Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors

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 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.

Fig. 1. The course of prostate cancer.

Reproduced with permission from Anantharaman A, Small EJ. Tackling nonmetastatic castration-resistant prostate cancer: special considerations in treatment. Expert Rev Anticancer Ther. 2017. ADT androgen-deprivation therapy, CRPC castration-resistant prostate cancer, HSPC hormone-sensitive prostate cancer, M0 nonmetastatic, Met metastatic, PSA prostate-specific antigen.

Fig. 2. Incidence of adverse events associated with ARIs reported in the final analyses of the A SPARTAN [42], B PROSPER [45], and C ARAMIS [48] clinical trials.

A SPARTAN: at final analysis, median follow-up was 52.0 months; median treatment duration in apalutamide arm was 32.9 months and in the placebo arm was 11.5 months. B PROSPER: at final analysis, median follow-up was 48.0 months; median treatment duration in enzalutamide arm was 33.9 months (95% CI 0.2–68.8) and in the placebo arm was 14.2 months (95% CI 0.1–51.3). ^aFatigue events included asthenia. ^bMusculoskeletal events included back pain, arthralgia, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal stiffness, muscular weakness, and muscle spasms. ^cFracture events included bone and joint injuries. ^dHypertension events included hypertensive retinopathy, increased blood pressure, systolic hypertension, and hypertensive crisis. ^eEvents of cognitive and memory impairment included disturbance in attention, cognitive disorders, amnesia, Alzheimer’s disease, dementia, senile dementia, mental impairment, and vascular dementia. ^fCardiovascular events included hemorrhagic central nervous system vascular conditions, ischemic central nervous system vascular conditions, and cardiac failure. ^gEvents of ischemic heart disease included myocardial infarction and other ischemic heart disease. ^hRash events included maculopapular rash, generalized rash, macular rash, papular rash, and pruritic rash. ⁱLoss-of-consciousness events included syncope and presyncope. ^jAngioedema events included urticaria, eyelid edema, periorbital edema, swollen tongue, swollen lip, face edema, laryngeal edema, and pharyngeal edema. ^kHepatic disorders included hepatic failure, fibrosis, cirrhosis, and other liver damage-related conditions, and hepatitis and liver-related investigations, signs, and symptoms. ^lThrombocytopenia events included decreases in platelet count. C ARAMIS: at final analysis, median follow-up was 29.0 months; median exposure in darolutamide arm was 18.5 months and in the placebo arm was 11.6 months. ^mCombined term comprising MedDRA terms of any fractures and dislocations, limb fractures and dislocations, skull fractures, facial bone fractures and dislocations, spinal fractures and dislocations, and thoracic cage fractures and dislocations. ⁿCombined term comprising MedDRA terms of asthenic conditions, disturbances in consciousness, decreased strength and energy, malaise, lethargy, and asthenia. ^oCombined term comprising MedDRA terms of rash, macular rash, maculopapular rash, papular rash, and pustular rash. ^pOne additional incidence of seizure occurred in the darolutamide group during the open-label period, in a patient with a history of epilepsy. ^qMedDRA High Level Group term. ^rAlthough the incidence of cardiac arrhythmia was higher with darolutamide than with placebo, both a history of cardiac arrhythmia and electrocardiogram abnormalities were present to a greater extent in the darolutamide group at baseline, as observed at primary analysis. ARI androgen receptor inhibitor, CI confidence interval, MedDRA Medical Dictionary for Regulatory Activities.

Fig. 3. The structure of apalutamide, darolutamide, and enzalutamide.

Obtained from the PubChem Open Chemistry Database.