madman
Super Moderator
Abstract
Background Nonmetastatic 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.
Methods In 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 the quality of life, physical capacity, and cognitive function.
Results and conclusions While 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.
Introduction
Since the establishment of prostate-specific antigen (PSA) screening in the 1980s, prostate cancer incidence rates have risen: ~1.3 million men are diagnosed each year, and up to 20% of men present with radiographic evidence of metastases at diagnosis [1, 2]. However, after primary treatment, the localized or locally advanced disease may progress to biochemical recurrence, sometimes termed “biochemical failure,” usually within 5 years [3]. If salvage surgery or radiotherapy is not an option or is ineffective, androgen-deprivation therapy (ADT), via chemical or surgical castration with gonadotropin-releasing hormone agonists or antagonists, or orchiectomy, represents the standard of care, but most patients eventually fail to maintain suppression of PSA levels [1, 4]. The mechanisms for this have been ascribed to dysregulated androgen signaling through gain-of-function mutations, splice variants, aberrant post-receptor regulation, and intratumoral androgen synthesis [5]. Such abnormal signaling contributes to neoplastic cellular proliferation and tumor progression to the more lethal forms of the disease [6]. Castration-resistant prostate cancer (CRPC) is defined by a castrate serum testosterone level <50 ng/dL with either biochemical or radiological progression [1, 7]. In patients with CRPC, metastases detected by conventional imaging with computerized tomography (CT) or technetium-99m scintigraphy are defined as metastatic castration-resistant prostate cancer (mCRPC), whereas CRPC without radiographic evidence of metastases is categorized as nonmetastatic CRPC (nmCRPC) [1, 8]. The course of prostate cancer is summarized in Fig. 1.
*This review discusses the rationale for early treatment of patients with nmCRPC to delay metastatic progression and ultimately prolong survival. We will focus on the treatment of nmCRPC with second-generation androgen receptor inhibitors (ARIs), the importance of balancing the clinical benefit of these treatments with potential adverse events (AEs), and the consequential impact on health-related quality of life (HRQoL), physical capacity, and cognitive function.
*Diagnosing nmCRPC in clinical practice
*Rationale for treating nmCRPC
*Second-generation ARIs for nmCRPC: benefit-risk considerations
*Current treatment guidelines
*Maintaining the quality of life in patients with nmCRPC
Conclusions
Clinical development in the field of nmCRPC is evolving rapidly. The second-generation ARIs, apalutamide, enzalutamide, and darolutamide, have revolutionized the treatment landscape for nmCRPC. All three ARIs have demonstrated significant prolongation of MFS, and the recently reported final analyses of the SPARTAN, PROSPER, and ARAMIS trials indicate a significant OS benefit in patients with nmCRPC [14–16, 42, 45, 48].
Although second-generation ARIs have acceptable tolerability and maintain quality of life in patients with nonmetastatic disease, their individual safety profiles and potential for drug-drug interactions with concomitant medications should be considered. The benefit-risk profile of ARIs in patients with nmCRPC is an important clinical consideration and therapies that do not compound ADT related AEs or contribute to the additional therapeutic burden due to drug–drug interactions may be preferred [37].
In summary, while delaying the onset of metastasis and ultimately prolonging survival represents the central objective of pharmacotherapy, appropriate treatment of patients with nmCRPC must strike an individualized balance between clinical benefit and potential risk [37].
Background Nonmetastatic 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.
Methods In 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 the quality of life, physical capacity, and cognitive function.
Results and conclusions While 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.
Introduction
Since the establishment of prostate-specific antigen (PSA) screening in the 1980s, prostate cancer incidence rates have risen: ~1.3 million men are diagnosed each year, and up to 20% of men present with radiographic evidence of metastases at diagnosis [1, 2]. However, after primary treatment, the localized or locally advanced disease may progress to biochemical recurrence, sometimes termed “biochemical failure,” usually within 5 years [3]. If salvage surgery or radiotherapy is not an option or is ineffective, androgen-deprivation therapy (ADT), via chemical or surgical castration with gonadotropin-releasing hormone agonists or antagonists, or orchiectomy, represents the standard of care, but most patients eventually fail to maintain suppression of PSA levels [1, 4]. The mechanisms for this have been ascribed to dysregulated androgen signaling through gain-of-function mutations, splice variants, aberrant post-receptor regulation, and intratumoral androgen synthesis [5]. Such abnormal signaling contributes to neoplastic cellular proliferation and tumor progression to the more lethal forms of the disease [6]. Castration-resistant prostate cancer (CRPC) is defined by a castrate serum testosterone level <50 ng/dL with either biochemical or radiological progression [1, 7]. In patients with CRPC, metastases detected by conventional imaging with computerized tomography (CT) or technetium-99m scintigraphy are defined as metastatic castration-resistant prostate cancer (mCRPC), whereas CRPC without radiographic evidence of metastases is categorized as nonmetastatic CRPC (nmCRPC) [1, 8]. The course of prostate cancer is summarized in Fig. 1.
*This review discusses the rationale for early treatment of patients with nmCRPC to delay metastatic progression and ultimately prolong survival. We will focus on the treatment of nmCRPC with second-generation androgen receptor inhibitors (ARIs), the importance of balancing the clinical benefit of these treatments with potential adverse events (AEs), and the consequential impact on health-related quality of life (HRQoL), physical capacity, and cognitive function.
*Diagnosing nmCRPC in clinical practice
*Rationale for treating nmCRPC
*Second-generation ARIs for nmCRPC: benefit-risk considerations
*Current treatment guidelines
*Maintaining the quality of life in patients with nmCRPC
Conclusions
Clinical development in the field of nmCRPC is evolving rapidly. The second-generation ARIs, apalutamide, enzalutamide, and darolutamide, have revolutionized the treatment landscape for nmCRPC. All three ARIs have demonstrated significant prolongation of MFS, and the recently reported final analyses of the SPARTAN, PROSPER, and ARAMIS trials indicate a significant OS benefit in patients with nmCRPC [14–16, 42, 45, 48].
Although second-generation ARIs have acceptable tolerability and maintain quality of life in patients with nonmetastatic disease, their individual safety profiles and potential for drug-drug interactions with concomitant medications should be considered. The benefit-risk profile of ARIs in patients with nmCRPC is an important clinical consideration and therapies that do not compound ADT related AEs or contribute to the additional therapeutic burden due to drug–drug interactions may be preferred [37].
In summary, while delaying the onset of metastasis and ultimately prolonging survival represents the central objective of pharmacotherapy, appropriate treatment of patients with nmCRPC must strike an individualized balance between clinical benefit and potential risk [37].
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