PII-068 - EXPOSURE-RESPONSE ANALYSES FOR EFFICACY AND SAFETY OF BMS-986365, A DUAL ANDROGEN RECEPTOR LIGAND-DIRECTED DEGRADER AND ANTAGONIST, IN PATIENTS WITH PROGRESSIVE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC)

C. Liu¹, J. Zhou¹, Y. Guo², S. Cheng¹, Y. Liu³, M. Ye¹, J. Han⁴, L. Zhu¹, V. Arora⁵, S. Suryawanshi¹; ¹Bristol Myers Squibb, Lawrenceville, NJ, USA, ²Bristol Myers Squibb, Shanghai, China, ³Bristol Myers Squibb, Tempa, FL, USA, ⁴Bristol Myers Squibb, San Francisco CA, United States, ⁵Bristol Myers Squibb, Princeton/NJ, United States.

Background: BMS-986365 is an orally bioavailable androgen receptor (AR) ligand-directed degrader (LDD), composed of an AR binding moiety, linker, and CRBN moiety. AR-LDD overcomes resistance to AR pathway inhibitors in patients with mCRPC via a first-in-class dual mechanism of AR degradation and antagonism. Phase 1 data (CC 94676-PCA-001) showed that BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated anti-tumor activity in heavily pretreated patients with mCRPC1. QTc prolongation was the most common adverse event (AE). All grade QTc prolongations were asymptomatic, and no treatment discontinuations occurred due to prolonged QTc. The aim of this exposure-response (E-R) analysis was to establish a quantitative relationship between drug exposure and critical efficacy (Prostate-Specific Antigen (PSA) and radiographic progression-free survival (rPFS)), and safety (QTc related AE) endpoints, to inform dose optimization and selection for a Phase 3 trial.

Methods: The analysis included 94 subjects with mCRPC in study CC 94676-PCA-001, part A and B, who had both measurable concentrations and specified efficacy / safety data. Logistic regression was employed to quantify the probability of achieving 30% PSA reduction (PSA30) based on drug exposure. The relationship between exposures and rPFS was characterized by time-to-event modeling and Cox Proportional Hazards methodology. QTc interval prolongation risk was assessed by concentration-QTc analysis based on a linear mixed effects model. All modeling and data presentations were conducted using Monolix (2020 R1) and R (4.0.3).

Results: The analysis suggests a positive E-R relationship, with increased drug exposure leading to higher response rates of PSA30, longer rPFS, and increased incidence of prolonged QTc. Of note, higher drug concentration and fewer lines of prior therapy were associated with longer rPFS. Drug concentration, baseline QTc, and time were significant predictors of QTc change.

Conclusion: The E-R analysis suggests that maintaining high drug exposure may offer better therapeutic benefits but must be balanced against QTc prolongation risk. QTc-related AEs can be resolved by dose reduction. The totality of data indicates the optimal Phase 3 dose corresponds to exposure resulting from 600 and 900 mg BID.