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Looking back at the preclinical discovery of enzalutamide, "Beyond the Abstract," by Yun-Sok Ha, MD, PhD and Isaac Yi Kim, MD, PhD

BERKELEY, CA (UroToday.com) - Enzalutamide (MDV3100, XTANDI®) is a novel AR antagonist that overcomes resistance to conventional anti-androgens by inhibiting nuclear localization and chromatin binding of AR.[1] According to a recent phase I/II study in patients with mCRPC, enzalutamide is safe and effective with objective PSA and radiographic response, and results in a median time to progression of 47 weeks.[2] The superiority of enzalutamide over placebo was confirmed in a phase III clinical trial that showed increased overall survival (4.8 months) and improvement in all secondary end points in patients with mCRPC after chemotherapy.[3] In the United States, enzalutamide (160 mg as four 40 mg oral capsules per day) was approved for the treatment of CRPC in patients who previously underwent chemotherapy. This review provides an overview of the history of the oral selective AR modulator, enzalutamide, and discusses its discovery and current preclinical experimental results, including resistance mechanisms. The article illustrates the history of discovery based on enzalutamide’s mechanism of action. Further, the drug’s clinical development and post-launch developments are highlighted.

Enzalutamide was discovered through a rational drug design based on the protein structure. Nearly 200 thiohydantoin derivatives of RU59063 were tested for AR agonism and antagonism in human prostate cancer (PCa) cells engineered to express increased levels of AR. Enzalutamide acts on the AR by directly binding to the ligand binding domain.[4] In a competition assay with 16β-[18F]-fluoro-5α-dihydrotestosterone (18-FDHT),[5] enzalutamide had approximately 8-fold higher binding affinity for AR compared to bicalutamide in castration-resistant LNCaP human PCa cells.[1]

bta Yun-Sok-Ha fig1 thumb 
Figure 1. Enzalutamide directly targets the AR and exerts its effects on three essential steps in the AR signaling pathway.
Testing of these agents in LNCaP/AR cells showed that bicalutamide, but not RD162 or enzalutamide, induced expression of AR-targeted genes PSA and transmembrane serine protease 2 (TMPRSS2). Both RD162 and enzalutamide induced apoptosis in VCaP cells, an AR gene amplified human PCa line, while bicalutamide was ineffective. Furthermore, these second generation antiandrogens inhibited transcription of mutant AR proteins isolated from a patient resistant to bicalutamide. In addition to this enhanced binding affinity of enzalutamide, AR translocated into the nucleus far less efficiently, and a significant AR fraction remained in the cytosol in the presence of enzalutamide. More importantly, enzalutamide did not induce the expression of the AR target genes PSA and TMPRSS2.[1] These observations collectively suggest that enzalutamide does not have an AR agonist activity in the context of CRPC. On the other hand, first-generation AR antagonists such as flutamide and bicalutamide have AR agonist properties.[6] Figure 1 shows the brief mechanism of action of enzalutamide.

The efficacy of enzalutamide in patients with mCRPC who had received prior docetaxel-based therapy was assessed in the phase III AFFIRM trial (NCT00974311).[3] In August 2012, based on the overwhelming positive findings from the AFFIRM trial, the FDA approved enzalutamide 160 mg daily for men post-docetaxel chemotherapy. A number of clinical trials are ongoing to better define the scope of the activity of enzalutamide across all stages of PCa. The second phase III trial, PREVAIL, is being conducted in men with asymptomatic mCRPC who have not yet been treated with chemotherapy.[7] Beer et al. presented the results of the first-line PREVAIL trial at the ASCO GU cancer symposium meeting in Feb 2014.[8] They reported that treatment with enzalutamide significantly improves overall survival and recurrence-free survival in men with chemotherapy-naïve mCRPC. Table 1 summarizes ongoing key clinical trials investigating enzalutamide.

The design, development, and approval of enzalutamide lend insights into an unprecedented success in CRPC therapy. The time required from development to FDA approval for enzalutamide was less than 6 years. While enzalutamide’s current clinical niche resides in the post-docetaxel space, there are promising reports that suggest this drug may be even more effective in the earlier disease setting. Notwithstanding, emergence of resistance to enzalutamide is inevitable. Thus future studies should focus on the mechanism of resistance, and potential for combination with other approved agents.

Table 1. Ongoing key trials investigating enzalutamide

Arms

Population

Primary end point

Clinical trial ID

MDV3100 vs. Placebo

Chemonaïve CRPC

OS, PFS

PREVAIL, NCT01212991[7]

MDV3100 vs. Bicalutamide

PCa patients who have progressed on GnRH analogue therapy or following surgical castration

PFS

TERRAIN, NCT01288911[9]

MDV3100 vs. Bicalutamide

patients with early CRPC that is either metastatic (N1/M0 or M1) or non-metastatic (N0/M0)

radiographic PFS

STRIVE, NCT01664923[10]

MDV3100

hormone naïve prostate cancer

PSA response

NCT01302041[11]

MDV3100 vs. MDV3100 + Leuprolide + Dutasteride

Patients Undergoing Prostatectomy for Localized Prostate Cancer

Pathological complete response

NCT01547299[12]

MDV3100 in Combination With Docetaxel

Chemonaïve advanced PCa

Safety and tolerability

NCT01565928[13]

MDV3100 in Combination With Abiraterone Acetate

Bone metastatic CRPC

Safety and tolerability

NCT01650194[14]

MDV3100

AR-positive breast cancer

Safety and tolerability

NCT01597193[15]

OS, overall survival; PFS, progression free survival, CRPC, castration resistance prostate cancer


References:

  1. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009;324:787-90. **The first preclinical report providing the mechanism of the action.
  2. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010;375:1437-46. *Phase I/II trial reporting the efficacy, safety and identification of the effective dose range of enzalutamide.
  3. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187-97. ** Phase III trials evaluating the efficacy of enzalutamide in patients with mCRPC who had received prior docetaxel-based therapy.
  4. Sadar MD. Small molecule inhibitors targeting the "achilles' heel" of androgen receptor activity. Cancer Res 2011;71:1208-13.
  5. Larson SM, Morris M, Gunther I, et al. Tumor localization of 16beta-18F-fluoro-5alpha-dihydrotestosterone versus 18F-FDG in patients with progressive, metastatic prostate cancer. J Nucl Med 2004;45:366-73.
  6. Kelly WK, Slovin S, Scher HI. Steroid hormone withdrawal syndromes. Pathophysiology and clinical significance. Urol Clin North Am 1997;24:421-31.
  7. A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer (PREVAIL) (NCT01212991) Available at: http://clinicaltrials.gov/ct2/show/NCT01212991 (Last accessed 9 February 2014)
  8. Beer TM, Armstring AJ, Sternberg CN et al. Enzalutamide in Men with Chemotherapy-naïve Metastatic Prostate Cancer (mCRPC): Results of Phase 3 PREVAIL Study. J Clin Oncol 2014;32(suppl 4):Abstract ID LBA1.
  9. A Study of MDV3100 Versus Bicalutamide in Castrate Men With Metastatic Prostate Cancer (NCT01288911) Available at: http://clinicaltrials.gov/ct2/show/NCT01288911 (Last accessed 9 February 2014)
  10. Safety and Efficacy Study of Enzalutamide Versus Bicalutamide in Men With Prostate Cancer (STRIVE) (NCT01664923) Available at: http://clinicaltrials.gov/ct2/show/NCT01664923 (Last accessed 9 February 2014)
  11. A Study to Test if MDV3100 is Effective and Safe in Prostate Cancer Patients Who Have Never Had Hormone Therapy (NCT01302041) Available at: http://clinicaltrials.gov/ct2/results?term=NCT01302041 (Last accessed 9 February 2014)
  12. Study of MDV3100 as a Neoadjuvant Therapy for Patients Undergoing Prostatectomy for Localized Prostate Cancer (NCT01547299) Available at: http://clinicaltrials.gov/ct2/results?term=NCT01547299 (Last accessed 9 February 2014)
  13. Safety and Tolerability Study of MDV3100 in Combination With Docetaxel in Men With Advanced Prostate Cancer (NCT01565928) Available at: http://clinicaltrials.gov/ct2/results?term=NCT01565928 (Last accessed 9 February 2014)
  14. A Study to Determine Safety and Tolerability of Enzalutamide (MDV3100) in Combination With Abiraterone Acetate in Bone Metastatic Castration-Resistant Prostate Cancer Patients (NCT01650194) Available at: http://clinicaltrials.gov/ct2/show/NCT01650194 (Last accessed 9 February 2014)
  15. Safety Study of Enzalutamide (MDV3100) in Patients With Incurable Breast Cancer (NCT01597193) Available at: http://clinicaltrials.gov/ct2/results?term=NCT01597193 (Last accessed 9 February 2014)

Written by:
Yun-Sok Ha, MD, PhDa, b and Isaac Yi Kim, MD, PhDa as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

aSection of Urologic Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA
bDepartment of Urology, School of Medicine, Kyungpook National University Medical Center, Daegu, Korea

Enzalutamide: Looking back at its preclinical discovery - Abstract

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