A phase 2 study of androgen deprivation therapy and the androgen receptor ligand–directed degrader (BMS-986365) prior to radical prostatectomy in patients with high-risk localized prostate cancer.

Abstract

TPS5152 Background: Although radical prostatectomy (RP) is a curative approach for patients (pts) with high-risk localized prostate cancer (PC), recurrence rates remain high. Neoadjuvant studies of androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) suggest improvement in local disease control at the time of RP and may be associated with better long-term outcomes (McKay et al. PC Prostatic Dis. 2018; McKay et al. ASCO 2023: #5095). An ongoing phase 3 study is evaluating ADT plus apalutamide for 6 months prior to RP in pts with high-risk or locally advanced PC; co-primary endpoints are pathologic complete response (pCR) and metastasis-free survival (NCT03767244). BMS-986365 is an orally administered ligand-directed degrader targeting the androgen receptor (AR) via a first-in-class dual mechanism of 1) AR degradation and 2) AR antagonism. A phase 1 study showed that BMS-986365 was well tolerated with a manageable safety profile, with antitumor activity in pts with metastatic castration-resistant PC (mCRPC) regardless of AR gene alterations (Rathkopf et al. Ann Oncol. 2025), leading to an ongoing phase 3 study in mCRPC (rechARge: NCT06764485). Due to its dual mechanism and promising data in mCRPC, we hypothesize that neoadjuvant treatment with ADT plus BMS-986365 prior to RP will result in robust pathologic response rates. Methods: This is a single center, phase 2, single-arm trial testing the combination of ADT plus BMS-986365 for 6 months prior to RP in pts with high-risk localized PC. Eligible pts include those who are candidates for RP and meet ≥ 1 high-risk criteria: PSA ≥ 20 ng/mL, Gleason ≥ 8, or clinical stage ≥ cT3a (N1M0 disease allowed). Pts will receive degarelix SC once monthly (first dose 240mg, maintenance dose 80mg) and BMS-986365 at a dose of 300mg PO twice daily (liquid-filled capsule formulation) for 6 months; RP will occur 2 weeks after the last dose of BMS-986365. The dose of BMS-986365 was selected based on the phase 1 data and equivalent doses utilized in the ongoing phase 3 rechARge study. The primary endpoint is the rate of pCR and/or minimal residual disease (MRD, defined as tumor ≤ 5mm) at the time of RP. A two-stage design will evaluate if pCR and/or MRD rate exceeds 0.20, which is the rate observed in historical studies of ADT and ARPI prior to RP (McKay et al. J Urol. 2021) 10 pts will be enrolled in Stage 1; if ≥ 3/10 pts achieve a pCR and/or MRD, an additional 20 pts will be enrolled in Stage 2. If ≥ 10/30 pts achieve a pCR and/or MRD, the treatment will be declared sufficiently active (alpha = 0.05, power 0.80). Secondary endpoints include safety and time to biochemical recurrence. As part of exploratory analyses, cfDNA, pre-/post-treatment (prostatectomy) tissue, and pre-/post-treatment multiparametric MRI will be collected. The study opened to accrual in January 2026. Clinical trial information: NCT07335796 .