PSA Response to Antiandrogen Withdrawal To Identify the Response on Type of Antiandrogens - Editorial

In 2021-2022, many more men globally will receive a potent AR inhibitor in either the metastatic hormone sensitive prostate cancer (mHSPC), non-metastatic castration resistant prostate cancer (nmCRPC), or mCRPC settings, with improved long term outcomes based on multiple positive phase 3 trials of abiraterone, enzalutamide, apalutamide, and darolutamide. This new form of maximal or combined androgen blockade in addition to ADT has extended survival, delaying symptomatic and metastatic progression, improving durable remissions based on PSA and imaging response criteria, major successes for our patients.

With first generation AR inhibitors such as flutamide and bicalutamide, prolonged responses to these therapies often led to anti-androgen withdrawal responses which were observed at progression after the patient stopped these agents. These withdrawal responses were due to point mutations in the ligand binding domains of the AR (such as T877A), turning these older agents into agonists that stimulated AR activity and PSA production. Withdrawal responses typically would last 3-6 months, but occasionally patients would experience prolonged withdrawal responses lasting over a year. However, the prevalence of withdrawal responses to stopping these novel AR inhibitors has not been well described.

Soo and colleagues conducted a systematic review of all studies that described withdrawal responses to abiraterone plus prednisone or enzalutamide through November of 2020. They found 23 studies encompassing 1474 men, typically with mCRPC, who were evaluable for analysis, most of whom received 1^st generation AR inhibitors (1212) but 108 were included who received a second generation AR inhibitor and 154 received abiraterone plus prednisone. Withdrawal responses were relatively common with first generation inhibitors (26% and 11% with any vs. PSA50 declines, respectively) but less common with abiraterone (26% and 4%), and rare with enzalutamide (7% and 1%). In most of these reports, durability of responses were unfortunately not described, but in those that did, these responses tended to last between a few weeks and a few months and thus were transient.