases on conventional imaging suffices to guide such therapeutic decisions. In addition, the prolonged metastasis-free survival and recently reported positive overall survival outcomes of the three second-generation androgen receptor inhibitors have provided further evidence for the early use of these agents in patients with nmCRPC in order to delay metastases and prolong survival. Here, we discuss the benefit-risk profiles of apalutamide, enzalutamide, and darolutamide based on the data available from their pivotal clinical trials in patients with nmCRPC.

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Second-Generation Androgen Receptor Antagonists as Hormonal Therapeutics for Three Forms of Prostate Cancer.

Publications

Second-Generation Androgen Receptor Antagonists as Hormonal Therapeutics for Three Forms of Prostate Cancer.

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