Mechanism of Action of Flutamide in Metastatic Prostate Cancer
The correct answer is D: Impaired androgen-receptor interaction. Flutamide is a nonsteroidal antiandrogen that competitively inhibits androgen binding to androgen receptors in target tissue, thereby blocking the effects of residual androgens on prostate cancer cells despite castrate levels of testosterone achieved by GnRH agonist therapy 1.
Understanding the Clinical Scenario
This patient developed castration-resistant prostate cancer (CRPC) while on GnRH agonist monotherapy, evidenced by:
- Rising PSA levels despite continued GnRH agonist therapy 1
- New nocturnal bone pain at the metastatic site 1
- Subsequent response to flutamide addition (pain relief and tumor shrinkage) 1
The GnRH agonist had already achieved medical castration by suppressing testicular testosterone production through decreased Leydig cell stimulation 1. However, residual androgens from adrenal sources (dehydroepiandrosterone, androstenedione) and intratumoral androgen synthesis continued to drive cancer progression 2.
Mechanism of Flutamide Action
Flutamide works by competitively blocking the androgen receptor itself, not by reducing androgen production 1. Specifically:
Competitive receptor antagonism: Flutamide and its active metabolite (2-hydroxyflutamide) bind to androgen receptors in prostate cancer cells, preventing dihydrotestosterone (DHT) and testosterone from activating these receptors 3, 4
Blocks residual androgen activity: Even at castrate serum testosterone levels (0.2-0.4 ng/mL), significant androgenic activity persists in target tissues from adrenal precursors and local androgen synthesis 2. Flutamide blocks this residual activity at the receptor level 1
Paradoxical testosterone rise: With flutamide therapy, serum testosterone actually rises due to loss of negative feedback inhibition, but this testosterone cannot activate receptors blocked by flutamide 1
Why Other Options Are Incorrect
Option A (Decreased androgen aromatization): This mechanism relates to aromatase inhibitors that prevent conversion of androgens to estrogens—not relevant to flutamide's mechanism 1
Option B (Decreased Leydig cell stimulation): This is the mechanism of GnRH agonists, which the patient was already receiving 1. The GnRH agonist had already suppressed Leydig cell function and testicular testosterone production 1
Option C (Decreased peripheral androgen conversion): This describes 5-alpha reductase inhibitors (finasteride, dutasteride) that block conversion of testosterone to DHT—not flutamide's mechanism 1
Option E (Inhibition of androgen synthesis): This describes agents like ketoconazole or abiraterone that inhibit enzymes in the androgen synthesis pathway 1. Flutamide does not inhibit androgen synthesis 1, 3
Clinical Application
The FDA-approved indication for flutamide is combination therapy with LHRH agonists for metastatic prostate cancer, with the standard dose being 250 mg orally three times daily 5. The combination provides "total androgen blockade" by:
- Suppressing testicular androgen production (GnRH agonist)
- Blocking androgen receptor activation by residual androgens (flutamide) 1, 5
Important caveat: While combined androgen blockade shows only modest survival benefit over castration alone (5-year survival 25.4% vs 23.6%, HR 0.92), it can provide meaningful symptom relief and tumor response in individual patients, as demonstrated in this clinical case 1.