We are doing this study to find the most effective, safe dose of an experimental drug called pocenbrodib (the study drug). We want to see how it works when it is given by itself and also when it is given with other drugs already approved for the treatment in people with metastatic castration-resistant prostate cancer (mCRPC).

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Adults ages 18+ who:

• Are diagnosed with prostate adenocarcinoma
• Have metastases that are documented by imaging
• Had their disease progress after or during previous ARSI treatment (i.e., enzalutamide, apalutamide, abiraterone acetate, or darolutamide)
• Do not have metastases to the liver

For more information, contact the study team at julia.hurrelbrink@duke.edu.

The study is designed in 2 parts, Phase 1b and Phase 2a. The Phase 1b part starts first and the Phase 2a part will start when Phase 1b ends. You will take part in either Phase 1b or Phase 2a. If you choose to join this study, the part in which you participate will depend on when you join.

Phase 1b will test the safety of study drug when it is given by itself at up to 5 different dose levels. The dose levels to be tested are:

• 50 mg
• 100 mg
• 150 mg
• 200 mg
• 250 mg

Phase 2a will start after Phase 1b is declared to be complete. Phase 2a includes 4 groups called "cohorts." Cohort A is testing the study drug by itself at 2 safe, effective doses identified in Phase 1b. Cohorts B, C, and D are testing the study drug in combination with an approved therapy to see if the combinations are safe and should be tested further in future studies.

If you are assigned to a combination cohort group, you will get the study drug as well as one of the following treatments which are already approved by to treat your type of cancer as shown:

• Cohort B - pocenbrodib + abiraterone acetate (by mouth daily)
• Cohort C - pocenbrodib + olaparib (by mouth daily)
• Cohort D - pocenbrodib + 177Lu-PSMA-617 (PLUVICTO®; given by vein via a needle in your arm once every six weeks up to 6 treatments)

We will follow up with you about every 3 months for up to 2 years after you stop the study's drug regimen. The study is estimated to take about 3 years to complete.