BMS-986365, a novel androgen receptor (AR) ligand-directed degrader, has shown promising results in a Phase I/II trial for castration-resistant prostate cancer (CRPC). Presented at ESMO 2024, the data suggests that this first-in-class agent could offer a new treatment option for patients who have progressed on prior AR-targeted therapies. The drug's unique dual mechanism of action, which both degrades and competitively inhibits the androgen receptor, sets it apart from existing treatments.
Dual Mechanism of Action
BMS-986365 is an orally bioavailable, heterobifunctional molecule that facilitates targeted ubiquitination and subsequent proteasome system-mediated AR degradation. It also binds and antagonizes the AR ligand-binding domain with low agonism potential. This dual mechanism allows the drug to effectively target the AR, potentially overcoming resistance seen with other AR pathway inhibitors (ARPIs).
Phase I/II Trial Results
The Phase I/II trial included men with CRPC who had received at least one prior ARPI. The dose expansion cohort included patients with no prior platinum chemotherapy, no history of brain or liver metastasis, and a PSA greater than or equal to 2. At the 900 milligram twice-daily (BID) dose, the PSA30 response rate was 70%, and the PSA50 response rate was 50%.
Radiographic progression-free survival (rPFS) data showed a median rPFS of 6.3 months for all patients in the part B BID cohorts. Notably, a post-hoc analysis revealed that patients with no prior chemotherapy had a median rPFS of 16.5 months, compared to 5.5 months for those with prior chemotherapy. This suggests a significant benefit in the pre-chemotherapy setting.
Activity Against Wild-Type and Mutant AR
The trial also assessed the drug's efficacy based on AR ligand-binding domain mutational status. Approximately 72% of patients were AR wild-type, while 22% had a ligand-binding domain mutation. Clinical benefit was observed in both groups, suggesting that BMS-986365 can be effective regardless of AR mutational status, including AR amplification.
Safety and Tolerability
The most common treatment-related adverse event was prolonged QTC, occurring in 47% of patients. Grade 3 treatment-related events occurred in 12% of patients, with six of these being asymptomatic prolonged QTC. All prolonged QTC events occurred within the first two cycles and were managed with dose modification. There were no grade 4 or 5 treatment-related adverse events, and no treatment-related adverse events led to drug discontinuation.
Expert Commentary
Dr. Dana Rathkopf from Memorial Sloan Kettering Cancer Center, who presented the data at ESMO 2024, highlighted the drug's potential to overcome resistance to ARPIs and its tolerability in clinical settings. She noted that the dual mechanism of action may potentiate the response to the compound, making it a promising candidate for further investigation in a phase III trial.
Future Directions
Based on these promising results, BMS-986365 is being considered for a phase III trial in patients with CRPC who have not yet received chemotherapy. Further studies will explore potential patient selection criteria and the drug's impact on quality of life.
