Phase II Results of BMS-986365 in Metastatic Castration-Resistant Prostate Cancer
BMS-986365 demonstrated a 32% PSA50 response rate (50% at the highest 900 mg dose) and median radiographic progression-free survival of 6.3 months (8.3 months at 900 mg) in heavily pretreated patients with metastatic castration-resistant prostate cancer, with a manageable safety profile dominated by asymptomatic QT prolongation and bradycardia. 1
Study Design and Patient Population
The CC-94676-PCA-001 phase I/II trial (NCT04428788) enrolled patients with progressive mCRPC who had failed multiple prior therapies 1:
- Part A (dose escalation): 27 patients
- Part B (dose expansion): 68 patients
- Median prior therapies: 4 (range 2-11)
- Required prior treatments: Androgen deprivation therapy, one or more androgen receptor pathway inhibitors (ARPIs), and taxane chemotherapy (unless declined/ineligible) 1
The study evaluated BMS-986365 doses up to 900 mg twice daily, with primary objectives of assessing safety, tolerability, and defining the maximum tolerated dose and recommended phase II dose 1.
Efficacy Outcomes
PSA Response Rates
Across the three highest doses (400-900 mg twice daily, n=60) 1:
- Overall PSA50 response: 32% (19/60 patients)
- PSA50 at 900 mg dose: 50% (10/20 patients)
This represents substantial biochemical activity in a heavily pretreated population where responses to subsequent therapies are typically limited 1.
Radiographic Progression-Free Survival
Median rPFS across highest doses (400-900 mg): 6.3 months (95% CI: 5.3-12.6 months) 1
Median rPFS at 900 mg dose: 8.3 months (95% CI: 3.8-16.6 months) 1
Impact of Prior Chemotherapy
A critical finding was the differential benefit based on prior chemotherapy exposure 1:
- Chemotherapy-naïve patients: Median rPFS 16.5 months (95% CI: 5.5 months-not evaluable)
- Prior chemotherapy patients: Median rPFS 5.5 months (95% CI: 2.7-8.3 months)
This suggests BMS-986365 may have substantially greater efficacy when used earlier in the treatment sequence, before chemotherapy-induced resistance mechanisms develop 1.
Activity Across AR Mutation Status
BMS-986365 demonstrated efficacy regardless of AR ligand-binding domain mutation status 1:
- Activity observed in both AR LBD wildtype patients
- Activity observed in patients with AR LBD mutations
This is particularly important because AR mutations are a common resistance mechanism to current ARPIs, and the ability to overcome this resistance represents a significant clinical advantage 1, 2.
Safety Profile
Most Common Treatment-Related Adverse Events
The safety profile was manageable with predominantly cardiovascular effects 1:
- Asymptomatic prolonged corrected QT interval: 47%
- Bradycardia: 34%
Dose-Limiting Toxicity
Maximum tolerated dose was not reached in Part A, and recommended phase II dose selection is ongoing 1. This suggests the drug has a favorable therapeutic window, allowing dose escalation to potentially more efficacious levels without prohibitive toxicity.
Clinical Implications of Safety Profile
The predominance of asymptomatic cardiac effects (QT prolongation and bradycardia) requires monitoring but does not typically necessitate treatment discontinuation, distinguishing BMS-986365 from chemotherapy agents that cause more symptomatic and dose-limiting toxicities 1.
Mechanism and Rationale
BMS-986365 is a first-in-class dual androgen receptor ligand-directed degrader and antagonist 1, 2:
- Degradation mechanism: Induces proteasomal degradation of AR protein
- Antagonism mechanism: Competitively blocks AR ligand-binding domain
- Advantage over current ARPIs: While enzalutamide and abiraterone can increase AR protein levels as a compensatory mechanism, BMS-986365 maintains low AR protein levels despite increased AR transcript 2
This dual mechanism addresses a key limitation of current ARPIs, which can lead to AR protein accumulation and subsequent resistance 2.
Context Within Treatment Landscape
Comparison to Standard Phase II Endpoints
According to Prostate Cancer Clinical Trials Working Group 2 criteria, phase II trials should focus on measures of progression rather than response alone, with time to progression being the most clinically relevant endpoint to inform phase III development 3. BMS-986365 meets this standard with demonstrated rPFS benefit 1.
Position in Treatment Sequence
Current guidelines establish that most patients with advanced prostate cancer progress to CRPC within 1-3 years of initiating castration 4. For metastatic CRPC, standard options include 3:
- Enzalutamide (median OS 18.4 months post-chemotherapy)
- Abiraterone (demonstrated survival benefit)
- Docetaxel (established first-line chemotherapy)
- Cabazitaxel (second-line post-docetaxel)
BMS-986365's 16.5-month median rPFS in chemotherapy-naïve patients compares favorably to these established agents, particularly considering the heavily pretreated population 1.
Clinical Implications and Future Development
Recommended Patient Population
Based on phase II results, BMS-986365 shows greatest promise in chemotherapy-naïve patients with mCRPC who have progressed on ARPIs 1. The substantial difference in rPFS (16.5 vs 5.5 months) based on prior chemotherapy suggests this should be the target population for phase III development.
Phase III Development
The rechARge trial (NCT06764485) is now enrolling approximately 960 patients with mCRPC whose disease progressed after one prior ARPI, randomizing to BMS-986365 versus investigator's choice (docetaxel or alternative ARPI) 5. This design directly addresses the clinical question of optimal sequencing after first ARPI failure.
Monitoring Requirements
Given the safety profile, patients receiving BMS-986365 require 1:
- Baseline and periodic ECG monitoring for QT interval prolongation
- Heart rate monitoring for bradycardia
- These are asymptomatic findings but require documentation and monitoring
Resistance Mechanisms
The activity across AR mutation status suggests BMS-986365 may overcome common resistance mechanisms to current ARPIs 1, 2. However, the reduced efficacy post-chemotherapy indicates that chemotherapy-induced resistance mechanisms (potentially non-AR-mediated) may still limit benefit 1.