A Brief Synopsis – Present Status; Current Research
Enzalutamide is now accepted as an important new treatment for metastatic castration-resistant prostate cancer (mCRPC) post docetaxel on the basis of the large randomized, placebo controlled trial, AFFIRM. Enzalutamide (E) will likely soon be FDA approved for treatment of men with mCRPC prior to chemotherapy on the strength of the PREVAIL trial. A promising Phase II trial suggests an efficacy similar to LHRH inhibitors (e.g. Lupron) in non-castrate men with progressive cancer. As experience with enzalutamide matures research is focusing on resistance to the drug and the mechanisms of resistance; concerns of cross-resistance with other agents; and sequencing, especially with its sister drug, abiraterone (Zytiga). Ongoing protocol studies are investigating relevant issues that address clinical practice. This synopsis will briefly summarize the current status of these subjects.

PIVOTAL ENZALUTAMIDE CLINICAL TRIALS

The AFFIRM Trial: First reported in June 2012, the trial found a median overall survival (mOS) of 18.4 months v. 13.6 months for the placebo arm, i.e. a 37% reduction of the rate of death. The PSA response rate (with response defined as an 80% or more decrease in PSA from baseline) was > 50% in 54% of men and > 90% in 25%. The time to progression for E was 8.3 months v. 3.0 months for placebo.

The PREVAIL Trial: As reported by TM Beer, NEJM, Jul 2014, and with the data still maturing at a median follow-up of 31 months, the estimated mOS for E was 32.4 months v. 30.2 months for placebo, i.e. a 30% decrease in the risk of death. “At 12-month follow-up the investigators demonstrated a 65% rate of PFS [progression-free survival] in the enzalutamide arm compared to 14% in the placebo arm …”

The time to initiation of chemotherapy following enzalutamide for men receiving the drug was 28 months v. 10.8 months for placebo. The occurrence of radiographic progression was reduced 81% compared to placebo. The objective soft tissue response for the drug was 58%.

The major adverse events were fatigue, 36%; back pain, 27%; and constipation, 22%.

Phase II Trial of Enzalutamide in hormone-naive men: In European Urology, January 2015, Tombal et al. reported “Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-Naive Prostate Cancer: 1- and 2-Year Open-label Follow-Up Results.”

In this small study of 67 men the mean PSA was 18.2, and eligibility required a testosterone level of
> 230 ng/dL. Of the 45 men still on study at 97 weeks 100% showed a > 90% decline in PSA from baseline; 100% achieved a PSA value of less than 4 ng/ml; and in 73% the PSA was < 0.1 ng/ml. These declines were seen equally in men with and without metastatic disease. “Of 26 patients with metastatic disease at baseline, 13 (50%) had a complete response and four (15.4%) has a partial response…”

Bone density was maintained. At 97 weeks the serum testosterone had doubled, serum DHT rose 74%. The serum estradiol (E2) increased by 81%, which may account for the maintenance of bone density (Vandenput et al. J Clin Endocrinol Metab 2014 Jul). Cholesterol rose 5%, hemoglobin A1c fell -4%, and the fasting glucose decreased -1%.

Principle adverse effects were fatigue, gynecomastia, hot flushes and nipple pain.

As reference, degarelix therapy results in a median PSA level of 0.5 ng/ml at one year and maintains a level of  <2 ng/ml over 5 years.

BRIEF SUMMARY OF CURRENT CLINICALLY RELEVANT STUDIES REPORTED IN THE LITERATURE:

Pharmacology: Dosed at the recommended 160mg/day, the serum half-life of enzalutamide is 5.8 days and a steady state is achieved at 28 days. The drug is metabolized in the liver, but only severe hepatic dysfunction affects excretion. Renal excretion is negligible. Enzalutamide may be taken in a single dose with food or without. (Gibbons et al., Clin Pharmacokinet. 2015 Apr)

Enzalutamide v. Bicalutamide (B): At the May 2015 AUA meeting, Dr. Higano reported a Phase II study comparing these two drugs in men with nonmetastatic or metastatic CRPC. PFS for E was 19.4 months v. 5.7 months for bicalutamide (Casodex) dosed at 50 mg/day.

A second trial reported at the AUA meeting compared the same drugs and included only CRPC patients with metastases: median PFS for E was 15.7 months v. 5.8 months for B. “Median time to PSA response of 90% decrease was 5.4 months in the enzalutamide group.”

Predicting Response to enzalutamide (and abiraterone): The duration of response to primary hormone therapy predicts time to progression on subsequent enzalutamide (and abiraterone [A]) treatment. In the study of 51 men with mCRPC the median time to progression on primary ADT was 1.9 years. Men receiving E or A whose progression on primary ADT was < 1 year  progressed on E or A in 3.4 months; for progression on ADT after 1 year, 7.6 months; and for progression on ADT beyond 5 years, the duration of E or A response was 8.1 months. (J Hung AUA 2015 poster)

Cross-resistance:  van Soest et al. (Eur Urol. June 2015) presented a potentially clinically significant finding in their study of mice harboring enzalutamide resistant tumors. Docetaxel effectiveness was diminished in castrated E resistant mice. “By contrast, cabazitaxel remained highly effective in enzalutamide-resistant tumors and demonstrated superior antitumor activity compared to docetaxel ….”

… and conversely:

As reported by Evan Yu, Bruce Montgomery et al. (Prostate Cancer and Prostatic Diseases. Jan 2015), “Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel.” The study analyzed 310 men with mCRPC who had been treated with enzalutamide. The median PSA progression-free survival for treatment with E alone was 5.5 months; for those with prior abiraterone therapy PSA-PFS was 4 months; prior docetaxel, 4.1 months; and both prior abiraterone and docetaxel, 2.8 months. Of those who had no response to abiraterone, 27% showed a 30% PSA decline.

… taken together the studies show a pattern of overlapping cross-resistance among these three drugs.

A small study of 37 men with mCRPC suggested that men with AR-V7 positive cancer responded to Docetaxel to a similar extent as those who lack the AR-V7 splice variant. The PSA progression-free survival was insignificantly different in the two groups.  These men had received prior ADT therapy and half had prior docetaxel treatment; 46% had detectable AR-V7-positive CTC. “The median PFS did not differ significantly according to AR-V7 status and was 4.5 months and 6.2 months in the AR-V7-positive and AR-V7-negative patients (P=.06).” (Avolinbsky, JAMA Oncology. June 2015)

Primary and Induced Resistance:  Androgen receptors encoded from AR splice variants lack the ligand binding domain through which testosterone and DHT function. As a consequence the androgen receptor blocker enzalutamide and androgen synthesis inhibitor, abiraterone, are functionless. It is estimated that in the early stage of prostate cancer 11% of men predominantly harbor the AR-V7 variant and are de novo unresponsive to E or A. The splice variant ARs, however, are active on their own and are associated with more aggressive cancer. The best studied variant is AR-V7, but other AR splice variants, e.g.  ARv567es, are now recognized — and there are more. [There is suggestive data that indomethacin can reverse enzalutamide resistance. (Liu et al. Cancer Res. Apr 2015)]  

Unfortunately, splice variant related AR dysfunction increases in more advanced and more heavily treated CRPC cancer. “There is rapidly increasing scientific evidence emphasizing the fact that androgen depletion induced AR spice variants (ARVs) in prostate cancer cells to retain basal AR activity [i.e. function independently]” (Farooqi, Sarker. Cancer Cell Int. 2015 Feb).

Antonarakis refers to his work with others (J Clin Oncol 2014; 32 Suppl; abstract 5001) in this statement, “In a very heterogeneous population of 62 enzalutamide- or abiraterone-treated patients, we identified AR-V7 in baseline CTC [circulating tumor cells] from 29% of such patients” (Antonarakis, Asian Journal of Andrology. 2014 Aug).

Preclinical data has suggested that enzalutamide resistance may be partially mediated by glucocorticoid receptors in CRPC and that concomitant decadron could possible limit its effectiveness (Sartor et al. Asian Journal of Andrology. 2014 Sept-Oct, and Farooqi, ibid)

ONGOING CLINICAL TRIALS EXPLORING NEW TREATMENT OPTIONS:

Combination therapy trial:  “Phase III Trial of Enzalutamide (NSC#766085) Versus Enzalutamide, Abiraterone and Prednisone for Castration Resistant Metastatic Prostate Cancer. NCI registry number: NCT1949337. (This trial is actively recruiting and available at Swedish Medical Center, Seattle WA – Dr. Zhao, contact person)

Combination of Enzalutamide plus Lupron:  “Phase 3, Randomized Efficacy 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.”  NCT02319837

Early use of Enzalutamide, the PROSPER trial:  A randomized, placebo controlled trial of Enzalutamide in patients with nonmetastatic prostate cancer progressing through hormonal suppression (i.e. CRPC). NCT02003924

To learn details of these studies go to Clinicaltrials.gov and enter the NCT number.

BOTTOM LINE:  Enzalutamide has already proven to be a significant therapeutic advance. Forthcoming molecular analyses will allow restricting its use to only those patients in whom it can be expected to be effective. Optimal patterns of sequencing and novel strategies to overcome resistance are being developed. Placing it earlier in the treatment schema and its use in combination with other drugs will likely increase its performance.

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