2. UroToday Home
  3. Clinical Trials
  4. From the Editor
Back to From the Editor Articles    

Androgen Receptor Ligand Binding Domain Mutations in Prostate Cancer Help Lend Credence to Adrenal Annihilation Using CYP11A1 Inhibition

It has been many years since I addressed ligand binding domain (LBD) mutations of the androgen receptor (AR).1  At one time it was felt that these mutations were infrequent drivers of disease pathogenesis.  Yet, the Prostate Cancer Foundation's (PCF) funding of the International Dream Team metastatic biopsy study found AR LBD mutations in 22/150 (14.7%) in those previously treated with docetaxel.2  In the modern era, with greater use of potent androgen and AR inhibiting therapies, such as abiraterone acetate, enzalutamide, apalutamide, and darolutamide, estimates for these AR LBD mutations approximate 20% of previously treated patients with metastatic castration-resistant prostate cancer after receipt of an AR pathway inhibitor.

Many of these mutations arise as a result of selective treatment pressure, with unique mechanisms of activation.  For instance, T878A and W742C have been previously shown to confer agonism to AR antagonists such as flutamide and bicalutamide, respectively.3,4  T878A can also be promiscuously stimulated by progesterone.  The F877L missense mutation confers resistance to both enzalutamide and apalutamide, also by conversion of these antagonists to agonists.5,6  There are other mutations, like L702H, that frequently confer promiscuous agonism with glucocorticoids.  This mutation may be especially impactful, as it arises as a mechanism of resistance after treatment with either abiraterone or enzalutamide.  Serial next generation sequencing studies, using ctDNA, have found L702H to be one of the most frequently arising LBD mutations.7  Stimulation with estradiol may even occur with the H875Y mutation.

Recently, a CYP11A1 inhibitor, termed ODM-208, contemporaneously known as MK-5684, has shown efficacy both in AR wt and especially the AR LBD mutant populations.  This agent is a novel nonsteroidal selective inhibitor of CYP11A1, which is the first and rate-limiting step of the steroidogenic pathway in which cholesterol is converted to pregnenolone.  The result is an inability to produce mineralocorticoids, glucocorticoids, and sex steroid hormones.  The most impressive efficacy of MK-5684 was in the AR LBD mutant population, with a 53% PSA decline rate of 50% or greater and a 26% RECIST 1.1 response rate for this heavily pre-treated population.8   This is likely due to the ability for a CYP11A1 inhibitor to inhibit all adrenal steroid hormone production, which may deplete the promiscuous stimulation of certain AR LBD mutants by alternative steroid hormones.  A key consideration with the use of this agent, however, is the need for exogenous dexamethasone and fludrocortisone replacement to avoid the potential toxicities of adrenal insufficiency.

Given the impressive efficacy data, MK-5684 is being explored in multiple randomized phase 3 registration trials.  These trials are unique in that they are statistically designed to evaluate the efficacy of MK-5684 both in the AR LBD mutant and non-mutant population.  Therefore, there is a possibility of showing efficacy in both biomarker-selected and an unselected population.  This offers promise for many potential clinical paths forward, including one that may require ctDNA next generation sequencing in patients who progress on a prior AR pathway inhibitor to potentially identify the most treatment-sensitive patients.  Please see below for trials that are open and actively accruing patients for monotherapy treatment with MK-5684.

Highlighted trials using MK-5684, a CYP11A1 inhibitor, in patients with prostate cancer

  • OMAHA-4: MK-5684 alternative next-generation hormonal agent (NHA) in metastatic castration resistant prostate cancer post one NHA in a chemotherapy-naïve population (NCT06136650)
  • OMAHA-3: MK-5684 vs. alternative next-generation hormonal agent (NHA) in metastatic castration resistant prostate cancer post one NHA and docetaxel chemotherapy (NCT06136624)
  • MK-5684 in Chinese participants with metastatic castration resistant prostate cancer (NCT06136598)
  • MK-5684 in Japanese participants with metastatic castration resistant prostate cancer (NCT06104449)

Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Yu EY. Androgen Receptor Mutations in Prostate Cancer, a Worthwhile Therapeutic Target? Urotoday 2019; May 15, 2019.
  2. Robinson D, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015; 161:1215-28.
  3. Hara T, et al. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res 2003; 63:149-53.
  4. Veldscholte J, et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophy Res Commun 1990; 173:534-40.
  5. Balbas MD, et al. Overcoming mutation-based resistance to antiandrogens with rational drug design. Elife 2013; 2:e00499.
  6. Korpal M, et al. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov 2013; 3:1030-43.
  7. Annala M, et al. Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition. Clin Cancer Res 2021; 27:4610-23.
  8. Fizazi K, et al. Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer. NEJM Evid 2024; Epub December 26, 2023.