(UroToday.com) The 2023 ESMO annual meeting included a session on prostate cancer, featuring a presentation by Dr. Daniel Petrylak discussing radiographic progression-free survival (rPFS) in patients with AR ligand-binding domain mutations in the phase 1/2 study of bavdegalutamide, a PROTAC androgen receptor degrader, in metastatic castration-resistant prostate cancer (mCRPC). Patients with mCRPC and mutations in the AR ligand binding domain (amino acids 671-920) have a poor prognosis. In matched real-world cohorts of patients with mCRPC, those with the AR ligand binding domain mutations T878 and/or H875 had significantly shorter real-world overall survival from first-line treatment initiation than those without these mutations (median 16.1 months vs 50.7 months). Oral bavdegalutamide (ARV-110) is a PROteolysis TArgeting Chimera (PROTAC) AR degrader that has activity against clinically relevant mutations by creating a trimer complex with AR and the cereblon E3 ubiquitin ligase to directly trigger ubiquitination and subsequent degradation of AR by the proteasome:
Additionally, bavdegalutamide has shown clinical activity in previously treated patients with mCRPC in a phase 1/2 study (NCT03888612), with enhanced activity seen in patients with the AR ligand binding domain mutations T878 and/or H875.
In phase 1, patients with mCRPC and ≥2 prior therapies (including a novel hormonal agent) received bavdegalutamide 35–700 mg once daily or 210–420 mg twice daily. In phase 2, patients with mCRPC and 1–2 novel hormonal agents ± prior chemotherapy were assigned to biomarker-defined subgroups; patients who had one prior novel hormonal agent and no prior chemotherapy were enrolled in a clinically defined subgroup. All phase 2 patients received 420 mg bavdegalutamide once daily. In exploratory analyses across the phase 1/2 population treated with 420 mg bavdegalutamide once daily, efficacy was assessed in patients with AR 878/875 mutations without an AR L702 mutation (AR 878/875 patients) and in those with any AR ligand binding domain missense mutation except AR L702H alone (AR ligand binding domain patients).
As of August 11, 2023, 153 patients across the phase 1/2 study received bavdegalutamide 420 mg daily, including 45 patients with AR ligand binding domain mutations excluding L702H alone, 26 of whom had AR 878/875 without L702H:
The median rPFS per PCWG3 was 8.2 months (95% CI 3.8–not reached) in AR ligand binding domain patients (20 events in 45 patients) and 11.1 months (95% CI 7.1 – not reached) in the AR 878/875 subgroup (10 events in 26 patients):
PSA declines of ≥50% and ≥30%, respectively, after ≥1 month of PSA follow-up were seen in 36.4% and 50.0% of AR ligand binding domain patients (n=44) and in 53.8% and 65.4% of patients in the AR 878/875 subgroup (n=26):
In response-evaluable patients with measurable disease at baseline, overall response rate was 10.0% in AR ligand binding domain (n=20) patients, and 9.1% in AR 878/875 patients (n=11); 55% and 54.5%, respectively, had stable disease. There were 16 (36%) AR ligand binding domain patients on treatment for >=24 weeks, with 4 ongoing, whereas 11 (42%) of AR 878/875 patients were on treatment for >=24 weeks, with 4 ongoing:
Across the phase 1/2 study, 147 (96%) of 153 patients had a treatment emergent adverse event, of which 47 (31%) had a grade 3/4 event. Overall 17 (11%) of patients had a treatment emergent adverse event that led to a dose reduction and 19 (12%) led to discontinuation. The most common treatment emergent adverse events were nausea, fatigue, and vomiting:
Dr. Petrylak concluded his presentation discussing rPFS in patients with AR ligand-binding domain mutations in the phase 1/2 study of bavdegalutamide, a PROTAC androgen receptor degrader, in mCRPC with the following concluding statements:
- In this post-novel hormonal agent mCRPC population, promising clinical activity for bavdegalutamide, a PROTAC AR degrader, was observed in patients with tumors harboring missense AR ligand binding domain mutations excluding L702H alone (median rPFS 8.2 months), including in the subgroup AR 878/875 mutations (rPFS 11.1 months)
- Bavdegalutamide 420 mg daily continues to be tolerable with manageable side effects
- These encouraging results in patients with AR ligand binding domain mutated mCRPC warrant further investigation
Presented by: Daniel P. Petrylak, MD, Yale University, New Haven, CT
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.