From the Desk of Evan Yu: “Androgen Receptor Mutations in Prostate Cancer; A Worthwhile Therapeutic Target?”

The importance of the androgen receptor (AR) in prostate cancer is without debate.  Androgen deprivation therapy is essentially the original “targeted therapy” in all of oncology.  This has been further emphasized with the next generation of regulatory-approved androgen- and AR-targeted agents, such as abiraterone acetate, enzalutamide, and apalutamide.  Certain spliced-variants of the AR, such as ARv7, have potential to serve as a disease biomarker, offering prognostic value with potential for predicting resistance to agents like abiraterone acetate and enzalutamide.1  However, therapeutic attempts to target ARv7 have been fraught with challenges when agents like galeterone and niclosamide have been utilized.2

Mutations of the AR have been felt to be less common occurring and infrequent drivers of disease pathogenesis.  However, a few series have perhaps shown greater frequency than once thought: 22/150 (14.7%) from the SU2C International Dream Team biopsy series3and 11% from plasma DNA in patients who previously were treated with docetaxel.4  Not all of these mutations have known functional importance; however, a few have been reasonably well characterized.  For instance, T878A and W742C have been previously shown to confer agonism to AR antagonists such as flutamide and bicalutamide, respectively.5,6 Other mutations, like L702H, may confer agonism with glucocorticoids.  The F877L missense mutation in the ligand binding domain of the AR confers resistance to both enzalutamide and apalutamide, also by conversion of these antagonists to agonists.7,8  It is possible we are finding more of these mutations due to increasing utilization of very potent androgen- and AR-targeting agents. In certain patient cases, these AR mutants may arise as a mechanism of resistance to therapy, although more work in this area is required.

Recently, the ARAMIS trial was successful in demonstrating darolutamide, a high-affinity AR antagonist, to offer a metastasis-free survival benefit for those patients with M0 castration-resistant prostate cancer and a PSA doubling time of <10 months.9  One interesting characteristic of darolutamide that has yet to be thoroughly investigated in a clinical setting, is the fact that it has been shown in preclinical studies to block the effect of multiple mutant ARs, including F877L, W742C and T878A.10  This certainly could be interesting to investigate in patients who may harbor these mutations, and who may have progressed on other androgen- or AR-targeted therapies. 

There are certainly many efforts to develop novel AR-inhibiting therapies.  These include agents that cause AR degradation, those that inhibit AR via siRNA and others that inhibit translocation from the cytoplasm to the nucleus.  Many of these could have potential to inhibit AR mutants and/or AR spliced-variants.  There are, however, currently a few agents in phase 1 trials where the concept of AR mutant inhibition has been strongly emphasized during early therapeutic development.  Below, I highlight a couple such trials.

Highlighted trials for prostate cancer patients with agents with potential to target AR mutants


Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine,  Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center.

References
  1. Antonarakis ES. "AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer" N Engl J Med 371, (Sep2014):1028-38. DOI: 10.1056/NEJMoa1315815
  2. Schweizer MT et al. "A Phase I Study of Niclosamide in Combination With Enzalutamide in Men With Castration-Resistant Prostate Cancer" PLoS One 2018; 13:e0198389.
  3. Robinson D et al. "Integrative clinical genomics of advanced prostate cancer." Cell 161, (May 2015):1215-28.
  4. Conteduca V et al.  "Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study." Ann Oncol 28, (Jul 2017):1508-16.
  5. Hara T et al. "Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome." Cancer Res 63, (Jan 2003):149-53.
  6. Veldscholte J, et al.  Biochem Biophy Res Commun 1990; 173:534-40.
  7. Balbas MD et al."Overcoming mutation-based resistance to antiandrogens with rational drug design."Elife 2, (Apr 2013):e00499.
  8. Korpal M et al. "An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide)."Cancer Discov 3,9 (Sept 2013):1030-43.
  9. Fizazi K et al. "Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer" N Engl J Med 380, (2019):1235-46.
  10. Moilanen AM et al. "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies."Sci Rep 5, (Jul 2015):12007.
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