Delayed Antiandrogen Withdrawal Syndrome After Discontinuation of Bicalutamide

Abstract

Prostate cancer is the most common solid tumor malignancy in men, in the United States, accounting for 233,000 new cases and 29,480 deaths in 20131. Inhibition of gonadal androgen synthesis, with or without androgen receptor (AR) blockade with an oral antiandrogen, is the mainstay of treatment for metastatic hormone-sensitive prostate cancer. Although most patients will initially respond to androgen deprivation therapy (ADT), responses are not durable, with median response duration of about 18 months2. Metastatic castration-resistant prostate cancer (mCRPC), the terminal stage of this disease, has an overall survival between 2-3 years3, 4. Common therapies include chemotherapy, targeted endocrine therapies, radiopharmaceuticals, and immunotherapy5. Prior to further therapies, if patients are on combined androgen blockade (CAB), the first maneuver is withdrawal of the antiandrogen with continuation of luteinizing hormone releasing hormone therapy. Kelly and Scher published an early description of withdrawal of an oral antiandrogen as a therapeutic maneuver in 19936. Since then, multiple case series, a randomized trial including ketoconazole, and a larger clinical trial have confirmed the clinical response to antiandrogen withdrawal (AAW) in patients who have progressed on CAB6-16. Clinical responses, observed either as a prostate-specific antigen (PSA) decline or improvement in symptoms, are noted between 1 and 6 weeks after discontinuation of the antiandrogen, depending on the half-life of the agent6-12, 15, 16. In the largest clinical trial, the median duration of response was 3 months. The recommended period of waiting for an AAW response of 4-6 weeks is based on the pharmacology of the antiandrogen and the half-life of PSA. The half-lives of flutamide, nilutamide, and bicalutamide are 7.8 hours, 56 hours, and 1 week, respectively17-19. Therefore, the time required to endure 4 half-lives for washout from the serum would be 31.2 hours, 9.3 days, and 4 weeks, respectively. The half-life of PSA in the serum is 2-3 days, resulting in an estimate 1 to 6 weeks for PSA to decline after AAW. Prior research has estimated that the AAW response, as measured by rates of PSA decline, occurs in 11 to 33% of patients undergoing antiandrogen withdrawal8, 12, 15, 16, 20, 21. To avoid misattribution of clinical benefit to a subsequent agent when commencing a new therapy immediately following AAW, clinical trials in mCRPC generally mandate a minimum 4-6 week AAW period before enrollment to ensure that a PSA decline does not occur22. We report a series of patients who underwent AAW after PSA progression on CAB while awaiting enrollment in a clinical trial. All patients had a delayed and unexpected AAW response even after continued PSA rises at 6 weeks after antiandrogen discontinuation. Appropriate institutional review board approval was obtained to describe this phenomenon.