Analyzing Adverse Events Related to ARSi Treatments for nmCRPC

Androgen deprivation therapy (ADT) is used as a first-line treatment for prostate cancer, yet cancer tumors often adapt to ADT by maintaining sustained androgen receptor (AR) signaling, often resulting in aggressive castration-resistant prostate cancer (CRPC). Next-generation androgen receptor signaling inhibitors (ARSis) have been used to inhibit AR signaling to stop tumor adaptation and are quickly becoming a standard treatment for prostate cancer. However, the side-effect profiles of ARSis are still unknown.

Researchers evaluated existing literature on adverse events in the ARSi drugs abiraterone, apalutamide, darolutamide, and enzalutamide for the treatment of metastatic CRPC (mCRPC), nonmetastatic CRPC (nmCRPC), and metastatic castration-sensitive prostate cancer (mCSPC) to determine how the drugs’ side-effect profiles compare.

Data on double-blind, randomized controlled trials (RCTs) of ARSi therapy up to September 2022 were collected from the PubMed, Web of Science, and Embase databases based on the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Studies were included if they were double-blind RCTs comparing abiraterone acetate, apalutamide, darolutamide, or enzalutamide with ADT, docetaxel, or ARSi therapies such as bicalutamide, nilutamide, or flutamide in the treatment of prostate cancer.

Based on surface under the cumulative ranking curve (SUCRA) values, enzalutamide was ranked as the most toxic treatment in regard to hypertension outcomes (SUCRA 0%) in patients with mCRPC or nmCRPC and was also ranked as the most toxic regarding headache across all prostate cancers (SUCRA 0% for mCRPC, 1% for nmCRPC, and 3% for mCSPC). While enzalutamide was ranked as the most toxic ARSi therapy, the side-effect profiles of all ARSi drugs were similar.

The side-effect profile of enzalutamide points to the importance of blood-pressure monitoring for patients with prostate cancer who are prescribed the drug, and future studies should examine possible connections between ARSi therapy and cardiovascular and neurological risk.