Androgen Receptor Addiction in Prostate Cancer, Breaking the Habit

Androgen receptor (AR) signaling is the most important driver of prostate cancer initiation, development, and progression, even into the castration-resistant state.  Androgen deprivation therapy (ADT) is the original “targeted therapy” in oncology.  The next generation androgen- and AR-targeted agents, such as abiraterone acetate, enzalutamide, apalutamide and darolutamide further prove the concept that AR signaling remains critical in even later disease states.  There are various mechanisms of resistance that continue to be inclusive of AR; this ranges from AR amplification, AR mutation, and potentially AR spliced variants.

Therapeutic targeting of AR has traditionally been through either inhibiting production of ligand e.g. luteinizing hormone-releasing hormone agonists/antagonists, abiraterone acetate, or direct binding of the ligand binding domain (LBD).  This is all in efforts to inhibit the normal scenario of androgenic ligand binding to the LBD, which induces a conformational change that results in dissociation of the AR from various heat shock proteins in the cytoplasm, allowing translocation to the nucleus.¹  This conformational change leads to the LBD interacting directly with the N-terminal domain (NTD) on the opposite side of the AR.  This also allows the nuclear localization signal (NLS) within the flexible hinge region (HR), proximal to the LBD, to interact with nuclear import proteins, which drive the AR into the nucleus.  Within the nucleus, AR can dimerize, and the DNA binding domain, which is just proximal to the HR, binds to androgen response elements of AR target genes.  Transcriptional initiation occurs with interaction with coactivators, and these genes generally promote proliferation and survival.²

Currently used LBD inhibitors include the first generation of agents, like bicalutamide, nilutamide and flutamide, and the second generation of agents like enzalutamide, apalutamide and darolutamide.  However, there are other agents, the “3^rd generation” of AR inhibitors, that are being developed both pre-clinically and in early phase clinical trials. 

These include Proteolysis Targeting Chimeric (PROTAC^â) agents, like ARV-110³ and ARD-61.⁴  The PROTAC^â methodology structurally connects a protein of interest, in this case the AR, with the E3 ubiquitin ligase ligand using a linker.  This leads to ubiquitination of the protein and targeting for proteosomal protein degradation.  Since the PROTAC binds to the LBD, it does not work for spliced variants that lack LBD, however, early work in AR mutants has shown promise.  ARV-110 has been studied in a Phase 1/2 trial, and in 140 biomarker evaluable patients for T878 and/or H875 mutations, it has shown PSA declines ≥50% (PSA₅₀) and ≥30% (PSA₃₀) of 46% and 58% in 26 patients with mutations, respectively, compared with 10% and 23% in 114 pts without these mutations.

Another new class of AR agents includes the NTD inhibitors, which has potential to interact with a broader AR population.⁵  In additional to inhibiting full length AR with a functional LBD or even a mutated LBD, this class may inhibit AR spliced variants.  AR spliced variants clearly possess prognostic ability;⁶ however, a question still remains as to whether they are predictive biomarkers and most importantly, whether they are true functional drivers of castration-resistant prostate cancer.  Early experience with AR NTD inhibitors have shown challenges with poor oral bioavailability.  A dose-escalation clinical trial with EPI-506 found drug-related adverse events to include diarrhea, nausea and fatigue.⁷  Although, 6 of 28 metastatic castration-resistant prostate cancer patients had some level of PSA decline, none met the pre-specified PSA response criteria.  The study was terminated prior to reaching the maximal tolerated dose, however, this work paved the path for developing newer agents in this class with improved bioavailability and potency.  For example, EPI-7386 (see below) is currently being studies in clinical trials, and early results were just presented at the ASCO GU 2023 Symposium.  The phase 1, dose escalation trial of 31 patients established the safe dose of up to 1200 mg a day, dosed twice daily.⁸  However, there was limited efficacy, and the focus of the presentation was on extension of PSA doubling times.  Another abstract just presented at the ASCO GU 2023 Symposium combined EPI-7386 with enzalutamide in patients with metastatic castration-resistant prostate cancer who were naïve to second-generation AR agents.⁹  Pharmacokinetic data from 7 patients showed that enzalutamide increased the AUC of EPI-7386.  Although the combination appeared safe, it is clear that enzalutamide decreases the availability of EPI-7386, and the next (3^rd) dose level has decreased enzalutamide dosing from 160 to 120 mg daily.  In regards to efficacy, 5 of 6 evaluable patients had at least 90% PSA decline.

There are certainly many ongoing efforts to develop novel AR-inhibiting therapies.  There are other novel classes of AR inhibitors in preclinical development as well, for example, agents that bind to both the LBD and NTD.  However, I will cover those in a future article, when those agents begin to enter clinical trial testing.  Currently, a few PROTAC agents (first 3 trials below) and NTD AR inhibitors (4^th trial below) are in early phase clinical trials, and I highlight a few ongoing, accruing example trials below.

Highlighted trials for prostate cancer patients with novel AR inhibiting agents:

• Phase 1/2 trial of ARV-110 for metastatic castration-resistant prostate cancer (NCT03888612)
• Phase 1 trial of ARV-110 and abiraterone for metastatic castration-resistant prostate cancer (NCT05177042)
• Phase 1 trial of CC-94676 for metastatic castration-resistant prostate cancer (NCT04428788)
• Phase 1 trial of EPI-7386 for metastatic castration-resistant prostate cancer (NCT04421222)

References

1. Tan M, et al. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin 2015; 36:2-23.
2. Maylin ZR, et al. Breaking androgen receptor addiction of prostate cancer by targeting different functional domains in the treatment of advanced disease. Transl Oncol 2021; 14:101115.
3. Gao X, et al. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 40, no. 6_suppl (February 20, 2022) 17-17.
4. Kregel S, et al. Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment. Neoplasia 2020; 22:111-9.
5. Antonarakis ES, et al. Targeting the N-Terminal Domain of the Androgen Receptor: A New Approach for the Treatment of Advanced Prostate Cancer. Oncologist 2016; 21:1427-35.
6. Antonarakis ES, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.  N Engl J Med 2014; 371:1028-38.
7. Maurice-Dror C, et al. Invest New Drugs 2022; 40:322-9.
8. Pachynski RK, et al. A Phase 1 Trial of Oral EPI-7386 in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC): Update From the First-in-Human Study. J Clin Oncol 41, no. 6_suppl (February 20, 2023) 177-177.
9. Laccetti AL, et al. Phase 1/2 Study of EPI-7386 in Combination with Enzalutamide (Enz) Compared with Enz Alone in Subjects with Metastatic Castration-Resistant Prostate Cancer (mCRPC) J Clin Oncol 41, no. 6_suppl (February 20, 2023) 179-179.