What are the implications and considerations for using BMS-986365 (CC-94676) in treatment?

BMS-986365 (CC-94676): Clinical Results and Treatment Implications

Overview and Mechanism of Action

BMS-986365 is a first-in-class, orally bioavailable androgen receptor ligand-directed degrader (AR LDD) that operates through a dual mechanism of AR protein degradation and competitive antagonism, designed specifically for metastatic castration-resistant prostate cancer (mCRPC) that has progressed after androgen receptor pathway inhibitor (ARPI) therapy. 1, 2, 3

The compound functions as a heterobifunctional cereblon-dependent degrader that both eliminates AR protein and blocks residual AR activity through ligand-binding domain occupancy 3. This dual mechanism distinguishes it from conventional ARPIs like enzalutamide, which can paradoxically increase AR protein levels in mCRPC models 3.

Phase I Clinical Trial Results (CC-94676-PCA-001)

Patient Population and Study Design

The phase I study (NCT04428788) enrolled heavily pretreated patients with progressive mCRPC who had received:

• Androgen deprivation therapy
• One or more prior ARPIs
• Taxane chemotherapy (unless declined or ineligible)
• Median of 4 prior therapies (range 2-11) in the expansion cohort 2

The study included dose escalation (Part A, n=27) and expansion (Part B, n=68) phases, testing doses up to 900 mg twice daily 2.

Efficacy Outcomes

At the three highest doses (400-900 mg twice daily, n=60), BMS-986365 demonstrated clinically meaningful activity with a PSA50 response rate of 32% overall and 50% at the 900 mg dose. 2

Key efficacy findings:

• Median radiographic progression-free survival (rPFS): 6.3 months (95% CI: 5.3-12.6 months) across all high doses 2
• rPFS at 900 mg dose: 8.3 months (95% CI: 3.8-16.6 months) 2
• Chemotherapy-naive patients: Median rPFS of 16.5 months (95% CI: 5.5 months-not evaluable) 2
• Prior chemotherapy patients: Median rPFS of 5.5 months (95% CI: 2.7-8.3 months) 2

Notably, efficacy was observed regardless of AR ligand-binding domain mutation status, including patients with wildtype AR and those with clinically relevant AR mutations 2, 3.

Safety Profile

BMS-986365 demonstrated a manageable safety profile with no maximum tolerated dose reached in dose escalation. 2

Most common treatment-related adverse events:

• Asymptomatic QTc prolongation: 47% of patients 2
• Bradycardia: 34% of patients 2
• Both events were generally asymptomatic and manageable 2

The compound was well tolerated overall, with adverse events predominantly mild to moderate in intensity 2.

Preclinical Mechanistic Data

BMS-986365 demonstrated superior activity compared to enzalutamide in preclinical models:

• More efficient inhibition of AR target gene transcription 3
• Greater suppression of AR-dependent cell proliferation 3
• Maintained low AR protein levels despite increased AR transcript levels, while enzalutamide increased AR protein 3
• Demonstrated activity in both castration-sensitive and therapy-resistant CRPC models 3

Ongoing Phase III Trial (rechARge)

A phase III randomized trial (NCT06764485) is currently enrolling approximately 960 patients with mCRPC whose disease progressed after one prior ARPI. 1

Trial design:

• Comparator arm: Investigator's choice of either docetaxel or switch to alternative ARPI (abiraterone or enzalutamide) 1
• Primary objectives: Compare efficacy and safety of BMS-986365 versus investigator's choice 1
• Target population: Patients with disease progression after one prior ARPI 1

Clinical Implications and Treatment Positioning

Key Advantages Over Current ARPIs

1. Overcomes ARPI resistance mechanisms: The dual degradation-antagonism mechanism addresses continued AR-driven disease despite ARPI therapy 2, 3

2. Mutation-agnostic activity: Effective against both wildtype AR and most clinically relevant AR mutations, eliminating the need for mutation testing to guide therapy 2, 3

3. Particularly promising in chemotherapy-naive patients: The 16.5-month median rPFS in chemotherapy-naive patients suggests optimal positioning before taxane therapy 2

Optimal Patient Selection

BMS-986365 should be prioritized for patients with mCRPC who have progressed on one ARPI, particularly those who are chemotherapy-naive, given the substantially longer rPFS observed in this subgroup (16.5 vs 5.5 months). 2

Consider BMS-986365 for:

• Post-ARPI progression with continued AR-driven disease 2
• Patients with or without AR mutations 2, 3
• Chemotherapy-naive patients as preferred population 2
• Patients who can tolerate mild cardiac monitoring requirements (QTc, heart rate) 2

Critical Monitoring Requirements

Implement cardiac monitoring for QTc prolongation and bradycardia, though these events are typically asymptomatic and manageable. 2

Required monitoring:

• Baseline and periodic ECG monitoring for QTc interval 2
• Heart rate assessment for bradycardia 2
• Standard prostate cancer monitoring (PSA, imaging) 2

Dose Considerations

The 900 mg twice daily dose demonstrated the highest response rates (50% PSA50) and longest rPFS (8.3 months), though the recommended phase II dose selection remains ongoing. 2

Comparison to Standard Post-ARPI Options

Unlike switching to an alternative ARPI (which may have limited benefit due to cross-resistance) or proceeding directly to chemotherapy, BMS-986365 offers a mechanistically distinct approach that maintains AR targeting while overcoming resistance mechanisms 1, 2, 3. The phase III trial will definitively establish its position relative to these standard options 1.