(UroToday.com) The 2023 GU ASCO annual meeting included a session on advanced prostate cancer, specifically new targets, new drugs, and new victories, featuring a presentation by Dr. Alice Bernard-Tessier discussing the potential of third generation inhibitors of the androgen receptor.
Dr. Bernard-Tessier notes that androgen receptor signaling inhibitors are the mainstay of prostate cancer treatment, however despite considerable benefit of 2nd generation androgen receptor signaling inhibitors in CSPC and CRPC, resistance is inevitable. So, is the androgen receptor pathway still a relevant target after 2nd generation androgen receptor signaling inhibitors? With regards to the biology of androgen receptor signaling inhibitors resistance, Dr. Bernard-Tessier notes that this is secondary to androgen receptor genomic alteration and alternative ligands:
For androgen receptor genomic alteration, ~5-10% are secondary to androgen receptor splicing variants, ~60% are secondary to androgen receptor amplification (ie. upstream enhancer or copy number gain), and ~15-25% are secondary to androgen receptor mutations.
Dr. Bernard-Tessier then discussed several agents that have previously been tested in early phase trials. The inhibitor of CYP17 galeterone was tested in a ARMOR3-SV trial (NCT02438007), with key eligibility criteria including treatment naïve mCRPC and no prior 2nd generation androgen receptor signaling inhibitors. However, many AR-V7+ patients dropped out of the study secondary to rapid disease progression or screen failure. Thus, the study was closed early as it was unlikely to meet its primary endpoint.
Presented at ASCO 2021, TAS3681, a 3rd generation androgen receptor antagonist for full length androgen receptor and androgen receptor-splice variants, was tested in a phase I dose escalation cohort. This treatment modality had confirmed PSA30 and PSA50 responses:
Cirtuvivint is a pan CLK/DYRK inhibitor that downregulates alternative splicing. In the ONC-01 monotherapy dose escalation trial (NCT03355066) across multiple tumor types, there was circulating tumor cell reduction in 4/5 patients. The RECIST best response is three patients with stable disease (out of three evaluable patients):
The dose expansion part of the study, of CRPC/AR-V7+ post androgen receptor signaling inhibitors (n = 20) is ongoing.
EPI-7386 (ANTINEN) is a small molecular targeting the androgen receptor N-terminal domain, which was is being tested as (i) a monotherapy (NCT04421222) in mCRPC patients treated with <=1 androgen receptor signaling inhibitor +/- prior chemotherapy, and (ii) in combination with enzalutamide (NCT05075577) in mCRPC patients with no prior androgen receptor signaling inhibitor treatment and >=1 prior chemotherapy regimen.
Results of the ARDENT ongoing phase II trial (NCT03888612) were presented at GU ASCO 2022, testing Bavdegalutamide (ARV-110; a PROTAC protein degrader, targeting wild-type and mutation androgen receptors) in men with mCRPC, 1-2 prior androgen receptor signaling inhibitors, and <=1 prior chemotherapy regimen. As follows are the results for best PSA change from baseline:
With regards to targeting alternative ligands, there has been interest in intra-tumoral steroidogenesis and targeting steroid synthesis. ODM208 is a non-steroidal selective CYP11A1 inhibitor that has been assessed in the CYPIDES (NCT03436485) trial, previously presented at GU ASCO 2022 and ESMO 2022. The trial design for CYPIDES is as follows:
Among the entire cohort, the PSA response rate >50% was 32%, however for those with androgen receptor ligand binding mutations was 68%.
Dr. Bernard-Tessier notes that maybe we will be able to tailor therapies with proper biomarkers. However, validation of these biomarkers is needed in prospective clinical trials, and biomarkers are needed for androgen receptor pathway activation. Perhaps a transcriptomic signature can be used as a potential biomarker?
Dr. Bernard-Tessier concluded her presentation discussing the potential of third generation inhibitors of the androgen receptor with the following take-home messages:
- The androgen receptor is still a relevant target, even after second generation androgen receptor signaling inhibitors
- We need to be ready, as 3rd generation androgen receptor targeting agents are coming
- We are awaiting results of phase III trials
Presented by: Alice Bernard-Tessier, MD, Gustave Roussy, Villejuif, France
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.