PCa Commentary | Volume 131 – February 2019

Posted by Edward Weber | February 2019

ENZALUTAMIDE (‘XTANDI’): AN UPDATE: The Many Faces of Enzalutamide

Many important developments have taken place since Enzalutamide (ENZ) was reviewed in the March/April 2014 issue. This Commentary will discuss these developments and the current indications for ENZ and new studies of ENZ as monotherapy. A subsequent Commentary will address sequencing, resistance, and possible potentiation of immunotherapy.

Current Indications for Enzalutamide:

It is traditional, and possibly inappropriate, to initially test new agents in more advanced disease states, and if found effective, sequentially introduce them at earlier stages. The testing of enzalutamide has followed this pattern. In a series of large randomized Phase III clinical trials, ENZ (160 mg/day) was combined with androgen deprivation therapy (ADT), i.e., Lupron or orchiectomy, and tested in all trials against ADT plus a placebo.

  • In the AFFIRM trial (2012), ENZ/ADT was tested in men with metastatic castration-resistant prostate cancer (mCRPC) after progression following docetaxel chemotherapy.
  • Result: median overall survival was prolonged by 4.9 months (18.4 v 13.6 months), and risk of death was reduced by 37%.
  • The PREVAIL trial (2014) tested ENZ/ADT in men with mCRPC prior to chemotherapy. This resulted in 65% Radiographic progression-free survival (rPFS) at one year for ENZ/ADT v. 14% for ADT/placebo. At the cut-off of the trail, ENZ/ADT had reduced the risk of death by 29%.
  • The PROSPER trial, published in June 2018, moved ENZ/ADT further forward in the treatment schema and tested in men free of metastases (i.e., CT and bone scan negative) experiencing PSA progression on ADT (PSA doubling time < 10 months) following primary therapy. The trial endpoint was metastasis-free survival (MFS).
    Result: MFS for ENZ/ADT was 36.6 v. 14.7 months for ADT/placebo.

[Results similar to the findings in PROSPER were reported for the combination of the newer antiandrogen, apalutamide (Erleada), in the same category of patients.]

  • Reported only partially, the multi-national ARCHES trail (December 2018) tested ENZ/ADT in a small, but numerically significant subset of men, estimated to be ~38,000 men yearly, presenting at diagnosis with metastatic spread (i.e. hormonally sensitive metastatic cancer). As of December 2018, the only information reported was that ENZ/ADT significantly prolonged radiographic PFS v. placebo.

[Three other trials have also addressed therapy for newly diagnosed hormone sensitive metastatic cancer combining new therapies with ADT v. ADT alone. One trial, CHAARTED (2014), combined ADT with docetaxel, and the LATITUDE and STAMPEDE trials both used abiraterone/ADT. All three showed significant gains in overall survival for combined therapy.]

The question, currently unanswered and under extensive study, is whether these men would benefit from also treating the primary tumor with surgery or radiation. Early data from the STAMPEDE trial reported a 3-year survival benefit for adding radiation directed to the primary tumor for men with low volume metastatic disease.

Is There One Step Further for ENZ in the Treatment Sequence? – Monotherapy with ENZ in men with rising PSA following primary therapy.

Brief background and underlying pharmacology:

Past methods have included the use of an antiandrogen to replace a treatment such as Lupron in addressing a rising PSA after primary therapy. Bicalutamide (Casodex, 150 mg/day) alone and also a novel combination of bicalutamide (50 mg/day), and the 5-alpha I&II reductase inhibitor dutasteride (Avodart) both have been studied in this space with credible results.

A large study (Thomsen et.al., European Journal of Cancer, 2015) reported at median of 14.6 years follow-up a regimen of 150 mg qd of Casodex v. placebo in men showing a PSA progression after primary therapy. The study states that “bicalutamide significantly improved [by 27%] overall survival in patients with locally advanced disease.” There was no benefit for men with localized disease.

Lupron, Degarelix, and orchiectomy suppress testicular testosterone (T) production, lower serum T, decreases the intraprostatic availability of T for conversion (by the alpha reductases) into the more potent dihydrotestosterone (DHT), and complete the pathway by reducing androgen signaling from the activated androgen receptor (AR).

In contrast, antiandrogen functions directly within the prostate cell and block access of T and DHT to the AR. This inhibition very effectively reduces AR signaling to the thousands of genes that comprise the androgen response family of genes (including the gene for PSA). ENZ has greater affinity than Casodex for the AR ligand pocket and is about 10 times more potent than Casodex.

ENZ’s action includes two additional functions that increase effectiveness. These two different pharmacologies produce some similar adverse effects — both cause fatigue, hot flushes, and some cognitive impairment. An important difference is that the LHRH inhibitors lower serum T to castrate levels, ENZ raises serum T by ~114% thus preserving bone integrity. In contrast, Lupron reduced bone density at 1 year by approximately 5% or more.

Encouraged by the potential of primary antiandrogen therapy, Tombal et al. conducted a phase II study: “Long-Term Antitumor Activity and Safety of Enzalutamide Monotherapy in Hormone Naive Prostate Cancer: 3-Year Open Label Use Follow-up Results.” They studied 67 men with hormone naive cancer and non-castrate testosterone (230 ng/dL or greater); 39% of which metastases. Enzalutamide dosage was 160 mg/day.


  • Of the 42 patients assessed at 3 years, 92.0% met the goal of a >80% decline in PSA from baseline. Additionally, “37 of 42 patients (88.1%) who were still on treatment [at 3 years] had a PSA decline of 90% or greater from baseline.” The average PSA decline from baseline at 3 years was 91.7%, with 71.6% reaching 0.1 ng/mL or less.
  • The mean bone mineral density (BMD) at 3 years compared to baseline ranged between -2.7% (hip) and -0.1% (spine). By comparison the mean BMD decreases reported for long-term Lupron range from -1.4% to -7.6%. At 3 years of ENZ therapy there was a decrease in bone turnover markers, a biologic indicator of relative bone density preservation.
  • Components of the metabolic syndrome responded favorably to ENZ. Lipid profile parameters increased by only a modest 6%. Total cholesterol decreased by -3.4% compared to Lupron, which increased by +9%. Fasting glucose levels were maintained (i.e. no increase in hemoglobin A1c).
  • Adverse effects reported during 3 years of treatment: gynecomastia, 49.3%; fatigue, 35.8%; hot flushes, 22.4%, and nipple pain, 20.9%. Infrequent adverse effects; diarrhea, 4.5%; hypertension, 3.0%; nausea, 7.5%; pain in extremities, 3.0%. Other sources report a ~1% incidence of seizures. As assessed by a standard questionnaire, “sexual activity was moderately decreased at 3 years relative to baseline.” Two men discontinued treatment due to fatigue and 2 for depression.
  • A significant limitation of this study is its small size. Before ENZ as monotherapy can take its place as an indicated treatment, study in a large trial is necessary.

The EMBARK Trial (NCT02319837 – begun December 2014):

The EMBARK Trial is “A Phase 3, Randomized, Efficiency and Safety Study of Enzalutamide Plus Leuprolide, Enzalutamide Monotherapy, and Placebo Plus Leuprolide in Men with High-Risk Nonmetastatic Prostate Cancer Progressing After Definitive Therapy.”

Eligibility for this study requires a PSA doubling time of < 9 months; PSA of > 1 ng/mL post prostatectomy and PSA of at least 2 ng/mL above nadir post radiation therapy; and serum testosterone > 150 ng/dL.

Primary outcome measure is MFS. Secondary outcome measures include: overall survival, time to castration resistance, safety, and many other categories. A separate comparison of ENZ monotherapy versus leuprolide plus placebo is planned.


Enzalutamide provides substantial benefit at many stages in the progression of prostate cancer. The EMBARK trial may establish enzalutamide as an effective alternative to Lupron in the treatment of men with a rising PSA following primary therapy.

Your comments and requests for information on a specific topic are welcome e-mail ecweber@nwlink.com.
Please also visit https://prostatecancerfree.org/prostate-cancer-news for a selection of past issues of the PCa Commentary covering a variety of topics.

“I want to thank Dawn Scott, Staffperson, Tumor Institute Radiation Oncology Group, & Mike Scully, Librarian, Swedish Medical Center for their unfailing, timely, and resourceful support of the Commentary project. Without their help this Commentary would not be possible.”


Edward Weber, MD, is a retired medical oncologist living in Seattle, Washington. He was born and raised in a suburb of Reading, Pennsylvania. After graduating from Princeton University in 1956 with a BA in History, Dr. Weber attended medical school at the University of Pennsylvania. His internship training took place at the University of Vermont in Burlington.

A tour of service as a Naval Flight Surgeon positioned him on Whidbey Island, Washington, and this introduction to the Pacific Northwest ultimately proved irresistible. Following naval service, he received postgraduate training in internal medicine in Philadelphia at the Pennsylvania Hospital and then pursued a fellowship in hematology and oncology at the University of Washington.

His career in medical oncology was at the Tumor Institute of the Swedish Hospital in Seattle where his practice focused largely on the treatment of patients experiencing lung, breast, colon, and genitourinary cancer and malignant lymphoma.

Toward the end of his career, he developed a particular concentration on the treatment of prostate cancer. Since retirement in 2002, he has authored the PCa Commentary, published by the Prostate Cancer Treatment Research Foundation, an analysis of new developments in the prostate cancer field with essays discussing and evaluating treatment management options in this disease. He is a regular speaker at various prostate cancer support groups around Seattle.