Nilutamide (Nilandron)

A Seldom Used Alternative Antiandrogen for HRPC Patients

It can also be used as a 2nd line hormonal therapy

Author: Howard Hansen

Date: 25 November 2008

Introduction

Nilandron (nilutamide) is a nonsteriodal androgen receptor antagonist . It has an affinity for androgen receptors, but not for progestogen, estrogen or glucocorticoid receptors. Its half life is 56 hours with peak plasma levels being reached within 3 hours of a single dose.  Nilutamide has a chemical structure unique from that of Casodex (bicalutamide) and Eulexin (flutamide.) Casodex is frequently used along with LHRH agonists such as Lupron or Zoladex for combined androgen blockade in hormone sensitive men.

For an overview of hormonal therapy listen to a talk given by Ian Tannock at the ESMO 2008 conference in Stockholm, On the Changing Face of Hormonal Therapy  go to

http://esmo.onsite.tv/data/popup_index.htm?presentationPath=session3/presentation1

To place nilutamide use in a 2nd line hormonal therapy context follow a sequence of hormonal therapies following mostly the one found in a paper by B. Seruga and Tannock (1) proceeding as follows:

1. Start with LHRH agonist monotherapy (Lupron or Zoladex). ==> failure.

2. Add an antiandrogen such as Casodex ==> response, then failure or no response.

3. Withdrawal of the antiandrogen ==> if PSA decreases and/or clinical regression of tumors = response or if PSA continues to increase = failure.

4. The next step is to treat with ketoconazole and a glucocorticoid such as hydrocortisone or a glucocorticoid such as dexamethasone alone.

5. Next would be to try an estrogen such as diethylstilbestrol (DES) or transdermal estrogen patches (the estrogen could be used instead of ketoconazole or simultaneously with it.)

6. Or one could add an alternative antiandrogen from the one originally used. Nilutamide is one possibility.

There are several clinical trials involving nilutamide as an alternative antiandrogen in HRPC men. Table 1 below summarizes each of these studies.

Table 1. Nilutamide as a 2nd Line Hormone Therapy. Review of Trials.

(a) Seven had been treated with prior bicalutamide), five with both bicalutamide and flutamide, and two had received bicalutamide and prior chemotherapy.

(b) 3 patients (20%) had brief PSA responses of less than 50%.

(c) All patients had previously received at least 1 antiandrogen (flutamide, then bicalutamide in 11 pts or bicalutamide 50mg 1st, then 150mg in 17 pts.)

In addition, all patients had medical or surgical castration, which failed. All patients had to have failed antiangrogen withdrawal.

(d) PSA response rate (≥ 50% Decrease) in patients who had a previous antiandrogen withdrawal response (5 of 5 pts - 100%) vs a non-response (3 of 17 pts, 18%.)  200mg vs 300mg/day - no significant difference seen in PSA response.

(e) Half of pts had previously used an antiandrogen (5 of 12 bicalutamide, 1/12 with flutamide.) One patient had CT evidence of progression without PSA progression. Progression-free survival of more than 6 months was noted in both antiandrogen (4/6) and non-antiandrogen (2/6) pretreated patients.

(f) 3/12 patients stopped taking nilutamide due to toxicities.

(g) Responders seemed to be mostly those who had received an LH-RH agonist or had had an orchidectomy as their 1st line hormone treatment. 

(h) Patients had radiographic or PSA progression on at least one antiandrogen (not nilutamide) despite continued androgen suppression and standard antiandrogen withdrawal periods. Median Gleason score 7 (6-9 month range). Median number of previous 2nd line therapies was 2 (1-4 range).  All had failed bicalutamide. 13 of 16 had radiographically evident disease, 9 with bone metastases and 4 with measurable metastases.

Side Effects

Nilutamide has a few unique, reversible side effects:

• Light-dark adaptation disorders (30%).

• Alcohol intolerance (5%).

• A severe, but rare interstitial pneumonitis (< 2%).

Other side effects from various papers are:

• Reference (5) noted that in 20% of the patients, the most common reversible side effect was mild to moderate visual adaptation effects.

• Reference (6) listed the following side effects: No grade 3/4 toxicity; the most frequent grade 1/2 toxicities were constipation (three), sensory neuropathy (four), fatigue (six), and visual changes (two) involving transiently altered colour vision and sensitivity to light, respectively.

Discussion

Most often, it appears that the FDA approved dose of 150mg/day of nilutamide is being used, although some studies have used 200 and 300mg/day.  Patients might have a better chance of a PSA response if they did have an antiandrogen withdrawal response while taking bicalutamide.  Also there might be a better response for patients who did respond to bicalutamide longer. 

One trial reported here seems to have had a negative outcome (Davis NB (6).) Why they did not see any activity of nilandron in their trial is not readily apparent. Perhaps it was the extent of the metastatic disease present.

Overall, PSA responses ranged from zero to 50%. There was few analyses of measurable disease and there were several retrospective analyses as opposed to the preferred prospective clinical trial. Also, most of the studies had very few patients.

References
 

1. B. Seruga and I. F. Tannock, The changing face of hormonal therapy for prostate cancer, Ann Oncol 2008 19: vii79-vii85; doi:10.1093/annonc/mdn477.

2. Desai A, Stadler WM, Vogelzang NJ, Nilutamide: possible utility as a second-line hormonal agent, Urology. 2001 Dec;58(6):1016-20. PMID: 11744479.

3. Kassouf W, Tanguay S, Aprikian AG, Nilutamide as second line hormone therapy for prostate cancer after androgen ablation fails, J Urol. 2003 May;169(5):1742-4. Comment in: J Urol. 2003 May;169(5):1745-6.

PMID: 12686822

4. A. O. Sartor, D. Lifsey, A. C. Dwight, Surprising activity of nilutamide in post-castration progressive prostate cancer, Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 4762. 

5. Nakabayashi M, Regan MM, Lifsey D, Kantoff PW, Taplin ME, Sartor O, Oh WK, Efficacy of nilutamide as secondary hormonal therapy in androgen-independent prostate cancer, BJU Int. 2005 Oct;96(6):783-6.  PMID: 16153200.

6. Davis NB, Ryan CW, Stadler WM, Vogelzang NJ, A phase II study of nilutamide in men with prostate cancer after the failure of flutamide or bicalutamide therapy, BJU Int. 2005 Oct;96(6):787-90. PMID: 16153201.

7. Bülent Akduman, MD; E. David Crawford, MD; Ali M. Ziada, MD, Long-Term Follow-up of Four Patients with Advanced Prostate Cancer Treated With Nilutamide After Failure of Other Antiandrogens. The full article is at http://www.pcaw.com/info_articles/articles/follow-up.html

Anecdotal Reports

Feb 4, 2008 hrpca post by RV: I tried Nilandron as a 2nd line HT and it put me in the hospital with interstitial pneumonia. It was pretty scary. I wore an oxygen supply for a few months. But, thank goodness, the condition was reversible and I was back to normal in about 6 months. I knew about the small risk, but did not think it would apply to me. Here's the timeline:

10/08/05 Changed from 50 mg/day Casodex to 150 mg/day Nilandron

11/21/05 Stopped 150 mg/day Nilandron – Hospitalized: Pneumonitis

12/15/05 First appointment with Oncologist. Resumed 50 mg day Casodex.

Another patient (HK) reports on his experience with nilutamide: Nilandron and Lupron combo has now lowered my psa to 5.6 from over 13 after 5 weeks. This is exceptionally good news. I wear amber glasses at night to drive and then have no problem. Energy is good, I walk 2 miles a day, mental processes not as sharp
as they once were but maybe just due to being 62 now.