Ed Weber, M.D., Editor
November – December, 2014

Recent studies have shown that even after lowering serum testosterone (T) to <20 or 30 ng/ml with Lupron or Degarelix, the prostate still has sufficient T within the gland to drive prostate cancer proliferation, especially later in the disease when the copy number of ARs increase. However, despite the persisting functionality of testosterone  within the gland, the lowered serum T level continues to confer its well known catalogue of adverse effects.

It may be counterintuitive to some readers, but anti-androgens such bicalutamide and enzalutamide do not lower serum T. Instead, with these drugs the serum T remains at baseline values or actually increases. However, these anti-androgens effectively lower intraprostatic androgen levels and achieve functional “androgen deprivation” by an alternate mechanism compared to LHRH agonists. They block intraprostatic access of T and DHT to the AR. Because of not lowering the serum T, anti-androgens have different side-effect profiles compared Lupron and Degarelix.

Prior studies and usage mainly in Europe have demonstrated that an anti-androgen regimen of bicalutamide 150 mg/daily parallels the effectiveness of LHRH agonists in achieving a period of control over prostate cancer progression.

Now the new information:

Abstract #5001 presented at the 2013 ASCO Annual Meeting offers a promising new candidate for anti-androgen monotherapy (Xtandi) for treatment of a rising PSA after primary therapy. A phase II study was presented at the Clinical Science Symposium, “The Future of Androgen Pathways Targeting Prostate Cancer” by Dr. Matthew Smith, representing an extensive consortium of European investigators.

The study targeted 67 men with hormone-naive prostate cancer who had non-castrate T levels, i.e  > 230ng/dL. The study group included men with all stages of prostate cancer. Enzalutamide (ENZA) was prescribed at 160 mg/d. The endpoint was achieving a > 80% decline in PSA at 25 weeks. Median age was 73 years; 39% had metastases. ENZA levels stabilized at about 4 weeks. “Mean T and estrogen increased 114% and 72%, respectively.”

The main adverse effects were:

  • gynecomastia, 36%;
  • fatigue, 34%;
  • nipple pain, 19%,
  • hot flush, 18%;
  • and hypertension of significance in 6%.

Their findings and summary:  At 25 weeks 93% of men met the PSA response goal. The median PSA decrease was -99.6%, “a decline similar to castration”.

Their conclusion: “In contrast to castration, BMD [bone mineral density] remained stable and metabolic variables (fat body mass, lipid and glycemic profiles) were not substantially impacted with ENZA monotherapy over the 6 month study period.”

This study was later reported in full in Lancet, Vol 15 May 2014, by Drs. Tombal, Smith, et al. Enzalutamide  monotherapy produced similar responses in men without and with metastases: PSA decline > 90% v. 92%; PSA nadir < 4 ng/ml 93% v. 92%, respectively.  These results mimic the performance of Lupron, which typically produces a “mean PSA declines of roughly 90% or to 4 ng/mL or less over 8 months.”

The Lancet article noted that “European Union (EU) guidelines support monotherapy with the non-steroidal anti-androgen bicalutamide (oral) 150 mg/day as an alternative to ADT for patients with locally advanced prostate cancer.”  This  approval was based on data from two studies of bicalutamide versus medical or surgical castration.

Dr. Peter Iverson in his review, “Antiandrogen monotherapy: indication and results,” (Urology, 2002) concluded:
“Mature combined data (56% mortality —[an indication of sufficient “events” to allow a statistically significant result]) from 2 large randomized studies show no statistically significant difference in overall survival between bicalutamide 150-mg monotherapy and castration in patients with locally advanced, non-metastatic (stage M0) disease.” In patients with metastatic disease the difference was 6 weeks in median survival favoring castration.

Abstract 5068 presented at the 2014 ASCO  Annual Meeting built on the earlier data from the 25 week trial,
“Enzalutamide monotherapy: One-year extended follow-up of a phase 2 study in hormone-naive prostate cancer patients,”  and was presented by Dr. Tombal, again representing the European consortium.

Of the 54 men completing the year study, 53 (98.1%) had > 90% PSA decrease from baseline. Favorable metabolic variables were maintained as in the 25 week study. “Total body BMD was maintained (-0.3% from baseline). Gynecomastia occurred in 47.8% of men and fatigue in 38.8%. “Qol [quality of life] scores at 1-year follow-up of hormone-naive patients demonstrate maintenance of global health status and a decrease in sexual activity and sexual functioning.”

Their conclusion: “Extended follow-up of hormone-naive patients demonstrated sustained PSA reduction up to 1 year of with enzalutamide therapy.” 

Regarding gynecomastia: “Prophylactic breast irradiation with a single dose of electron beam radiotherapy (10 Gy) significantly reduced [by 50%] the incidence of bicalutamide-induced gynecomastia,” (Tyrrell CJ et al. Int J Radiat Oncol Biol Phys. 2004 Oct). Not all patients need radiation prophylaxis, however, since only about 50% experience moderate-severe discomfort. Anti-estrogens such as Tamoxifen can be additionally helpful.

BOTTOM LINE:  This is a small trial and its findings require extended follow-up and validation. However, this study of enzalutamide (Xtandi) in men with hormone-naive prostate cancer represents just the beginning of the quest for a new regimen that is equally or more effective than LHRH agonists, but carry a more acceptable side-effect profile.

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