BMS-986365 and Abiraterone Resistance: A Novel Mechanism to Overcome Treatment Failure
BMS-986365 represents a promising strategy to overcome abiraterone resistance through its dual mechanism of androgen receptor degradation and antagonism, demonstrating clinical activity in heavily pretreated mCRPC patients who previously failed abiraterone and other androgen receptor pathway inhibitors. 1
Mechanism of Action: Why BMS-986365 Can Overcome Abiraterone Resistance
BMS-986365 is fundamentally different from abiraterone because it employs a first-in-class dual mechanism that both degrades the androgen receptor protein and antagonizes its function, rather than simply blocking androgen synthesis like abiraterone does. 1 This distinction is critical because:
Abiraterone resistance often occurs through continued AR signaling despite castrate testosterone levels, including through AR splice variants (like AR-V7), AR mutations in the ligand-binding domain (F876L, T877A), and AR overexpression. 2
BMS-986365 directly targets and degrades the AR protein itself, which theoretically bypasses the resistance mechanisms that allow AR signaling to persist after abiraterone failure. 1
The drug demonstrated efficacy regardless of AR ligand-binding domain mutation status, suggesting it can overcome specific mutations that confer abiraterone resistance. 1
Clinical Evidence Supporting Reactivation of AR-Targeted Therapy
Phase I Trial Results (CC-94676-PCA-001)
In heavily pretreated patients with mCRPC who had progressed on prior ARPIs (including abiraterone) and taxane chemotherapy:
PSA50 response rate was 32% across the three highest doses (400-900 mg twice daily), with 50% response at the 900 mg dose. 1
Median radiographic progression-free survival was 6.3 months (8.3 months at 900 mg dose), demonstrating meaningful disease control in patients who had exhausted standard options. 1
Patients enrolled had received a median of 4 prior therapies (range 2-11), confirming this was a heavily pretreated population where abiraterone and other ARPIs had already failed. 1
Safety Profile
BMS-986365 was well tolerated with a manageable safety profile:
Most common treatment-related adverse events were asymptomatic QT prolongation (47%) and bradycardia (34%). 1
The maximum tolerated dose was not reached in dose escalation, suggesting a favorable therapeutic window. 1
Comparison to Current Standard Approaches After Abiraterone Failure
Current guidelines recommend specific sequencing after abiraterone failure:
Cabazitaxel is the preferred option for patients with good performance status who progressed on abiraterone after docetaxel, based on the CARD trial showing superiority over switching between ARPIs. 3, 4
Switching from abiraterone to enzalutamide (or vice versa) is no longer preferred due to demonstrated cross-resistance between these agents. 3, 4
For chemotherapy-naive patients who failed abiraterone, docetaxel-based chemotherapy is the standard recommendation. 3
BMS-986365 offers a mechanistically distinct approach that may provide benefit even after both abiraterone and enzalutamide failure, filling an unmet need in the treatment sequence. 1
Evidence for AR-Targeted Therapy Rechallenge
Limited but supportive evidence exists for rechallenge strategies:
A case report demonstrated successful abiraterone rechallenge after docetaxel in a patient who converted from AR-V7 positive to negative on CTC analysis, suggesting that changing the resistance mechanism can restore sensitivity. 5
This supports the concept that targeting AR through a different mechanism (degradation vs. synthesis inhibition) could overcome prior resistance. 5, 2
Optimal Patient Selection for BMS-986365
Based on the phase I data, BMS-986365 appears most promising in:
Chemotherapy-naive patients: rPFS was 16.5 months without prior chemotherapy versus 5.5 months with prior chemotherapy. 1
Patients with AR-driven disease who have progressed on one or more ARPIs but maintain good performance status. 1
Patients with AR mutations that confer resistance to current ARPIs, as efficacy was observed regardless of AR LBD mutation status. 1
Ongoing Phase III Trial (rechARge)
The rechARge trial (NCT06764485) is evaluating BMS-986365 versus investigator's choice (docetaxel or switch to alternative ARPI) in approximately 960 patients with mCRPC who progressed after one prior ARPI. 6 This will definitively establish whether BMS-986365 can "reactivate" AR-targeted therapy in the post-abiraterone setting.
Clinical Implications and Practical Considerations
For patients who have failed abiraterone with good performance status:
First-line recommendation remains cabazitaxel if they received prior docetaxel, or docetaxel if chemotherapy-naive. 3, 4
BMS-986365 represents an investigational option that may overcome abiraterone resistance through AR degradation, particularly for patients enrolled in clinical trials. 1, 6
Do not switch from abiraterone to enzalutamide expecting substantial benefit due to cross-resistance. 3, 4
Consider PSMA-directed therapy (Lutetium-177 PSMA-617) for PSMA-positive patients who failed both docetaxel and ARPIs. 3, 4
Critical monitoring for BMS-986365 includes cardiac monitoring for QT prolongation and bradycardia, which were the most common adverse events. 1