Antiandrogen Withdrawal Syndrome After Stopping Enzalutamide in Metastatic Castration-Resistant Prostate Cancer: Two Case Reports & Review

[God_Loves_Me]

cureus.com/articles/267994-...

Abstract

Metastatic prostate cancer treatment is based on androgen deprivation, with pharmacological or surgical castration. This treatment may be complemented with the addition of antiandrogenic drugs. In the setting of prostate-specific antigen (PSA) progression and subsequent suspension of the antiandrogenic drug, there might occur a phenomenon of antiandrogen withdrawal, leading to a decrease in PSA and/or improvement in imaging or clinical outcomes after discontinuation of the antiandrogenic agent. Although there are some descriptions of withdrawal after the cessation of enzalutamide, the physiological mechanism behind it, as well as its frequency and impact on patient survival, remain unknown. We present two clinical cases of antiandrogenic withdrawal after enzalutamide discontinuation and discuss potential contributing factors to this phenomenon.

Introduction

Prostate cancer is the second most common cancer worldwide, with more than 1.4 million new cases globally in 2020 [1]. In Portugal, 6,912 new cases were recorded in 2019 (data from the national cancer registry of 2019) with a standardized incidence rate for the European population of 90.9 per 100,000 inhabitants. Its prevalence is increasing due to population growth and aging and to increasing overall survival (OS) of these patients, probably related to new and more effective treatment options [2]. This cancer is unique because of its relationship with androgens as a growth factor. Hence, androgen deprivation is the major strategy in clinical practice, and metastatic prostate cancer is divided into two clinical states regarding its sensitivity to androgen deprivation therapy (ADT) as “hormone-sensitive prostate cancer” (mHSPC) and “castration-resistant prostate cancer” (mCRPC) [3].

In the metastatic setting, prostate-specific antigen (PSA) levels are used for monitoring treatment response, and a rise in PSA levels often indicates disease progression before radiological progression, although up to a quarter of patients may experience disease progression without an increase in PSA levels. On the other hand, a decrease in PSA levels is usually correlated with disease control [4-6].

Antiandrogen withdrawal syndrome (AAWS) is defined as a decrease in PSA levels in more than half of the baseline value after discontinuation of antiandrogen therapy in the context of combined androgen blockade [7]. This was initially described for older agents, such as flutamide, bicalutamide, and nilutamide; moreover, before the approval of enzalutamide and abiraterone, this phenomenon could be used to postpone the beginning of chemotherapy in mCRPC [7]. AAWS after enzalutamide is not well established. Some evidence suggests that AAWS may happen with enzalutamide in a minority of patients with mCRPC. We report two cases in which AAWS after enzalutamide occurred.

Case Presentation

Case 1

A 68-year-old male, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, with a medical history of hypertension, dyslipidemia, and benign prostate hyperplasia, was diagnosed in June 2013 with prostate cancer Gleason 9 (4+5). He was submitted to radical prostatectomy, and the tumor was staged as pT3a, pN0, cM0, and R0 surgery, with a detectable PSA after surgery (0.45 ng/mL). He underwent postoperative radiotherapy in December 2013 (external radiotherapy to the pelvic region, total radiation of 66 Gy in 33 fractions). The PSA nadir was 0.229 ng/mL (four months after the end of radiotherapy).

Two years after the diagnosis, biochemical recurrence occurred (PSA 14.45 ng/mL) with radiological evidence of bone and nodal metastases, defining mHSPC. The patient was asymptomatic and in December 2015, ADT was started with three-monthly goserelin 10.8 mg subcutaneously. Figure 1 shows a schematic representation of the evolution of PSA over time and the drugs administered.

[Justfor_]

Have you heard about the Laffer* curve in economics?

Same underline principle IMO. When cells are completely deprived from T they will find an alternate supply route which being out of the normal regulatory channels can easily go wild.

For just this reason, I believe in and practice the Minimum Efective Dosage instead of of the Maximum Tolerable one, plus adjusting it to a low, but NOT UNDETECTABLE, PSA count.

(*) American economist Arthur Laffer developed a bell-curve analysis in 1974 that plotted the relationship between changes in the government tax rate and tax receipts. The analysis is known as the Laffer curve.

[NanoMRI in reply to Justfor_]

brilliant!!

[MateoBeach]

General understanding is that the anti androgen which binds to and blocks the androgen receptors. After some time (a few years typically) there are AR mutations such that the drug switches to activating rather than blocking the receptor, which causes acceleration of growth of the cancer cell. Thus PSA begins rising faster. When the drug is stopped this stimulation is removed and PSA goes back down. It should not be used again. Of the available androgen receptor blockers, darolutamide is the least susceptible to this antagonist to agonist switching failure. MB