This is a dose-finding study to assess the safety and preliminary antitumor activity of Pocenbrodib alone or with darolutamide in patients with metastatic castration-resistant prostate cancer (mCRPC)

This is a Phase 1b/2a multicenter, open-label study to confirm the safety, pharmacokinetics (PK), preliminary antitumor activity, and pharmacodynamics (PD) of pocenbrodib for the treatment of participants with mCRPC who have progressed following prior therapy and have been treated with at least 1 potent anti-androgen therapy (enzalutamide, apalutamide, abiraterone acetate, or darolutamide).

Phase 1b is a dose escalation and optimization study of pocenbrodib monotherapy and in combination with darolutamide in order to determine the maximum tolerated dose (MTD) in participants (n=80) and to determine the recommended Phase 2 dose(s) (RP2D(s)).

Phase 1b consists of three arms: Arm 1 (50-250mg QD 5/2), Arm 2 (continuous monotherapy, 125mg-150mg BID), and Arm 3 (continuous combination of pocenbrodib 125-150mg BID + darolutamide 600mg BID), with DRC safety gates governing study progression between arms. Arm 3 is considered the safety run-in for the combination therapy.

Phase 2a is a dose expansion portion of the study to further evaluate the combination of pocenbrodib and darolutamide in participants with mCRPC who have progressed following lutetium-Lu-177-vipivotide-tetraxetan (PLUVICTO) and prior to initiation of taxane-based therapy and will consist of 2 cohorts:

Cohort 1: pocenbrodib RP2D high + darolutamide

Cohort 2: pocenbrodib RP2D low + darolutamide

Safety will be monitored by the DRC

1b / 2a Inclusion Criteria:

1. ≥18 years of age
2. Histologic documentation of prostate adenocarcinoma
3. Metastatic disease, documented by imaging. Imaging performed within 56 days prior to Screening is acceptable

1b / 2a Exclusion Criteria:

1. Current or prior evidence of any small cell or neuroendocrine histology on the most recent prostate biopsy.
2. Any liver metastases confirmed by biopsy or evidence of lesions >1 cm consistent with liver metastases on imaging.
3. Intervention with any chemotherapy, investigational agent, or other anticancer drug, including enzalutamide, apalutamide, or darolutamide, 14 days prior to Cycle 1 Day 1 or 5 half-lives (whichever is shorter).
4. Any other serious underlying medical, psychiatric, psychological, familial, or geographical condition, which in the judgment of the Investigator may interfere with study participation and compliance or place the participant at high risk from treatment-related complications.

2a only -key inclusion criteria:

1. Must have received at least 2 cycles of PLUVICTO®
2. 1 line of prior any ARPI therapy
3. No prior chemotherapy for mCRPC

Males with prostate issues

Pathos AI, Inc. will determine once safety and preliminary efficacy is defined.