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Advances in mCRPC

CE / CME

Advances in Metastatic Castration-Resistant Prostate Cancer: Biomarker-Driven Treatment Strategies and Emerging Therapeutic Approaches

ABIM MOC: maximum of 0.50 Medical Knowledge MOC point

Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™

Released: July 20, 2026

Expiration: January 19, 2027

Neal D. Shore
Neal D. Shore, MD, FACS
CME/CE Information

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Course Completed

Mechanism of Action: BMS-986365

This figure provides a useful overview of how BMS-986365 works. It is a heterobifunctional molecule, meaning it has a dual mechanism of action. The molecule engages the CRBN binding moiety, facilitating targeted ubiquitination and proteasome-mediated degradation of the AR. In essence, the receptor is degraded or destroyed. BMS-986365 also inhibits existing AR activity. Therefore, even if not all AR is degraded, some receptor activity may continue to be inhibited. This mechanism is based on preclinical data; the clinical relevance of the mechanism remains under investigation.

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BMS-986365: PROTAC Protein Degrader Targeting AR

BMS-986365 is an investigational oral AR ligand–directed degrader that also has AR antagonist activity. The phase I data shown here evaluated twice-daily dosing in patients with progressive mCRPC, with PSA declines observed across several dose levels.28

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rechARge: Study Design

BMS-986365 is under investigation in the phase III rechARge study. Key eligibility criteria include confirmed mCRPC after 1 ARPI and asymptomatic or mildly symptomatic disease. Patients with liver or brain metastases are not permitted. During the dose-selection portion, participants are randomized to BMS-986365 or investigator’s choice of docetaxel plus prednisone/prednisolone or a second ARPI. The confirmatory portion evaluates the selected BMS-986365 dose vs investigator’s choice. The primary endpoint is rPFS by BICR.29

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Phase I Trial of BMS-986365 in mCRPC: PSA Response by AR Status and Dose; rPFS by AR-LBD Status

In the phase I study of BMS-986365, PSA responses were quite impressive. Effectiveness was seen at the 400 mg, 600 mg, and 900 mg twice-daily dose levels. PSA responses were observed regardless of the presence or absence of AR-LBD mutations. Median rPFS was 6.3 months in the AR-LBD-mutant population and 8.3 months in the AR-LBD wild-type population.28

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Phase I Trial of BMS-986365 in mCRPC: rPFS by Prior chemotherapy

Additional findings from this phase I trial showed that rPFS may be longer in patients who have not received chemotherapy than in those who have, with a dramatic separation of curves. Overall, these data show potential for BMS-986365 to overcome resistance to current ARPIs, regardless of AR-LBD mutation status.28

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ARV-766: PROTAC Protein Degrader Targeting AR

Another investigational PROTAC targeting AR  is ARV-766. This novel, potent, orally available AR degrader targets both wild-type AR and relevant AR-LBD mutants, including L702H, H875Y, and T878A. These are some of the most common AR-LBD mutations and are the same mutations I referred to when describing the rechARge trial. They are associated with a poor prognosis and are 1 reason I encourage next-generation sequencing for all patients with resistant disease. I also obtain next-generation sequencing in patients with sensitive disease and perform germline testing in all patients.

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Phase I/II Trial of ARV-766 in mCRPC

ARV-766 is being studied in a phase I/II trial in patients with mCRPC whose disease progressed on prior treatment with a novel hormonal agent. This waterfall plot shows PSA response after ARV-766 monotherapy treatment among patients with a mutation in the AR-LBD. Even though this was a small study of 47 patients, the PSA30 response was 51%, and the PSA50 response was 43%.30

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