Enzalutamide (ENZ) was reviewed in the PCa Commentary of March/April 2014. Many important developments have taken place since then. This Commentary will discuss 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.

  • 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 prolonged by 4.9 months (18.4 v 13.6 months), a 37% reduction in the risk of death.
  • The PREVAIL trial (2014) tested ENZ/ADT in men with mCRPC prior to chemotherapy. Result: Radiographic progression-free survival (rPFS) at one year was 65% 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%.
  • In the PROSPER trial (June 2018) ENZ/ADT was moved 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 end-point was metastases-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) ENZ/ADT was tested 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 Taxotere, and the LATTITUDE and STAMPEDE trials both used abiraterone (ZYTIGA)/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:

Using an antiandrogen to replace (say) Lupron in addressing a rising PSA after primary therapy is not a new idea. Bicalutamide (Casodex, 150 mg/day) alone and also a novel combination of Casodex, 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. “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, decrease 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 1000’s 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. Its action includes two additional functions that increase ENZ effectiveness.

These two different pharmacologies produce some similar adverse effects — both cause fatigue, hot flushes, and some cognitive impairment, but an important difference is that whereas 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 about 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,” J Urol, Feb 2018. They studied 67 men with hormone naive cancer and noncastrate testosterone (230 ng/dL or greater); 39% with metastases. Enzalutamide dosage was 160 mg/day.

Findings:

  • Of 42 patients assessed at 3 years, 92.0% met the goal of a > 80% decline in PSA from baseline. “Furthermore, 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 longterm 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, +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 indicated.

The EMBARK Trial (NCT02319837 – begun December 2014):

“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 metastases-free survival. Secondary outcome measures include: overall survival, time to castration resistance, safety, and many other categories. A separate comparison of ENZ monotherapy versus leuprolide + placebo is planned.

BOTTOM LINE:

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

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