Second-Line Hormonal for Castrate-Resistant Prostate Cancer

Flutamide

When patients fail the first-line ADT with LHRH agonist/antagonist, antiandrogens are usually added for a complete androgen blockade. Among antiandrogens, flutamide is one of the first nonsteroidal pure antiandrogens as it inhibits androgen uptake and/or nuclear binding of androgen in target tissues. It has a relatively short half-life of 5.5 h. Following rapid absorption, the drug is metabolized to a biologically active alpha-hydroxylated derivative. Among the first-generation antiandrogens, flutamide has the lowest binding affinity for the androgen receptor.

The benefit of adding flutamide to men who have failed the standard ADT was first reported by Labrie et al. in 1988. In this study, a total of 209 patients with disease progression were treated with flutamide following orchiectomy or DES or an LHRH agonist. Overall response rate was 34.5% (13 patients complete response, 20 partial response, 39 stable disease). Probability of survival at 2 years for partial, stable, and nonresponders was 87%, 67%, and 17%, respectively.

Deferred use of antiandrogens following disease progression was further assessed by Fowler et al. Their study included 45 patients with localized cancer and 50 patients with metastatic disease. Following flutamide therapy, a PSA decrease of ≥50% was noted in 32 (80%) and 27 (54%) patients, respectively.

Currently, the approved indications for the use of flutamide include the following: in combination with LHRH agonists, adjunctive therapy to orchiectomy, and prior to and during definitive external beam radiotherapy for patients with bulky locally advanced prostate carcinoma. Adverse effects include gastrointestinal symptoms, gynecomastia, breast tenderness, and hepatitis. Postmarketing studies have noted occasional hospitalizations due to liver dysfunction as well as rare instances of deaths. Liver function tests are recommended prior to initiation, monthly for the first 4 months of therapy and periodically thereafter.

Bicalutamide

Bicalutamide is an oral nonsteroidal competitive inhibitor of androgen receptor. As with flutamide, bicalutamide is approved for combination therapy with LHRH analog for the treatment of metastatic prostate cancer. It has a relatively long half-life of 6 days and is extensively metabolized in the liver. Adverse effects are similar to flutamide and include hepatitis. Thus, monitoring liver function is mandatory. The concept of bicalutamide withdrawal effect has been analyzed, as discussed later.

The use of high-dose bicalutamide in patients previously treated with long-term flutamide therapy has been described. In a pilot study of 31 patients with progressive disease treated with 150 mg bicalutamide daily, Joyce et al. reported a ≥50% PSA decline rate in 7/31 patients (22.5%), overall duration of response 4 months (3–13+ months). Response rate in patients on ADT + long-term flutamide was 6 out of 14 (43%).

Nilutamide

Nilutamide is another oral nonsteroidal agent that binds and inhibits androgen receptor. Its rapid and complete absorption results in persistent plasma concentrations followed by extensive liver metabolism and eventual excretion in urine. The elimination half-life of nilutamide is approximately 41–49 h. Nilutamide is FDA approved to be used in combination with surgical castration for the treatment of metastatic prostate cancer.

In 2001, Desai et al. reported their series on the use of nilutamide as a second-line hormonal agent. In men who failed prior antiandrogen therapy, 7 of 14 (50%) patients treated with nilutamide experienced a greater than 50% decline in their serum PSA levels. In a separate study by Kassouf et al., a retrospective analysis of 28 men with castration-resistant prostate cancer subsequently treated with nilutamide revealed that 18 men (64%) experienced a reduction in PSA and 12 men had greater than 50% PSA decline (48%).

Side effect profile of nilutamide is similar to the other nonsteroidal antiandrogens. A notable adverse effect is alcohol intolerance, presenting as facial flushing, malaise, and hypotension. Other unique side effects include a 13% to 57% incidence of delay in adaptation to dark, ranging from seconds to a few minutes. Postmarketing data also indicate a 2% incidence of interstitial pneumonitis and pulmonary fibrosis, usually presenting within the first 3 months, leading to hospitalization and potential death. Monitoring parameters include liver function tests, chest X-ray ± pulmonary function tests at baseline, first 4 months of treatment then periodically thereafter. Table 57.1 summarizes the clinical indications, mechanism of action, and adverse effects of common antiandrogens.