Dataset Information

Second-Generation Antiandrogens: From Discovery to Standard of Care in Castration Resistant Prostate Cancer.

ABSTRACT: Prostate cancer is the most commonly diagnosed cancer affecting men in the United States. The prostate is a hormone-dependent gland in which androgen hormones testosterone and dihydrotestosterone bind to and activate the androgen receptor, initiating nuclear translocation of androgen receptor and a subsequent signaling cascade. Due to the androgen dependency of the prostate, androgen deprivation therapies have emerged as first line treatment for aggressive prostate cancer. Such therapies are effective until the point at which prostate cancer, through a variety of mechanisms including but not limited to generation of ligand-independent androgen receptor splice variants, or intratumoral androgen production, overcome hormone deprivation. These cancers are androgen ablation resistant, clinically termed castration resistant prostate cancer (CRPC) and remain incurable. First-generation antiandrogens established androgen receptor blockade as a therapeutic strategy, but these therapies do not completely block androgen receptor activity. Efficacy and potency have been improved by the development of second-generation antiandrogen therapies, which remain the standard of care for patients with CRPC. Four second-generation anti-androgens are currently approved by the Food and Drug Administration (FDA); abiraterone acetate, enzalutamide, and recently approved apalutamide and darolutamide. This review is intended to provide a thorough overview of FDA approved second-generation antiandrogen discovery, treatment application, strategies for combination therapy to overcome resistance, and an insight for the potential future approaches for therapeutic inhibition of androgen receptor.

SUBMITTER: Rice MA

PROVIDER: S-EPMC6723105 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Second-Generation Antiandrogens: From Discovery to Standard of Care in Castration Resistant Prostate Cancer.

Rice Meghan A MA Malhotra Sanjay V SV Stoyanova Tanya T

Frontiers in oncology 20190828

Prostate cancer is the most commonly diagnosed cancer affecting men in the United States. The prostate is a hormone-dependent gland in which androgen hormones testosterone and dihydrotestosterone bind to and activate the androgen receptor, initiating nuclear translocation of androgen receptor and a subsequent signaling cascade. Due to the androgen dependency of the prostate, androgen deprivation therapies have emerged as first line treatment for aggressive prostate cancer. Such therapies are eff ...[more]

PMID: 31555580

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Project description:ImportancePrevious studies have shown a consistent association between hormone therapy (HT), such as androgen deprivation therapy, to treat prostate cancer and depression risk. However, the association between second-generation antiandrogens (AAs) and depression is unknown.ObjectiveTo test the a priori hypothesis that second-generation AAs are associated with an increased risk of depression, including compared with traditional forms of HT.Design, setting, and participantsThis retrospective cohort study analyzed patients aged 66 years and older who were diagnosed with prostate cancer without a second cancer in 12 months from January 2011 to December 2015. Patients with continuous Medicare Parts A, B, and D coverage were included. Individuals who received any form of HT prior to prostate cancer diagnosis and those previously diagnosed with depression were excluded. Data were collected from the Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry-Medicare linked databases. Data were analyzed from February to May 2021.ExposuresThe following treatment groups were compared: (1) no HT group, (2) traditional HT group (HT without second-generation AA exposure), and (3) second-generation AA group.Main outcomes and measuresRisk of depression in the second-generation AA group compared with the no HT and traditional HT groups, determined prior to data collection, stratified by diagnosis stage.ResultsOf 210 804 patients diagnosed with prostate cancer during the study window, 30 069 men (11 484 [38%] aged 66-70 years; 22 594 [75%] White) who met inclusion criteria were identified. Overall, 17 710 (59%) received no HT, 11 311 (38%) received traditional HT only, and 1048 (3%) received a second-generation AA. Those receiving a second-generation AA were more likely to be older (aged ≥81 years: second-generation AA group, 246 [24%]; traditional HT group, 1997 [18%]; no HT group, 1173 [7%]) and present with advanced disease (eg, distant disease: second-generation AA group, 562 [24%]; traditional HT group, 876 [8%]; no HT group, 129 [0.7%]). Multivariable Cox proportional hazards analysis showed that the second-generation AA group had an increased risk of depression compared with the no HT group (hazard ratio [HR], 2.15; 95% CI, 1.79-2.59; P < .001) and the traditional HT group (HR, 2.26; 95% CI, 1.88-2.73; P < .001), including specifically among those with metastatic disease at diagnosis (HR, 2.40; 95% CI, 1.38-4.15; P = .002).Conclusions and relevanceIn this cohort study, patients with prostate cancer who received a second-generation AA had a large and clinically significant increased risk of depression compared with patients who received traditional HT alone or no HT, including when limiting our analysis to individuals with metastatic disease at diagnosis.

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.

Dataset Information

Second-Generation Antiandrogens: From Discovery to Standard of Care in Castration Resistant Prostate Cancer.

Publications

Second-Generation Antiandrogens: From Discovery to Standard of Care in Castration Resistant Prostate Cancer.

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